[
    {
        "pmid": "10983851",
        "target": "[\"Span: 4 injections of 60 or 120 mg/kg | Label: Dosage\", \"Span: 4 injections of 180 or 240 mg/kg | Label: Dosage\", \"Span: 180 mg/kg | Label: Dosage\"]",
        "text": "[Title]: Evaluation of the effects of alpha-phenyl-N-tert-butyl nitrone pretreatment on the neurobehavioral effects of methamphetamine.\n[Abstract]: A relationship between formation of reactive oxygen species (ROS) and energy depletion has been proposed to play an important role in mediating methamphetamine (METH)-induced neurotoxicity. To evaluate this relationship, we examined the effect of the spin-trap agent, alpha-phenyl-N-tert-butyl nitrone (PBN) on hyperthermia and self-injurious behavior (SIB) and striatal dopamine (DA) depletion produced by METH (4 injections of 4 mg/kg, 2 hr intervals, s.c.) in BALB/c mice. Repeated administration of METH induced hyperthermia, incidence of SIB and striatal DA depletion (84% after 3 days). Pretreatment with PBN (4 injections of 60 or 120 mg/kg, i.p.) reduced METH-induced hyperthermia, but did not significantly attenuate METH-induced SIB or the striatal DA depletion. On the other hand, pretreatment with high doses of PBN (4 injections of 180 or 240 mg/kg, i.p.) protected against METH-induced hyperthermia and SIB, and PBN (180 mg/kg) also completely protected against the acute striatal DA depletion 60 min after the last injection of the drug. However, the long-lasting striatal DA depletion was only attenuated by 52 or 56%, respectively. These results indicate that METH-induced hyperthermia contributes to, but is not solely responsible for METH-induced neurotoxicity, and supports a role for formation of ROS and other mechanisms in the generation of METH-induced striatal dopaminergic neurotoxicity. In addition, the difference in the efficacy of PBN to protect against the acute or long-lasting striatal DA depletion induced by METH may indicate that both ROS formation and other mechanisms are required for METH-induced neurotoxicity to develop.\n[Drug-Disease]: PBN - hyperthermia"
    },
    {
        "pmid": "1098524",
        "target": "[\"Span: 2.5 mg | Label: Dosage\"]",
        "text": "[Title]: A Double-blind crossover trial of pseudoephedrine and triprolidine, alone and in combination, for the treatment of allergenic rhinitis.\n[Abstract]: In a double-blind crossover trial of pseudoephedrine 60 mg and triprolidine 2.5 mg, alone and in combination, on 40 volunteers suffering from allergic rhinitis, both drugs were found superior to placebo in reducing the effects of allergic rhinitis and were of equal efficacy. The combination tablet was consistently better than either drug in several of the assessments and was the treatment which the subjects, as a whole, preferred. Side effects were not a problem with any of the medications.\n[Drug-Disease]: triprolidine - allergenic rhinitis"
    },
    {
        "pmid": "1098524",
        "target": "[\"Span: 60 mg | Label: Dosage\"]",
        "text": "[Title]: A Double-blind crossover trial of pseudoephedrine and triprolidine, alone and in combination, for the treatment of allergenic rhinitis.\n[Abstract]: In a double-blind crossover trial of pseudoephedrine 60 mg and triprolidine 2.5 mg, alone and in combination, on 40 volunteers suffering from allergic rhinitis, both drugs were found superior to placebo in reducing the effects of allergic rhinitis and were of equal efficacy. The combination tablet was consistently better than either drug in several of the assessments and was the treatment which the subjects, as a whole, preferred. Side effects were not a problem with any of the medications.\n[Drug-Disease]: pseudoephedrine - allergenic rhinitis"
    },
    {
        "pmid": "10986547",
        "target": "[\"Span: 5 to 20 mg/d | Label: Dosage\"]",
        "text": "[Title]: Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.\n[Abstract]: BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.\n[Drug-Disease]: Olanzapine - acute bipolar mania"
    },
    {
        "pmid": "1098684",
        "target": "[]",
        "text": "[Title]: Procainamide and phenytoin. Comparative study of their antiarrhythmic effects at apparent therapeutic plasma levels.\n[Abstract]: The antiarrhythmic effects of procainamide and phenytoin were studied in 81 patients admitted to the coronary care unit at the University Hospital in Linkoping because of a suspected or proven diagnosis of acute myocardial infarction, and who developed ventricular arrhyhmias, requiring treatment, during the first 8 hours in hospital. Patients were randomly allocated to a procainamide of phenytoin group. The drugs were given as intravenous and oral loading doses followed by oral maintenance therapy. Plasma levels of the two druge were frequently determined and the electrocardiogram was continuously recorded during the 24-hour trial and analysed minute by minute. A significantly higher frequency of therapeutic failure was found in the phenytoin group (23 of 35 patients)compared to the procainamide group(13 of 39 aptients) during the first 2 hours after initiation of therapy. Four patients in the phenytoin group and 2 in the procainamide group developed symptoms probably caused by the trial drugs, necessitating discontinuation of therapy. The mean plasma levels were usually within the apparent therapeutic range (for phenytoin 40-72 mumol/l (10-18 mug/ml), and for procainamide 17-34 mumol/l (4-8 mug/ml). Seventeen patients (68%) in the phenytoin group and 10 patients (48%) in the procainamide group had plasma concentrations within this range when the therapeutic failure was observed. Nine patients died in hospital but only one of them during the trial. The results of this investigation clearly demonstrate the overall superiority of procainamide over phenytoin as an antiarrhythmic drug in short-term therapy after acute myocardial infarction.\n[Drug-Disease]: procainamide - acute myocardial infarction"
    },
    {
        "pmid": "10988282",
        "target": "[\"Span: 50 mg losartan once daily | Label: Dosage\"]",
        "text": "[Title]: Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.\n[Abstract]: NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.\n[Drug-Disease]: losartan - hypertensive"
    },
    {
        "pmid": "10992828",
        "target": "[\"Span: 1-9 yr | Label: Age\", \"Span: 0.5 microgram kg-1 i.v. | Label: Dosage\"]",
        "text": "[Title]: Comparison of intravenous and oral ketoprofen for postoperative pain after adenoidectomy in children.\n[Abstract]: One hundred children, aged 1-9 yr, undergoing adenoidectomy were randomized to receive ketoprofen 1 mg kg-1 either i.v. with an oral placebo (n = 40) or ketoprofen 1 mg kg-1 orally with an i.v. placebo (n = 40), or both oral and i.v. placebo (n = 20). The study design was prospective and double blind with parallel groups. The pain was assessed at rest and during swallowing using the Maunuksela pain scale (0 = no pain, 10 = worst possible pain) after surgery for 3 h. Fentanyl 0.5 microgram kg-1 i.v. was given for rescue analgesia. Children in the i.v. group needed significantly less doses (1, 1-3; median and 10th/90th percentiles) of rescue analgesic compared with the oral group (2, 1-3; P = 0.024). Of those who needed rescue analgesic, three out of 30 children in the i.v. group required three or more doses of fentanyl compared with 10 out of 28 children in the oral group. There were no differences between the groups with respect to pain scores, operation times, perioperative bleeding or frequency of adverse events.\n[Drug-Disease]: fentanyl - postoperative pain"
    },
    {
        "pmid": "10992828",
        "target": "[\"Span: 1-9 yr | Label: Age\", \"Span: 1 mg kg-1 either i.v. | Label: Dosage\", \"Span: 1 mg kg-1 orally | Label: Dosage\"]",
        "text": "[Title]: Comparison of intravenous and oral ketoprofen for postoperative pain after adenoidectomy in children.\n[Abstract]: One hundred children, aged 1-9 yr, undergoing adenoidectomy were randomized to receive ketoprofen 1 mg kg-1 either i.v. with an oral placebo (n = 40) or ketoprofen 1 mg kg-1 orally with an i.v. placebo (n = 40), or both oral and i.v. placebo (n = 20). The study design was prospective and double blind with parallel groups. The pain was assessed at rest and during swallowing using the Maunuksela pain scale (0 = no pain, 10 = worst possible pain) after surgery for 3 h. Fentanyl 0.5 microgram kg-1 i.v. was given for rescue analgesia. Children in the i.v. group needed significantly less doses (1, 1-3; median and 10th/90th percentiles) of rescue analgesic compared with the oral group (2, 1-3; P = 0.024). Of those who needed rescue analgesic, three out of 30 children in the i.v. group required three or more doses of fentanyl compared with 10 out of 28 children in the oral group. There were no differences between the groups with respect to pain scores, operation times, perioperative bleeding or frequency of adverse events.\n[Drug-Disease]: ketoprofen - postoperative pain"
    },
    {
        "pmid": "10995136",
        "target": "[\"Span: 66% nitrous oxide in oxygen | Label: Dosage\"]",
        "text": "[Title]: Continuous propofol administration for suxamethonium-induced postoperative myalgia.\n[Abstract]: The effect of continuous propofol administration on creatine kinase and suxamethonium-induced postoperative myalgia was evaluated in 50 patients randomised into two groups of 25 patients each. Induction of anaesthesia was identical in all patients. Anaesthesia was maintained with 66% nitrous oxide in oxygen supplemented by either isoflurane 1% or continuous propofol. Creatine kinase was measured before and after operation. Myalgia was evaluated postoperatively by a blinded observer. The median level of myalgia was reduced significantly in the continuous propofol group (p = 0.011). The median creatine kinase value increased significantly in the isoflurane group (from 90 to 160 IU, p = 0.001).\n[Drug-Disease]: propofol - postoperative myalgia"
    },
    {
        "pmid": "10997865",
        "target": "[\"Span: 7.5-10.0mg/day | Label: Dosage\"]",
        "text": "[Title]: Olanzapine optimal dose: results of an open-label multicenter study in schizophrenic patients. Olanzapine Late-Phase II Study Group.\n[Abstract]: This open-label clinical study was conducted for patients with schizophrenia in order to investigate the efficacy, safety and optimal dose of olanzapine. One hundred and fifty-six of the 159 enrolled patients were included in the analysis set. For the primary efficacy measure, the Final Global Improvement Rating (FGIR) score, 15.4% of patients had remarkable improvement, 58.3% of patients had moderate improvement or more, 79.5% of patients had slight improvement or more, and 10.3% of patients had increase in disease symptomatology (worsening). Results from the Brief Psychiatric Rating Scale (BPRS) in all individual items were improved from baseline. Olanzapine was effective not only against positive psychotic symptoms but also against negative symptoms. This was consistent with results from the Positive and Negative Syndrome Scale (PANSS). For the majority of patients, a dose range of 7.5-10.0mg/day, as a lower bound on the minimally effective dose, was suggested by the results of the dose to first response based on improvement in Global Improvement Rating (GIR) analyses. The ratio of olanzapine dose to equivalent haloperidol dose was estimated at 1.2 :1. The most commonly reported treatment-emergent signs and symptoms (TESS) occurring at a frequency of 10% or more were insomnia, weight increase, excitement, sleepiness, anxiety, malaise and dull headaches. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms; the most commonly reported were akathisia (6.4%), tremor (5.8%) and muscle rigidity (2.6%).\n[Drug-Disease]: olanzapine - schizophrenia"
    },
    {
        "pmid": "11002857",
        "target": "[]",
        "text": "[Title]: [Effects of calcium antagonists on atherosclerosis progression and intima media thickness].\n[Abstract]: Calcium antagonists are currently considered first-choice agents for treating hypertension. They are also active antianginal drugs. Their protective effects against ischaemia and their antiatherogenic potential, which have been demonstrated in various experimental models, may contribute to their preventive effect against the early atherosclerotic processes. However, their effects on survival and cardiovascular events have been inconsistent and controversial. Recent studies have suggested that mortality may be increased by short-acting agents. The effects of certain long-acting calcium antagonists may be different. In early clinical trials, nifedipine and nicardipine did not alter the progression of significant coronary artery narrowing, but did reduce the development of new atherosclerotic lesions. Nevertheless, the number of cardiovascular events was not decreased. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) showed a higher incidence of angina and more frequent cardiovascular events in patients treated with isradipine. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), after 3 years' follow-up, progression of significant atherosclerotic lesions and the development of new lesions were not significantly altered by treatment with amlodipine. However, it would appear that quantitative angiography may not be appropriate for monitoring the progression of atherosclerosis. Because of arterial remodelling, angiographic images may not show changes in the arterial lumen, in arteries where intravascular ultrasound may detect important atherosclerotic plaques. High resolution B-mode ultrasonography of the carotid artery may be more informative, since carotid intima media thickness is strongly correlated with cardiovascular risk factors, the prevalence of cardiovascular disease, and the presence of atherosclerotic lesions at other arterial sites. In the PREVENT trial, carotid ultrasonography showed that intima media thickness was stabilised in the amlodipine group, while progression was uninterrupted in the placebo group. The mechanism of amlodipine in slowing the progression of intima media thickness may be related to its antiatherogenic effect, as well as to its effect on cellular growth and hyperplasia of the arterial wall. It is interesting to note that, as a secondary objective of the PREVENT trial, patients treated with amlodipine had fewer ischaemic events than those treated with placebo. The beneficial effects of amlodipine on arterial thickening and on the prevention of ischaemic events suggest that amlodipine may be recommended for the management of all patients with stable angina. A larger trial with a longer follow-up period should be performed in order to confirm the promising results of PREVENT.\n[Drug-Disease]: nicardipine - atherosclerotic lesions"
    },
    {
        "pmid": "11002857",
        "target": "[]",
        "text": "[Title]: [Effects of calcium antagonists on atherosclerosis progression and intima media thickness].\n[Abstract]: Calcium antagonists are currently considered first-choice agents for treating hypertension. They are also active antianginal drugs. Their protective effects against ischaemia and their antiatherogenic potential, which have been demonstrated in various experimental models, may contribute to their preventive effect against the early atherosclerotic processes. However, their effects on survival and cardiovascular events have been inconsistent and controversial. Recent studies have suggested that mortality may be increased by short-acting agents. The effects of certain long-acting calcium antagonists may be different. In early clinical trials, nifedipine and nicardipine did not alter the progression of significant coronary artery narrowing, but did reduce the development of new atherosclerotic lesions. Nevertheless, the number of cardiovascular events was not decreased. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) showed a higher incidence of angina and more frequent cardiovascular events in patients treated with isradipine. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), after 3 years' follow-up, progression of significant atherosclerotic lesions and the development of new lesions were not significantly altered by treatment with amlodipine. However, it would appear that quantitative angiography may not be appropriate for monitoring the progression of atherosclerosis. Because of arterial remodelling, angiographic images may not show changes in the arterial lumen, in arteries where intravascular ultrasound may detect important atherosclerotic plaques. High resolution B-mode ultrasonography of the carotid artery may be more informative, since carotid intima media thickness is strongly correlated with cardiovascular risk factors, the prevalence of cardiovascular disease, and the presence of atherosclerotic lesions at other arterial sites. In the PREVENT trial, carotid ultrasonography showed that intima media thickness was stabilised in the amlodipine group, while progression was uninterrupted in the placebo group. The mechanism of amlodipine in slowing the progression of intima media thickness may be related to its antiatherogenic effect, as well as to its effect on cellular growth and hyperplasia of the arterial wall. It is interesting to note that, as a secondary objective of the PREVENT trial, patients treated with amlodipine had fewer ischaemic events than those treated with placebo. The beneficial effects of amlodipine on arterial thickening and on the prevention of ischaemic events suggest that amlodipine may be recommended for the management of all patients with stable angina. A larger trial with a longer follow-up period should be performed in order to confirm the promising results of PREVENT.\n[Drug-Disease]: nifedipine - atherosclerotic lesions"
    },
    {
        "pmid": "11002857",
        "target": "[]",
        "text": "[Title]: [Effects of calcium antagonists on atherosclerosis progression and intima media thickness].\n[Abstract]: Calcium antagonists are currently considered first-choice agents for treating hypertension. They are also active antianginal drugs. Their protective effects against ischaemia and their antiatherogenic potential, which have been demonstrated in various experimental models, may contribute to their preventive effect against the early atherosclerotic processes. However, their effects on survival and cardiovascular events have been inconsistent and controversial. Recent studies have suggested that mortality may be increased by short-acting agents. The effects of certain long-acting calcium antagonists may be different. In early clinical trials, nifedipine and nicardipine did not alter the progression of significant coronary artery narrowing, but did reduce the development of new atherosclerotic lesions. Nevertheless, the number of cardiovascular events was not decreased. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) showed a higher incidence of angina and more frequent cardiovascular events in patients treated with isradipine. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), after 3 years' follow-up, progression of significant atherosclerotic lesions and the development of new lesions were not significantly altered by treatment with amlodipine. However, it would appear that quantitative angiography may not be appropriate for monitoring the progression of atherosclerosis. Because of arterial remodelling, angiographic images may not show changes in the arterial lumen, in arteries where intravascular ultrasound may detect important atherosclerotic plaques. High resolution B-mode ultrasonography of the carotid artery may be more informative, since carotid intima media thickness is strongly correlated with cardiovascular risk factors, the prevalence of cardiovascular disease, and the presence of atherosclerotic lesions at other arterial sites. In the PREVENT trial, carotid ultrasonography showed that intima media thickness was stabilised in the amlodipine group, while progression was uninterrupted in the placebo group. The mechanism of amlodipine in slowing the progression of intima media thickness may be related to its antiatherogenic effect, as well as to its effect on cellular growth and hyperplasia of the arterial wall. It is interesting to note that, as a secondary objective of the PREVENT trial, patients treated with amlodipine had fewer ischaemic events than those treated with placebo. The beneficial effects of amlodipine on arterial thickening and on the prevention of ischaemic events suggest that amlodipine may be recommended for the management of all patients with stable angina. A larger trial with a longer follow-up period should be performed in order to confirm the promising results of PREVENT.\n[Drug-Disease]: amlodipine - ischaemia"
    },
    {
        "pmid": "11004045",
        "target": "[\"Span: 5 mg IV | Label: Dosage\"]",
        "text": "[Title]: A comparative study between a calcium channel blocker (Nicardipine) and a combined alpha-beta-blocker (Labetalol) for the control of emergence hypertension during craniotomy for tumor surgery.\n[Abstract]: We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.\n[Drug-Disease]: labetalol - breakthrough hypertension"
    },
    {
        "pmid": "11004045",
        "target": "[\"Span: 2 mg IV | Label: Dosage\"]",
        "text": "[Title]: A comparative study between a calcium channel blocker (Nicardipine) and a combined alpha-beta-blocker (Labetalol) for the control of emergence hypertension during craniotomy for tumor surgery.\n[Abstract]: We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.\n[Drug-Disease]: nicardipine - breakthrough hypertension"
    },
    {
        "pmid": "11004045",
        "target": "[\"Span: 1.25 mg IV | Label: Dosage\"]",
        "text": "[Title]: A comparative study between a calcium channel blocker (Nicardipine) and a combined alpha-beta-blocker (Labetalol) for the control of emergence hypertension during craniotomy for tumor surgery.\n[Abstract]: We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.\n[Drug-Disease]: enalaprilat - breakthrough hypertension"
    },
    {
        "pmid": "11004058",
        "target": "[\"Span: bolus 2 mg/kg, then infusion 3 mg. kg. h | Label: Dosage\"]",
        "text": "[Title]: The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers.\n[Abstract]: UNLABELLED: Although effective in neuropathic pain, the efficacy of systemic lidocaine in non-neuropathic pain remains uncertain. We investigated the analgesic effect of systemic lidocaine on the heat/capsaicin sensitization model of experimental pain in 24 volunteers. Sensitization was produced by heating the skin to 45 degrees C for 5 min, followed by a 30-min application of 0.075% capsaicin cream, and maintained by periodically reheating the sensitized skin. Subjects received IV lidocaine (bolus 2 mg/kg, then infusion 3 mg. kg. h), or saline for 85 min. Areas of secondary hyperalgesia, heat pain detection thresholds, and painfulness of stimulation with 45 degrees C for 1 min (long thermal stimulation) were quantified. Systemic lidocaine reduced the area of secondary hyperalgesia to brush, but not to von Frey hair stimulation. Lidocaine did not alter heat pain detection thresholds or painfulness of long thermal stimulation in normal skin. We conclude that, at infusion rates in the low- to mid-antiarrhythmic range, lidocaine has no effect on acute nociceptive pain but does have a limited and selective effect on secondary hyperalgesia. IMPLICATIONS: The efficacy of systemic lidocaine in nonneuropathic pain remains uncertain. This study investigates the effect of systemic lidocaine on experimental-induced hyperalgesia in 25 volunteers. Hyperalgesia was induced by using an experimental pain model that uses heat and capsaicin in combination. Systemic lidocaine showed a selective effect on secondary hyperalgesia.\n[Drug-Disease]: lidocaine - hyperalgesia"
    },
    {
        "pmid": "11005120",
        "target": "[\"Span: gestational age greater than 22 weeks | Label: Age\", \"Span: gravidae | Label: Gender\", \"Span: 250-500 mg methyldopa, three to four times a day for a minimum of 5-7 days | Label: Dosage\"]",
        "text": "[Title]: The effect of methyldopa on retinal artery circulation in pre-eclamptic gravidae.\n[Abstract]: OBJECTIVE: To evaluate the effect of methyldopa on retinal artery circulation in pre-eclamptic gravidae using color Doppler imaging and spectral analysis. METHODS: Fifty-three pre-eclamptic singleton gravidae of gestational age greater than 22 weeks were examined. Patients with sustained hypertension after 1-2 days hospital rest were treated with oral antihypertensive medication, 250-500 mg methyldopa, three to four times a day for a minimum of 5-7 days. The right central retinal arteries were insonated and Doppler waveform values were analysed before and after medication. RESULTS: The change of the maternal heart rate after methyldopa treatment was -3.96 +/- 7.88 beats per min (P = 0.0006). The change of fetal heart rate was not significantly altered. The change of the diastolic arterial blood pressure after treatment was -4.19 +/- 12.36 mmHg (P = 0.0169). In 36 gravidae, in whom hypotensive effects were noted after treatment with methyldopa, the increase in peak velocity, end-diastolic velocity and mean velocity of the retinal artery were 2.41 +/- 2.20 (P < 0.0001); 1.48 +/- 1.23 (P < 0.0001) and 1.70 +/- 1.42 (P < 0.0001), respectively. The decrease in pulsatility index of the retinal artery after treatment with methyldopa was -0.17 +/- 0.22 (P < 0.0001). In the remaining 17 gravidae, in whom no hypotensive effects were noted after treatment with methyldopa, the decrease in end-diastolic velocity and mean velocity were -1.50 +/- 1.70 (P = 0.0022) and -0.98 +/- 1.90 (P = 0.0488), respectively. The increase in pulsatility index was 0.34 +/- 0.30 (P = 0.0003). CONCLUSIONS: In pre-eclamptic gravidae in whom the hypotensive effects were noted after treatment with methyldopa, the mean velocity of the retinal arteries was significantly higher and the mean pulsatility index lower after treatment. We conclude that the hypotensive effect of methyldopa in pre-eclamptic gravidae is associated with a significant decrease in retinal artery vascular resistance.\n[Drug-Disease]: methyldopa - hypertension"
    },
    {
        "pmid": "11007035",
        "target": "[]",
        "text": "[Title]: Pathologic, cytogenetic and molecular assessment of acute promyelocytic leukemia patients treated with arsenic trioxide (As2O3).\n[Abstract]: Arsenic trioxide (As2O3) shows great promise as an effective therapy for patients with all-trans retinoic acid (ATRA)-resistant acute promyelocytic leukemia (APL). Little data is available addressing the pathology of As2O3 treated APL and whether the antileukemic mechanism of As2O3 is primarily cytolysis or through stimulation of cell differentiation. In this report, we made a morphologic, cytogenetic, and molecular evaluation of five ATRA-refractory APL patients who were treated with As2O3. Four of the five patients had morphologic responses after one or two cycles of As2O3 treatment. Of the four responders based on bone marrow morphology, two achieved molecular remission (negative RT-PCR for PML- RAR alpha fusion transcripts) by the end of the second and third cycles of As2O3 therapy. Two patients exhibited marked leukocytosis during the first cycle of As2O3, and at that time point the APL cells were largely replaced by the cells showing partial differentiation towards myelocytes with co-expression of CD11b and CD33. Nevertheless, these \"myelocyte-like\" cells that showed the t(15;17) translocation eventually disappeared with continuous As2O3 therapy. As2O3 treatment appears to be effective therapy for the patients with relapsed APL after the failure of conventional chemotherapy and ATRA therapy. The pathologic findings in these five cases suggest that at low doses As2O3 primarily induces differentiation of the APL cells, generating abnormal myelocytes resembling APL cells treated with ATRA, whereas at higher doses AS2O3 induces marrow necrosis.\n[Drug-Disease]: AS2O3 - acute promyelocytic leukemia"
    },
    {
        "pmid": "11007831",
        "target": "[\"Span: 10 mg/day | Label: Dosage\", \"Span: NIDDM patients | Label: Comorbidity\", \"Span: DD | Label: Gene\", \"Span: ID | Label: Gene\", \"Span: II | Label: Gene\"]",
        "text": "[Title]: ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus.\n[Abstract]: BACKGROUND: ACE polymorphism, especially genotype DD or D allele, may be involved in the progression of diabetic nephropathy. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. We investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (Benazepril 10 mg/day or Perindopril 4 mg/day) in 83 NIDDM patients with overt proteinuria (urinary protein excretion over 500 mg/day). METHODS: We recruited NIDDM patients with overt proteinuria from our renal clinic. Before entry, previously used ACE inhibitors were withdrawn for at least 2 weeks and baseline proteinuria and albuminuria were measured. Patients were classified into three groups in accordance with ACE genotypes (17 DD; 33 ID; 33 II) and prospectively followed up for 3 months. Various clinical parameters including age, DM duration, body mass index (BMI), 24-h urine sodium, protein and albumin, BUN, serum creatinine, creatinine clearance (Ccr), mean arterial pressure (MAP), and HbA(1c) were measured in the pre- and post-treatment periods. ACE genotypes were determined by polymerase chain reaction. RESULTS: There were no significant differences in the clinical parameters such as age, DM duration, BMI, BUN, serum creatinine, Ccr, MAP, HbA(1c), and daily urinary excretion of sodium, protein and albumin among three groups (P>0.05). After the 3-month treatment period using ACE inhibitors, there were no significant differences in the reduction of MAP and Ccr among the three groups (P>0.05). However, the percentage reductions in urinary excretion of protein and albumin for DD genotype were significantly higher than in ID and II genotypes (50.9+/-19.2% vs 19.2+/-16.0%, 20.2+/-20.4%; 52.6+/-23.6% vs. 13.5+/-51.8%, 24.8+/-23.9%, P<0.05). There were no statistically significant correlations between the levels of baseline proteinuria and albuminuria and the magnitudes of the reduction of proteinuria and albuminuria under ACE inhibition (P>0.05). CONCLUSIONS: Our results suggest that the ACE gene polymorphism might have a role in determining the responsiveness to the antiproteinuric effect of ACE inhibition in proteinuric NIDDM patients.\n[Drug-Disease]: Benazepril - proteinuria"
    },
    {
        "pmid": "11007831",
        "target": "[\"Span: 4 mg/day | Label: Dosage\", \"Span: NIDDM patients | Label: Comorbidity\", \"Span: DD | Label: Gene\", \"Span: ID | Label: Gene\", \"Span: II | Label: Gene\"]",
        "text": "[Title]: ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus.\n[Abstract]: BACKGROUND: ACE polymorphism, especially genotype DD or D allele, may be involved in the progression of diabetic nephropathy. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. We investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (Benazepril 10 mg/day or Perindopril 4 mg/day) in 83 NIDDM patients with overt proteinuria (urinary protein excretion over 500 mg/day). METHODS: We recruited NIDDM patients with overt proteinuria from our renal clinic. Before entry, previously used ACE inhibitors were withdrawn for at least 2 weeks and baseline proteinuria and albuminuria were measured. Patients were classified into three groups in accordance with ACE genotypes (17 DD; 33 ID; 33 II) and prospectively followed up for 3 months. Various clinical parameters including age, DM duration, body mass index (BMI), 24-h urine sodium, protein and albumin, BUN, serum creatinine, creatinine clearance (Ccr), mean arterial pressure (MAP), and HbA(1c) were measured in the pre- and post-treatment periods. ACE genotypes were determined by polymerase chain reaction. RESULTS: There were no significant differences in the clinical parameters such as age, DM duration, BMI, BUN, serum creatinine, Ccr, MAP, HbA(1c), and daily urinary excretion of sodium, protein and albumin among three groups (P>0.05). After the 3-month treatment period using ACE inhibitors, there were no significant differences in the reduction of MAP and Ccr among the three groups (P>0.05). However, the percentage reductions in urinary excretion of protein and albumin for DD genotype were significantly higher than in ID and II genotypes (50.9+/-19.2% vs 19.2+/-16.0%, 20.2+/-20.4%; 52.6+/-23.6% vs. 13.5+/-51.8%, 24.8+/-23.9%, P<0.05). There were no statistically significant correlations between the levels of baseline proteinuria and albuminuria and the magnitudes of the reduction of proteinuria and albuminuria under ACE inhibition (P>0.05). CONCLUSIONS: Our results suggest that the ACE gene polymorphism might have a role in determining the responsiveness to the antiproteinuric effect of ACE inhibition in proteinuric NIDDM patients.\n[Drug-Disease]: Perindopril - proteinuria"
    },
    {
        "pmid": "11009193",
        "target": "[]",
        "text": "[Title]: Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease.\n[Abstract]: L-Dopa-induced dyskinesias constitute a challenge to the management of advanced Parkinson's disease. According to recent reports, treatment with the NMDA receptor antagonist amantadine may significantly diminish L-dopa-induced dyskinesias. In the present study, the effect of amantadine on L-dopa-induced dykinesias was assessed in a 5-week, double-blind crossover trial. Dyskinesia severity as assessed following oral L-dopa challenges and by self-scoring dyskinesia diaries were reduced approximately 50% after amantadine treatment compared with baseline or placebo phases. Similarly, dyskinesia assessments on the Unified Parkinson's Disease Rating Scale, part IV (items 32 and 33) also revealed significant improvement after treatment with amantadine. The magnitude of the L-dopa motor response to oral challenges was not different after amantadine or placebo treatment, and there was no significant reduction of daily off-time when patients received active treatment. These results confirm previous observations concerning the antidyskinetic potential of amantadine.\n[Drug-Disease]: amantadine - dyskinesia"
    },
    {
        "pmid": "1101099",
        "target": "[]",
        "text": "[Title]: Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone in Parkinson's disease.\n[Abstract]: A double-blind study comparing the effects of carbidopa and levodopa combined in a single tablet with levodopa alone was undertaken in 50 patients with Parkinson's disease. After 6 months, there was a statistically significant improvement over baseline in total score, rigidity, and tremor only in the patients randomized to carbidopa/levodopa. In addition, 40 percent of the patients treated with carbidopa/levodopa showed obvious clinical improvement (a greater than 50 percent reduction in their total score) over treatment with levodopa alone. However, after 2 years, only 20 percent continued to show this improvement. Nausea, vomiting, and anorexia developed in 56 percent of patients on levodopa but in only 27 percent of patients on carbidopa/levodopa. However, abnormal involuntary movements, observed in 48 percent of patients on levodopa, were present in 77 percent of patients on carbidopa/levodopa. Despite the increase in abnormal involuntary movements, carbidopa/levodopa is more effective than levodopa.\n[Drug-Disease]: carbidopa/levodopa - Parkinson's disease"
    },
    {
        "pmid": "11011337",
        "target": "[\"Span: 50 to 100 mg daily | Label: Dosage\"]",
        "text": "[Title]: Long-term central hemodynamic effects at rest and during exercise of losartan in essential hypertension.\n[Abstract]: BACKGROUND: Losartan reduces blood pressure in patients with essential hypertension, but the long-term central hemodynamic effects at rest and during exercise are not known. METHODS AND RESULTS: After 8 months of losartan treatment (50 to 100 mg daily, mean 82 mg), intra-arterial pressure was reduced from 165/102 mm Hg to 145/91 mm Hg at rest and from 193/104 mm Hg to 179/96 mm Hg during 100 W exercise in 28 patients with essential hypertension. Cardiac index and heart rate remained unchanged, but total peripheral resistance index was reduced 12% to 15%. Stroke index was unchanged at rest but increased 7% to 9% during exercise. Twenty-four-hour ambulatory blood pressure was reduced 10% to 13%. Left ventricular mass was reduced 27% in patients with left ventricular hypertrophy (n = 18). CONCLUSION: Losartan lowers blood pressure by reducing total peripheral resistance at rest and during exercise but cardiac pump function is unchanged or slightly improved. In patients with left ventricular hypertrophy, losartan induces a sizeable reduction in left ventricular mass.\n[Drug-Disease]: losartan - hypertension"
    },
    {
        "pmid": "11011337",
        "target": "[\"Span: 50 to 100 mg daily | Label: Dosage\"]",
        "text": "[Title]: Long-term central hemodynamic effects at rest and during exercise of losartan in essential hypertension.\n[Abstract]: BACKGROUND: Losartan reduces blood pressure in patients with essential hypertension, but the long-term central hemodynamic effects at rest and during exercise are not known. METHODS AND RESULTS: After 8 months of losartan treatment (50 to 100 mg daily, mean 82 mg), intra-arterial pressure was reduced from 165/102 mm Hg to 145/91 mm Hg at rest and from 193/104 mm Hg to 179/96 mm Hg during 100 W exercise in 28 patients with essential hypertension. Cardiac index and heart rate remained unchanged, but total peripheral resistance index was reduced 12% to 15%. Stroke index was unchanged at rest but increased 7% to 9% during exercise. Twenty-four-hour ambulatory blood pressure was reduced 10% to 13%. Left ventricular mass was reduced 27% in patients with left ventricular hypertrophy (n = 18). CONCLUSION: Losartan lowers blood pressure by reducing total peripheral resistance at rest and during exercise but cardiac pump function is unchanged or slightly improved. In patients with left ventricular hypertrophy, losartan induces a sizeable reduction in left ventricular mass.\n[Drug-Disease]: losartan - left ventricular hypertrophy"
    },
    {
        "pmid": "1101464",
        "target": "[\"Span: every 8 hours for 6 days | Label: Dosage\"]",
        "text": "[Title]: Comparison of a 9-phenanthrene methanol (WR33063), a 4-quinoline methanol (WR30090), and quinine for falciparum malaria in Thailand.\n[Abstract]: Quinine was compared with a 9-phenanthrene methanol (WR33063) and a 4-quinoline methanol (WR30090) for the treatment of 207 patients with falciparum malaria in Southeast Thailand. Quinine eradicated parasitaemia (average 70 hours) more rapidly than either WR30090 (72 hours) or WR33063 (77 hours). But WR33063 had a higher cure rate (92%) than WR30090 (86%) or quinine (85%). The mean duration of fever and of parasitaemia were combined with the failure rate to form an arbitrary efficacy index. Using this concept WR33063 was the most effective drug. The recrudescence rate correlated with the degree and duration of parasitaemia and with the duration of fever. WR33063 was the least toxic drug. Side effects associated with WR30090 appeared to be headache, backache and urticaria. Quinine was the most toxic drug. All 3 drugs were inconvenient in having to be administered every 8 hours for 6 days. One patient did not respond to oral quinine but did respond to an intravenous quinine infusion (IVQ). A \"Medication Ward Round\" was perfected during the study and comprised sequential history, drug administration, physical examination, dose notation and patient observation. Falciparum nephrosis was diagnosed in one patient.\n[Drug-Disease]: quinine - falciparum malaria"
    },
    {
        "pmid": "11017840",
        "target": "[]",
        "text": "[Title]: Thiabendazole for the treatment of strongyloidiasis in patients with hematologic malignancies.\n[Abstract]: A total of 21 patients with hematologic malignancies were given thiabendazole for treatment of strongyloidiasis. Fifteen patients were cured. Since there were no relapses, it is unlikely that maintenance therapy has a role in the management of strongyloidiasis in this population of patients.\n[Drug-Disease]: thiabendazole - strongyloidiasis"
    },
    {
        "pmid": "11019834",
        "target": "[]",
        "text": "[Title]: Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies.\n[Abstract]: We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000-1500 microM x min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen.\n[Drug-Disease]: BU - hematologic malignancies"
    },
    {
        "pmid": "11019834",
        "target": "[]",
        "text": "[Title]: Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies.\n[Abstract]: We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000-1500 microM x min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen.\n[Drug-Disease]: cyclophosphamide - hematologic malignancies"
    },
    {
        "pmid": "11019834",
        "target": "[]",
        "text": "[Title]: Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies.\n[Abstract]: We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000-1500 microM x min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen.\n[Drug-Disease]: thiotepa - hematologic malignancies"
    },
    {
        "pmid": "11023927",
        "target": "[]",
        "text": "[Title]: Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT).\n[Abstract]: BACKGROUND: This long-term, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial, angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients. METHODS AND RESULTS: There were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L; HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, -0.07 versus -0.14 mm (P:=0.004); minimum diameters, -0.09 versus -0.16 mm (P:=0. 0001); and percent diameter stenosis, 1.67% versus 3.83% (P:=0.0003). These benefits were not observed in patients on enalapril when compared with placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for percutaneous transluminal coronary angioplasty (8 versus 21 events; P:=0.020), and fewer enalapril patients experienced the combined end point of death/myocardial infarction/stroke (16 versus 30; P:=0.043) than their respective placebo patients. CONCLUSIONS: This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere.\n[Drug-Disease]: enalapril - coronary atherosclerosis"
    },
    {
        "pmid": "11023927",
        "target": "[]",
        "text": "[Title]: Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT).\n[Abstract]: BACKGROUND: This long-term, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial, angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients. METHODS AND RESULTS: There were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L; HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, -0.07 versus -0.14 mm (P:=0.004); minimum diameters, -0.09 versus -0.16 mm (P:=0. 0001); and percent diameter stenosis, 1.67% versus 3.83% (P:=0.0003). These benefits were not observed in patients on enalapril when compared with placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for percutaneous transluminal coronary angioplasty (8 versus 21 events; P:=0.020), and fewer enalapril patients experienced the combined end point of death/myocardial infarction/stroke (16 versus 30; P:=0.043) than their respective placebo patients. CONCLUSIONS: This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere.\n[Drug-Disease]: Simvastatin - coronary atherosclerosis"
    },
    {
        "pmid": "11027905",
        "target": "[\"Span: 1 mg | Label: Dosage\"]",
        "text": "[Title]: Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.\n[Abstract]: Pain not responsive to morphine is often problematic. Animal and clinical studies have suggested that N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, may be effective in improving opioid analgesia in difficult pain syndromes, such as neuropathic pain. A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) was given to 10 cancer patients whose pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. Pain intensity on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes (T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all the patients at both doses. This effect was more relevant in patients treated with higher doses. Hallucinations occurred in 4 patients, and an unpleasant sensation (\"empty head\") was also reported by 2 patients. These episodes reversed after the administration of diazepam 1 mg intravenously. Significant increases in drowsiness were reported in patients treated with ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. However, the occurrence of central adverse effects should be taken into account, especially when using higher doses. This observation should be tested in studies of prolonged ketamine administration.\n[Drug-Disease]: diazepam - Hallucinations"
    },
    {
        "pmid": "11027905",
        "target": "[\"Span: A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) | Label: Dosage\"]",
        "text": "[Title]: Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.\n[Abstract]: Pain not responsive to morphine is often problematic. Animal and clinical studies have suggested that N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, may be effective in improving opioid analgesia in difficult pain syndromes, such as neuropathic pain. A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) was given to 10 cancer patients whose pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. Pain intensity on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes (T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all the patients at both doses. This effect was more relevant in patients treated with higher doses. Hallucinations occurred in 4 patients, and an unpleasant sensation (\"empty head\") was also reported by 2 patients. These episodes reversed after the administration of diazepam 1 mg intravenously. Significant increases in drowsiness were reported in patients treated with ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. However, the occurrence of central adverse effects should be taken into account, especially when using higher doses. This observation should be tested in studies of prolonged ketamine administration.\n[Drug-Disease]: ketamine - pain"
    },
    {
        "pmid": "11027906",
        "target": "[\"Span: 20 microg | Label: Dosage\"]",
        "text": "[Title]: An assessment of the safety, efficacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: a pilot study.\n[Abstract]: The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 microg of fentanyl citrate and were asked to rate their pain using a visual analogue scale (VAS) before INFC, then after 3, 5, 10, 15, 30, 45, and 60 minutes. Eight patients (66%) had reductions in pain scores, four within 5 minutes and seven within 10 minutes of taking INFC. Ratings for INFC were very good (5 = 42%), good (3 = 25%), moderate (1 = 8%), and bad (3 = 25%). In comparison to oral morphine, INFC was better (6 = 50%), the same (3 = 25%), or worse (3 = 25%). Nine patients (75%) said they would continue to use INFC. Of the three patients who did not experience a positive result, two were taking relatively higher baseline opioid doses and one was found to have a fracture. No systemic adverse events were noted; two patients reported nasal itching or discomfort on first use that disappeared with repeated use. Intranasal fentanyl citrate appears safe and well tolerated by these patients. Randomized placebo-controlled and dose-ranging studies are required to confirm these findings.\n[Drug-Disease]: fentanyl citrate - pain"
    },
    {
        "pmid": "11027910",
        "target": "[\"Span: 1,200 mg/day to a maximum of 2,400 mg/day | Label: Dosage\"]",
        "text": "[Title]: Gabapentin vs. amitriptyline in painful diabetic neuropa+B42thy: an open-label pilot study.\n[Abstract]: The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.\n[Drug-Disease]: gabapentin - pain"
    },
    {
        "pmid": "11030483",
        "target": "[]",
        "text": "[Title]: A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder.\n[Abstract]: BACKGROUND: Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I. METHOD: A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication. RESULTS: Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine. CONCLUSION: These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.\n[Drug-Disease]: olanzapine - bipolar disorder"
    },
    {
        "pmid": "11030483",
        "target": "[]",
        "text": "[Title]: A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder.\n[Abstract]: BACKGROUND: Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I. METHOD: A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication. RESULTS: Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine. CONCLUSION: These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.\n[Drug-Disease]: clozapine - bipolar disorder"
    },
    {
        "pmid": "11030483",
        "target": "[]",
        "text": "[Title]: A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder.\n[Abstract]: BACKGROUND: Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I. METHOD: A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication. RESULTS: Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine. CONCLUSION: These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.\n[Drug-Disease]: risperidone - bipolar disorder"
    },
    {
        "pmid": "1103205",
        "target": "[]",
        "text": "[Title]: A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics.\n[Abstract]: In a double-blind, cross-over study, the comparative therapeutic effects of 6-week courses of two prototypic neuroleptics--haloperidol and chlorpromazine--and the reversal of those effects with benztropine were investigated in a group of 18 schizophrenics. Periodic measurements were made for 32 dimensions of psychopathology, social participation, span of attention, sleeplessness, pulse rate and neurological side effects. The results showed that haloperidol was generally a more effective drug over the period studied. This was particularly apparent in terms of social and emotional responsiveness, communicativeness and cognitive processes. The only superiority of chlorpromazine seemed to be that patients felt less dysphoric on it than they did on haloperidol. Haloperidol also proved to be more rapid in its action. The data failed to support the clinical validity of the distinction often made between \"sedative\" and \"activating\" neuroleptics. Consistent with previous reports, benztropine had the effect of diminishing therapeutic response to both neuroleptics. However, haloperidol again proved less susceptible to this effect. The slowness and lesser therapeutic efficiency of chlorpromazine and its greater susceptibility to benztropine reversal were all considered to be due to its built-in anti-cholinergic properties acting in opposition to its antipsychotic activity. The low potency of chlorpromazine-like drugs was attributed to their inherent anticholinergic characteristics. It was suggested that one of the factors determining potency difference among neuroleptics may be the degree of built-in anticholinergic activity.\n[Drug-Disease]: chlorpromazine - schizophrenia"
    },
    {
        "pmid": "1103205",
        "target": "[]",
        "text": "[Title]: A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics.\n[Abstract]: In a double-blind, cross-over study, the comparative therapeutic effects of 6-week courses of two prototypic neuroleptics--haloperidol and chlorpromazine--and the reversal of those effects with benztropine were investigated in a group of 18 schizophrenics. Periodic measurements were made for 32 dimensions of psychopathology, social participation, span of attention, sleeplessness, pulse rate and neurological side effects. The results showed that haloperidol was generally a more effective drug over the period studied. This was particularly apparent in terms of social and emotional responsiveness, communicativeness and cognitive processes. The only superiority of chlorpromazine seemed to be that patients felt less dysphoric on it than they did on haloperidol. Haloperidol also proved to be more rapid in its action. The data failed to support the clinical validity of the distinction often made between \"sedative\" and \"activating\" neuroleptics. Consistent with previous reports, benztropine had the effect of diminishing therapeutic response to both neuroleptics. However, haloperidol again proved less susceptible to this effect. The slowness and lesser therapeutic efficiency of chlorpromazine and its greater susceptibility to benztropine reversal were all considered to be due to its built-in anti-cholinergic properties acting in opposition to its antipsychotic activity. The low potency of chlorpromazine-like drugs was attributed to their inherent anticholinergic characteristics. It was suggested that one of the factors determining potency difference among neuroleptics may be the degree of built-in anticholinergic activity.\n[Drug-Disease]: haloperidol - schizophrenia"
    },
    {
        "pmid": "11035390",
        "target": "[\"Span: 2 and 4 mg doses | Label: Dosage\", \"Span: 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes | Label: Comorbidity\"]",
        "text": "[Title]: Apomorphine: an update of clinical trial results.\n[Abstract]: Apomorphine SL (TAP Holdings, Deerfield, IL) is a centrally acting treatment for erectile dysfunction (ED) that has been undergoing phase III trials. Over 3000 men have received apomorphine SL and over 75,000 doses have been taken. In the first three phase III parallel arm cross-over double-blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 y old and outcome measures included per attempt rates of intercourse and erections firm enough for intercourse as well as psychometric instruments and partner responses. The majority (74.1%) had moderate and severe grades of ED on admission to the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes. Erections occurred rapidly (10-25 min) and in 54.4% of attempts at 4 mg (vs 33.8% placebo). A majority of the attempts at intercourse (50.6%) were successful at 4 mg in patients when recorded on a per-attempt basis. The most common but infrequent and mild side effect of nausea decreases with use. The phase III trials of apomorphine SL show that there is a clinically important restoration of erectile function from this new formulation of apomorphine. It has a rapid and safe effect through action in the central nervous system. Apomorphine SL brings a new choice to the management of ED that will further benefit the millions of couples affected. International Journal of Impotence Research (2000) 12, Suppl 4, S67-S73.\n[Drug-Disease]: Apomorphine - erectile dysfunction"
    },
    {
        "pmid": "1103606",
        "target": "[]",
        "text": "[Title]: Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension.\n[Abstract]: The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.\n[Drug-Disease]: chlorthalidone - normoreninemic hypertension"
    },
    {
        "pmid": "1103606",
        "target": "[]",
        "text": "[Title]: Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension.\n[Abstract]: The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.\n[Drug-Disease]: propranolol - normoreninemic hypertension"
    },
    {
        "pmid": "1103606",
        "target": "[]",
        "text": "[Title]: Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension.\n[Abstract]: The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.\n[Drug-Disease]: spironolactone - normoreninemic hypertension"
    },
    {
        "pmid": "11037905",
        "target": "[]",
        "text": "[Title]: The effect of phenylephrine on pain and flare intensity in eyes with uveitis.\n[Abstract]: PURPOSE: To investigate the influence of protein concentration in the anterior chamber, measured by laser flare meter, on pain sensation after phenylephrine instillation in patients with iridocyclitis. METHODS: Twenty-five consecutive patients with iridocyclitis were included. Patients with cataract, exfoliation syndrome, diabetes mellitus, glaucoma or any other previous ocular diseases or ocular surgery were excluded. Patients were divided into two groups: Group 1--without fibrinoid reaction (FR) in the anterior chamber (18 patients), and Group 2--with FR (7 patients). Protein concentration in the anterior chamber was measured with laser flare meter (FC 500, Kowa Co., Japan). Pupil size was measured by Alcon Tilo Scale, and pain sensation was estimated by Visual Analogue Scale (VAS, Kabi Pharmacia). All measurements were done before and 1 hour after topical instillation of 10% phenylephrine hydrochloride into the subconjunctival sac of the inflamed eyes. RESULTS: Eyes with iridocyclitis and fibrinoid reaction (FR) have a higher flare intensity compared to those without FR (p<0.05). Pupil size was significantly increased after phenylephrine instillation in both study groups (Wilcoxon test, p<0.05). The VAS pain and flare intensity were significantly decreased in group without FR after phenylephrine instillation (Group 1) compared to values before treatment (Wilcoxon test, p<0.05). In eyes with FR (Group 2), no significant influence of phenylephrine instillation was found on VAS pain and flare intensity. CONCLUSIONS: After phenylephrine instillation, flare intensity and pain were significantly decreased only in eyes with iridocyclitis and without FR. The decreasing level of flare intensity, and paralysis of the pupil after phenylephrine instillation seem to alleviate pain in those eyes.\n[Drug-Disease]: phenylephrine - pain"
    },
    {
        "pmid": "11037905",
        "target": "[]",
        "text": "[Title]: The effect of phenylephrine on pain and flare intensity in eyes with uveitis.\n[Abstract]: PURPOSE: To investigate the influence of protein concentration in the anterior chamber, measured by laser flare meter, on pain sensation after phenylephrine instillation in patients with iridocyclitis. METHODS: Twenty-five consecutive patients with iridocyclitis were included. Patients with cataract, exfoliation syndrome, diabetes mellitus, glaucoma or any other previous ocular diseases or ocular surgery were excluded. Patients were divided into two groups: Group 1--without fibrinoid reaction (FR) in the anterior chamber (18 patients), and Group 2--with FR (7 patients). Protein concentration in the anterior chamber was measured with laser flare meter (FC 500, Kowa Co., Japan). Pupil size was measured by Alcon Tilo Scale, and pain sensation was estimated by Visual Analogue Scale (VAS, Kabi Pharmacia). All measurements were done before and 1 hour after topical instillation of 10% phenylephrine hydrochloride into the subconjunctival sac of the inflamed eyes. RESULTS: Eyes with iridocyclitis and fibrinoid reaction (FR) have a higher flare intensity compared to those without FR (p<0.05). Pupil size was significantly increased after phenylephrine instillation in both study groups (Wilcoxon test, p<0.05). The VAS pain and flare intensity were significantly decreased in group without FR after phenylephrine instillation (Group 1) compared to values before treatment (Wilcoxon test, p<0.05). In eyes with FR (Group 2), no significant influence of phenylephrine instillation was found on VAS pain and flare intensity. CONCLUSIONS: After phenylephrine instillation, flare intensity and pain were significantly decreased only in eyes with iridocyclitis and without FR. The decreasing level of flare intensity, and paralysis of the pupil after phenylephrine instillation seem to alleviate pain in those eyes.\n[Drug-Disease]: phenylephrine - iridocyclitis"
    },
    {
        "pmid": "11040906",
        "target": "[\"Span: 2% | Label: Dosage\"]",
        "text": "[Title]: Prilocaine versus lignocaine for minor lid procedures.\n[Abstract]: PURPOSE: To determine whether prilocaine is a more comfortable local infiltration anaesthetic agent than the more widely used lignocaine for minor eyelid procedures. METHODS: A prospective randomised study was undertaken to compare the discomfort between local infiltration of plain 2% prilocaine versus its equivalent, plain 2% lignocaine. One hundred and twenty-five patients were recruited. Pain was assessed subjectively using a visual analogue pain score, graded from 0 to 10. RESULTS: The mean pain score for the prilocaine group was 1.82 compared with 3.19 for the lignocaine group. Using the Mann-Whitney U-test for significance, U = 1236.5; p < 0.001. CONCLUSION: Prilocaine is a more comfortable local infiltration anaesthetic agent than lignocaine when used for minor eyelid procedures.\n[Drug-Disease]: Prilocaine - pain"
    },
    {
        "pmid": "11045392",
        "target": "[\"Span: pediatric patients | Label: Age\", \"Span: 0.2-0.6 mg/kg per day for 24-84 months | Label: Dosage\"]",
        "text": "[Title]: Enalapril and prednisone in children with nephrotic-range proteinuria.\n[Abstract]: The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administered at doses of 0.2-0.6 mg/kg per day for 24-84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.\n[Drug-Disease]: enalapril - albuminuria"
    },
    {
        "pmid": "11045392",
        "target": "[\"Span: pediatric patients | Label: Age\", \"Span: 0.2-0.6 mg/kg per day for 24-84 months | Label: Dosage\"]",
        "text": "[Title]: Enalapril and prednisone in children with nephrotic-range proteinuria.\n[Abstract]: The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administered at doses of 0.2-0.6 mg/kg per day for 24-84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.\n[Drug-Disease]: enalapril - edema"
    },
    {
        "pmid": "11045392",
        "target": "[\"Span: pediatric patients | Label: Age\", \"Span: 0.2-0.6 mg/kg per day for 24-84 months | Label: Dosage\"]",
        "text": "[Title]: Enalapril and prednisone in children with nephrotic-range proteinuria.\n[Abstract]: The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administered at doses of 0.2-0.6 mg/kg per day for 24-84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.\n[Drug-Disease]: enalapril - hypertensive"
    },
    {
        "pmid": "11045392",
        "target": "[\"Span: pediatric patients | Label: Age\", \"Span: 0.2-0.6 mg/kg per day for 24-84 months | Label: Dosage\"]",
        "text": "[Title]: Enalapril and prednisone in children with nephrotic-range proteinuria.\n[Abstract]: The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administered at doses of 0.2-0.6 mg/kg per day for 24-84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.\n[Drug-Disease]: enalapril - proteinuria"
    },
    {
        "pmid": "11050808",
        "target": "[]",
        "text": "[Title]: [Amantadine for the treatment of levodopa dyskinesias in Parkinson's disease].\n[Abstract]: The development of dyskinesias is a common side effect during chronic levodopa therapy in parkinsonian patients. Recent reports suggest that amantadine, a drug with well known antiparkinsonian activity, is effective in the treatment of this complication. In order to evaluate its usefulness we conducted an open label, prospective and longitudinal study in 26 patients with Parkinson's disease (PD) on chronic levodopa therapy who presented peaks of dose dyskinesias. After 3 weeks' treatment dyskinesia severity was reduced by 70% (p < 0.0001) on the I SAPD scale and by 68.8% (p < 0.0002) on the UPDRS IV subscale. Patients were later evaluated every 45 days showing persistent drug benefit during follow-up ranging from 2 to 11 months (mean 6.5 months). One third of our series presented unwanted effects which were only severe enough in 2 cases to discontinue treatment. In the others, side effects were transient or readily abated with amantadine dose reduction. Our findings support amantadine as a safe and useful drug to treat levodopa-induced dyskinesias which on occasion prove as disabling as PD itself. Treatment with amantadine should routinely be considered before indicating pallidotomy for levodopa-induced dyskinesias.\n[Drug-Disease]: amantadine - dyskinesias"
    },
    {
        "pmid": "11050808",
        "target": "[]",
        "text": "[Title]: [Amantadine for the treatment of levodopa dyskinesias in Parkinson's disease].\n[Abstract]: The development of dyskinesias is a common side effect during chronic levodopa therapy in parkinsonian patients. Recent reports suggest that amantadine, a drug with well known antiparkinsonian activity, is effective in the treatment of this complication. In order to evaluate its usefulness we conducted an open label, prospective and longitudinal study in 26 patients with Parkinson's disease (PD) on chronic levodopa therapy who presented peaks of dose dyskinesias. After 3 weeks' treatment dyskinesia severity was reduced by 70% (p < 0.0001) on the I SAPD scale and by 68.8% (p < 0.0002) on the UPDRS IV subscale. Patients were later evaluated every 45 days showing persistent drug benefit during follow-up ranging from 2 to 11 months (mean 6.5 months). One third of our series presented unwanted effects which were only severe enough in 2 cases to discontinue treatment. In the others, side effects were transient or readily abated with amantadine dose reduction. Our findings support amantadine as a safe and useful drug to treat levodopa-induced dyskinesias which on occasion prove as disabling as PD itself. Treatment with amantadine should routinely be considered before indicating pallidotomy for levodopa-induced dyskinesias.\n[Drug-Disease]: levodopa - PD"
    },
    {
        "pmid": "11057441",
        "target": "[\"Span: hypertriglyceridaemia (> or = 2.3 mmol/l) | Label: Comorbidity\", \"Span: impaired glucose tolerance (OMS-ADA) | Label: Comorbidity\", \"Span: Obese | Label: Body Type\"]",
        "text": "[Title]: Haemodynamic and metabolic effects of rilmenidine in hypertensive patients with metabolic syndrome X. A double-blind parallel study versus amlodipine.\n[Abstract]: OBJECTIVE: To compare the effects of rilmenidine with those of amlodipine on blood pressure, glucose metabolism, plasma lipid concentration and fibrinolysis parameters. DESIGN: A four-month randomized double-blind, parallel group study. PATIENTS AND METHODS: Obese hypertensive patients with hypertriglyceridaemia (> or = 2.3 mmol/l) and impaired glucose tolerance (OMS-ADA) were included (n = 52). A placebo run-in period of 2 weeks was followed by 4 months of double-blind treatment with either rilmenidine or amlodipine. Blood pressure was recorded using a mercury sphygmomanometer. Glucose metabolism was evaluated by an oral glucose tolerance test RESULTS: Of the 52 patients recruited, 47 (21 rilmenidine and 26 amlodipine) completed the 4-month treatment period. The intention-to-treat analysis showed a comparable reduction in systolic and diastolic blood pressure (SBP, DBP) with the two anti-hypertensive treatments (rilmenidine -13.9/-13.5 mmHg; amlodipine - 17.6/-15.0 mmHg). Insulin concentrations under basal conditions and 2 h after a standard oral glucose load did not change significantly after treatment in both groups. Plasma glucose under basal conditions and 2 h after a standard oral glucose load as well as the area under the plasma glucose concentration curve tended to decrease in the rilmenidine group and to increase in the amlodipine group so that the changes in these parameters were significantly different between the two study groups (P= 0.041, P = 0.042 and P = 0.015, respectively). Plasminogen activator inhibitor type 1 (PAI-1) antigen and PAI-1 activity were only decreased in the rilmenidine group (not statistically significant). CONCLUSION: Our results demonstrate that rilmenidine and amlodipine have a comparable anti-hypertensive effect but only rilmenidine is able to improve glucose metabolism.\n[Drug-Disease]: rilmenidine - hypertensive"
    },
    {
        "pmid": "11057441",
        "target": "[\"Span: hypertriglyceridaemia (> or = 2.3 mmol/l) | Label: Comorbidity\", \"Span: impaired glucose tolerance (OMS-ADA) | Label: Comorbidity\", \"Span: Obese | Label: Body Type\"]",
        "text": "[Title]: Haemodynamic and metabolic effects of rilmenidine in hypertensive patients with metabolic syndrome X. A double-blind parallel study versus amlodipine.\n[Abstract]: OBJECTIVE: To compare the effects of rilmenidine with those of amlodipine on blood pressure, glucose metabolism, plasma lipid concentration and fibrinolysis parameters. DESIGN: A four-month randomized double-blind, parallel group study. PATIENTS AND METHODS: Obese hypertensive patients with hypertriglyceridaemia (> or = 2.3 mmol/l) and impaired glucose tolerance (OMS-ADA) were included (n = 52). A placebo run-in period of 2 weeks was followed by 4 months of double-blind treatment with either rilmenidine or amlodipine. Blood pressure was recorded using a mercury sphygmomanometer. Glucose metabolism was evaluated by an oral glucose tolerance test RESULTS: Of the 52 patients recruited, 47 (21 rilmenidine and 26 amlodipine) completed the 4-month treatment period. The intention-to-treat analysis showed a comparable reduction in systolic and diastolic blood pressure (SBP, DBP) with the two anti-hypertensive treatments (rilmenidine -13.9/-13.5 mmHg; amlodipine - 17.6/-15.0 mmHg). Insulin concentrations under basal conditions and 2 h after a standard oral glucose load did not change significantly after treatment in both groups. Plasma glucose under basal conditions and 2 h after a standard oral glucose load as well as the area under the plasma glucose concentration curve tended to decrease in the rilmenidine group and to increase in the amlodipine group so that the changes in these parameters were significantly different between the two study groups (P= 0.041, P = 0.042 and P = 0.015, respectively). Plasminogen activator inhibitor type 1 (PAI-1) antigen and PAI-1 activity were only decreased in the rilmenidine group (not statistically significant). CONCLUSION: Our results demonstrate that rilmenidine and amlodipine have a comparable anti-hypertensive effect but only rilmenidine is able to improve glucose metabolism.\n[Drug-Disease]: amlodipine - hypertensive"
    },
    {
        "pmid": "11061656",
        "target": "[]",
        "text": "[Title]: Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.\n[Abstract]: OBJECTIVE AND METHODS: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months. RESULTS: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. CONCLUSION: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.\n[Drug-Disease]: HU - HIV-1 infection"
    },
    {
        "pmid": "11061656",
        "target": "[]",
        "text": "[Title]: Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.\n[Abstract]: OBJECTIVE AND METHODS: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months. RESULTS: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. CONCLUSION: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.\n[Drug-Disease]: didanosine - HIV-1 infection"
    },
    {
        "pmid": "11061656",
        "target": "[]",
        "text": "[Title]: Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.\n[Abstract]: OBJECTIVE AND METHODS: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months. RESULTS: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. CONCLUSION: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.\n[Drug-Disease]: stavudine - HIV-1 infection"
    },
    {
        "pmid": "11063766",
        "target": "[\"Span: slow intravenous injection every 12 hours for 10 days | Label: Dosage\"]",
        "text": "[Title]: Renoprotective role of nifedipine during gentamicin therapy: randomized controlled trial.\n[Abstract]: AIM: To investigate the protective effect of nifedipine, a dihydropyridine calcium-channel blocker, on renal function (glomerular and tubular) in patients treated with gentamicin, an aminoglycoside antibiotic. METHODS: Thirty-two patients with gentamicin sensitive upper urinary tract infection have been screened and randomized to two groups. The placebo group was given gentamicin and placebo, and the intervention group gentamicin and nifedipine. Gentamicin was given in slow intravenous injection every 12 hours for 10 days, and nifedipine 10 mg orally, 3 times a day. RESULTS: Nifedipine administration during gentamicin therapy promoted primarily the glomerular filtration. In 62% of the patients treated with nifedipine creatinine clearance increased significantly by the end of the study. In the placebo group, 69% of the patients had a creatinine clearance significantly below the baseline at the end of the study. The decrease in creatinine clearance by more than 50% from the initial values was found in 2 patients (1 in each group). There was a significant increase in gammaGT/creatinine clearance ratio in both groups at the end of therapy, indicating that nifedipine did not prevent the brush-border membranous enzyme release caused by gentamicin. CONCLUSION: Nifedipine has positive effects on renal hemodynamics in patients treated with gentamicin. Most likely, the mechanism of action is an increase in glomerular filtration caused by preglomerular vasodilatation.\n[Drug-Disease]: gentamicin - upper urinary tract infection"
    },
    {
        "pmid": "11064608",
        "target": "[\"Span: lidocaine 20.0 mg in 2.0 ml | Label: Dosage\"]",
        "text": "[Title]: Peripheral lidocaine but not ketamine inhibits capsaicin-induced hyperalgesia in humans.\n[Abstract]: We examined the effect of the subcutaneous infiltration of ketamine, lidocaine and saline before injury on capsaicin-induced pain and hyperalgesia. Twelve healthy volunteers participated in two separate, randomized, double-blind, placebo-controlled crossover experiments. In experiment 1, 100 micrograms capsaicin was injected intradermally in one volar forearm 10 min after the skin had been pretreated with lidocaine 20.0 mg in 2.0 ml or 0.9% saline 2.0 ml at the capsaicin injection site. In experiment 2, a similar capsaicin test was given 10 min after the skin had been pretreated with ketamine 5 mg in 2.0 ml or 0.9% saline 2.0 ml. To control for possible systemic effects, the capsaicin injection site was pretreated by injection of saline into the skin and the contralateral arm was treated with active drug, and vice versa. Outcome measures were spontaneous pain, pain evoked by punctate and brush stimuli, and areas of brush-evoked and punctate-evoked hyperalgesia. Lidocaine reduced all measures compared with placebo (P < 0.001), whereas ketamine failed to change any measures. Pain scores and areas of hyperalgesia were not affected when the contralateral site was infiltrated with ketamine or lidocaine. Lidocaine produced no side-effects, whereas ketamine produced paraesthesia, dizziness and sleepiness in six out of 24 (25%) cases. Blocking peripheral sodium channels with locally administered lidocaine reduces spontaneous pain and capsaicin-induced hyperalgesia but local block with the NMDA-type glutamate receptor antagonist ketamine has no effect on capsaicin-induced pain and hyperalgesia.\n[Drug-Disease]: lidocaine - hyperalgesia"
    },
    {
        "pmid": "11064608",
        "target": "[\"Span: lidocaine 20.0 mg in 2.0 ml | Label: Dosage\"]",
        "text": "[Title]: Peripheral lidocaine but not ketamine inhibits capsaicin-induced hyperalgesia in humans.\n[Abstract]: We examined the effect of the subcutaneous infiltration of ketamine, lidocaine and saline before injury on capsaicin-induced pain and hyperalgesia. Twelve healthy volunteers participated in two separate, randomized, double-blind, placebo-controlled crossover experiments. In experiment 1, 100 micrograms capsaicin was injected intradermally in one volar forearm 10 min after the skin had been pretreated with lidocaine 20.0 mg in 2.0 ml or 0.9% saline 2.0 ml at the capsaicin injection site. In experiment 2, a similar capsaicin test was given 10 min after the skin had been pretreated with ketamine 5 mg in 2.0 ml or 0.9% saline 2.0 ml. To control for possible systemic effects, the capsaicin injection site was pretreated by injection of saline into the skin and the contralateral arm was treated with active drug, and vice versa. Outcome measures were spontaneous pain, pain evoked by punctate and brush stimuli, and areas of brush-evoked and punctate-evoked hyperalgesia. Lidocaine reduced all measures compared with placebo (P < 0.001), whereas ketamine failed to change any measures. Pain scores and areas of hyperalgesia were not affected when the contralateral site was infiltrated with ketamine or lidocaine. Lidocaine produced no side-effects, whereas ketamine produced paraesthesia, dizziness and sleepiness in six out of 24 (25%) cases. Blocking peripheral sodium channels with locally administered lidocaine reduces spontaneous pain and capsaicin-induced hyperalgesia but local block with the NMDA-type glutamate receptor antagonist ketamine has no effect on capsaicin-induced pain and hyperalgesia.\n[Drug-Disease]: lidocaine - pain"
    },
    {
        "pmid": "11069031",
        "target": "[\"Span: i.v. busulfan diluted in 50 ml of 0.9% normal saline | Label: Dosage\", \"Span: busulfan in a 500-ml 5% dextrose solution | Label: Dosage\"]",
        "text": "[Title]: A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.\n[Abstract]: Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.\n[Drug-Disease]: busulfan - chronic myeloid leukemia"
    },
    {
        "pmid": "11069031",
        "target": "[\"Span: i.v. busulfan diluted in 50 ml of 0.9% normal saline | Label: Dosage\", \"Span: busulfan in a 500-ml 5% dextrose solution | Label: Dosage\"]",
        "text": "[Title]: A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.\n[Abstract]: Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.\n[Drug-Disease]: busulfan - acute myeloid leukemia"
    },
    {
        "pmid": "11069031",
        "target": "[\"Span: i.v. busulfan diluted in 50 ml of 0.9% normal saline | Label: Dosage\", \"Span: busulfan in a 500-ml 5% dextrose solution | Label: Dosage\"]",
        "text": "[Title]: A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.\n[Abstract]: Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.\n[Drug-Disease]: busulfan - acute lymphocytic leukemia"
    },
    {
        "pmid": "11070477",
        "target": "[\"Span: children | Label: Age\"]",
        "text": "[Title]: White matter changes on MRI during treatment in children with acute lymphoblastic leukemia: correlation with neuropsychological findings.\n[Abstract]: BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (ALL) may cause structural and functional brain damage. To find out the incidence of white matter changes during therapy, a prospective MRI study was designed, and the findings were correlated with neuropsychological evaluation. PROCEDURE: Thirty-three children with ALL underwent serial cranial MRI before, during, and after therapy. Twenty-eight of these children underwent also neuropsychological assessment at the end of treatment. They all received intravenous and intrathecal methotrexate for central nervous system (CNS) therapy, 15 patients received cranial irradiation in addition. RESULTS: Transient high-intensity white matter changes were observed by MRI in three children 9% (95% CI, 2-24%) who received chemotherapy only. The high-intensity changes were most prominent in the frontal lobes in two of these children. The children with white matter changes were significantly younger than those with normal MRI (2.8 vs. 7.4 years; mean). There was no correlation between neuropsychological tests and white matter changes, except in attention and in tests referring to the frontal areas in general. CONCLUSIONS: White matter changes are occasionally observed during therapy with the current Nordic protocols. Young children may be more susceptible to developing white matter changes after repeated intravenous methotrexate injections. There is no systematic correlation between neuropsychological deficits and MRI findings.\n[Drug-Disease]: methotrexate - acute lymphoblastic leukemia"
    },
    {
        "pmid": "11070746",
        "target": "[\"Span: black | Label: Body Type\", \"Span: 16-70 years | Label: Age\", \"Span: 20 mg of 'Accolate' twice daily | Label: Dosage\"]",
        "text": "[Title]: Efficacy and safety of Zafirlukast ('Accolate') in the management of patients with mild-to-moderate asthma.\n[Abstract]: The efficacy and safety of the oral leukotriene receptor antagonist Zafirlukast ('Accolate') was assessed as maintenance therapy for black (Nigerian) patients with mild to moderate asthma. A total of eighty-one patients aged 16-70 years were screened and sixty patients were enrolled in a 7-week multicenter open study to receive 20 mg of 'Accolate' twice daily. Those enrolled had FEV1 > or = 60%, reversibility > or = 15% and cumulative daytime asthma symptoms score > or = 10 over seven consecutive days before visit 2 to be considered eligible to receive trial therapy, and the patients were maintained on as required beta 2-agonist therapy. Efficacy was assessed by changes in symptoms, number of times beta 2-agonist was used and results of pulmonary function tests. Safety was assessed by adverse event experiences, results of laboratory tests and physical examination. At the endpoint, patients reported a statistically significant increase in lung function and a significant reduction in episodes of asthma symptoms either in the morning, day or night. The mean beta 2-agonist use was also statistically reduced over the weeks as treatment progressed while the cumulative daytime total asthma score showed a sharp decline following drug use. Change in symptoms, beta 2-agonist use and pulmonary function occurred within one week of Zafirlukast treatment and continued throughout the trial. Zafirlukast was well tolerated. Headaches and pneumonia were the only side effects in three patients and these were not considered to be related to trial therapy. No clinically significant changes were observed in laboratory test results, or on physical examination. We conclude that Zafirlukast ('Accolate') 20 mg b.d. is an effective and well tolerated medication for maintenance therapy in black (Nigerian) patients with mild-to-moderate asthma.\n[Drug-Disease]: Accolate - asthma"
    },
    {
        "pmid": "11071027",
        "target": "[\"Span: 0.005% | Label: Dosage\"]",
        "text": "[Title]: A randomized, comparative open-label study on the efficacy of latanoprost and timolol in steroid induced ocular hypertension after photorefractive keratectomy.\n[Abstract]: PURPOSE: To evaluate the effect of 0.005% latanoprost and 0.50% timolol for the treatment of steroid-induced ocular hypertension (SIOH) after excimer laser photorefractive keratectomy (PRK). METHODS: In this comparative, open-label study we enrolled 29 patients who received steroid therapy after PRK and developed intraocular pressure (IOP) elevation within 30 days of treatment. Fifteen were randomized to 0.005% latanoprost (group A) and 14 to 0.50% timolol (group B). IOP measurements were scheduled at 1, 3, 7, 15, 30, 60, 90 and 120 days of therapy. RESULTS; We did not find any real differences between latanoprost and timolol except at the 7-day and 15-day timepoints, when latanoprost reduced IOP significantly more than timolol (p=0.033, 0.035, respectively). After 7 days of therapy two of the 14 timolol-treated patients had high IOP (24 and 26 mmHg) but these promptly returned to normal when latanoprost was added. No significant differences were observed in the ocular side effects considered. CONCLUSIONS: 0.005% latanoprost is as safe and effective as 0.50% timolol in the treatment of SIOH after PRK. Both drugs provide a significant and stable IOP reduction in the majority of patients after short-term treatment. These findings are encouraging for the use of latanoprost in the management of SIOH after PRK, although further trials are necessary to consider it as a primary treatment.\n[Drug-Disease]: latanoprost - ocular hypertension"
    },
    {
        "pmid": "11071027",
        "target": "[\"Span: 0.50% | Label: Dosage\"]",
        "text": "[Title]: A randomized, comparative open-label study on the efficacy of latanoprost and timolol in steroid induced ocular hypertension after photorefractive keratectomy.\n[Abstract]: PURPOSE: To evaluate the effect of 0.005% latanoprost and 0.50% timolol for the treatment of steroid-induced ocular hypertension (SIOH) after excimer laser photorefractive keratectomy (PRK). METHODS: In this comparative, open-label study we enrolled 29 patients who received steroid therapy after PRK and developed intraocular pressure (IOP) elevation within 30 days of treatment. Fifteen were randomized to 0.005% latanoprost (group A) and 14 to 0.50% timolol (group B). IOP measurements were scheduled at 1, 3, 7, 15, 30, 60, 90 and 120 days of therapy. RESULTS; We did not find any real differences between latanoprost and timolol except at the 7-day and 15-day timepoints, when latanoprost reduced IOP significantly more than timolol (p=0.033, 0.035, respectively). After 7 days of therapy two of the 14 timolol-treated patients had high IOP (24 and 26 mmHg) but these promptly returned to normal when latanoprost was added. No significant differences were observed in the ocular side effects considered. CONCLUSIONS: 0.005% latanoprost is as safe and effective as 0.50% timolol in the treatment of SIOH after PRK. Both drugs provide a significant and stable IOP reduction in the majority of patients after short-term treatment. These findings are encouraging for the use of latanoprost in the management of SIOH after PRK, although further trials are necessary to consider it as a primary treatment.\n[Drug-Disease]: timolol - ocular hypertension"
    },
    {
        "pmid": "11077134",
        "target": "[\"Span: age >18 years | Label: Dosage\", \"Span: 12.5-25 mg losartan within 24 h of hospital admission | Label: Dosage\"]",
        "text": "[Title]: First dose hypotension after angiotensin converting enzyme inhibitor captopril and angiotensin II blocker losartan in patients with acute myocardial infarction.\n[Abstract]: BACKGROUND: First dose hypotension after the administration of an angiotensin-converting enzyme inhibitor in patients with acute myocardial infarction is one of the most important adverse events of this type of treatment. There is no information about first dose hypotension after angiotensin type 1-receptor blocker in this type of patient. AIM: To compare the first dose responses to low dose captopril and losartan in patients with acute myocardial infarction. METHODS: Single blind, randomised, multicentric, prospective study. Patients (n=320) with confirmed acute myocardial infarction, age >18 years, treated by direct percutaneous transluminal coronary angioplasty, thrombolysis and/or heparin, were randomised to receive a single dose of 6.25-12.5 mg captopril or 12.5-25 mg losartan within 24 h of hospital admission. Baseline laboratory and clinical examinations were performed before entering the study. Blood pressure monitoring started at hospital admission and continued for at least 8 h after the medication (second dose of captopril was given after 8 h). RESULTS: The maximal blood pressure fall appeared about 1 h after the first dose of captopril and 3.5 h after the first dose of losartan. Patients in the captopril group had significantly higher incidence of asymptomatic hypotension (38%) than patients treated with losartan (24%) (P<0.001). No difference in hypotension requiring a change in medication was observed. CONCLUSION: Low dose of losartan is safe for initiating therapy in patients with acute myocardial infarction within 24 h of hospital admission.\n[Drug-Disease]: losartan - acute myocardial infarction"
    },
    {
        "pmid": "11078032",
        "target": "[\"Span: 20-mg/day | Label: Dosage\"]",
        "text": "[Title]: Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose.\n[Abstract]: BACKGROUND: The efficacy and safety of fluoxetine in adults with moderate-to-severe major depression are well established. However, most analyses combined dosages (20-80 mg/day) of the compound. We hypothesized that in patients taking 20 mg/day, efficacy would be maintained but the incidence of adverse events would be lower. We present a meta-analysis of efficacy and safety data for fluoxetine, 20 mg/day. METHOD: Data were from 3 double-blind studies (N = 417) that included patients with moderate-to-severe major depression (DSM-III or DSM-III-R criteria) who received placebo or fixed-dose 20-mg/day treatment with fluoxetine. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D; HAM-D-17 total score and anxiety/somatization, retardation, sleep disturbance, and cognitive disturbance factors) and response and remission rates. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, and adverse events leading to discontinuation. Adverse events were evaluated to determine the emergence of activation and/or sedation. RESULTS: At 20 mg/day, fluoxetine-treated patients demonstrated significantly greater remission and response rates and mean changes on HAM-D-17 total score and anxiety/somatization, retardation, and cognitive disturbance factor scores than placebo-treated patients (p < .001). The incidence of specific adverse events leading to discontinuation and the frequency of study discontinuations due to adverse events were similar among fluoxetine-treated and placebo-treated patients (6.1% vs. 5.8%, p = .879). Several adverse events (insomnia, asthenia, somnolence, gastroenteritis, decreased libido, chills, and confusion) occurred significantly more frequently among fluoxetine-treated patients. A significant change in sedation, but not activation, occurred in patients in the fluoxetine 20-mg/day group compared with the placebo group. CONCLUSION: These data affirm that fluoxetine at 20 mg/day is efficacious, safe, and of similar activation potential when compared with placebo in patients with major depression.\n[Drug-Disease]: fluoxetine - major depression"
    },
    {
        "pmid": "11078175",
        "target": "[]",
        "text": "[Title]: Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril.\n[Abstract]: Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population. Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure (BP). The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake, whereas the angiotensin-converting enzyme (ACE) inhibitors' effects can be blunted by a high-sodium diet. This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril. Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril. The response was assessed by ambulatory BP measurement. Indomethacin raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine. The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril. Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin. It is postulated that the effect is due to inhibition of prostaglandin synthesis, which causes sodium retention. In patients taking amlodipine, the fall in plasma renin ameliorates the effect of sodium retention on BP. In patients taking enalapril, plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme. Thus, the full effect of sodium retention on BP is expressed. In patients treated with indomethacin, fewer patients may respond to ACE inhibitors. However, the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs, which, if a person is treated by an ACE inhibitor causes BP to go out of control. In such patients amlodipine would appear to be a preferred choice to enalapril.\n[Drug-Disease]: enalapril - hypertension"
    },
    {
        "pmid": "11078175",
        "target": "[]",
        "text": "[Title]: Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril.\n[Abstract]: Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population. Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure (BP). The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake, whereas the angiotensin-converting enzyme (ACE) inhibitors' effects can be blunted by a high-sodium diet. This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril. Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril. The response was assessed by ambulatory BP measurement. Indomethacin raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine. The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril. Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin. It is postulated that the effect is due to inhibition of prostaglandin synthesis, which causes sodium retention. In patients taking amlodipine, the fall in plasma renin ameliorates the effect of sodium retention on BP. In patients taking enalapril, plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme. Thus, the full effect of sodium retention on BP is expressed. In patients treated with indomethacin, fewer patients may respond to ACE inhibitors. However, the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs, which, if a person is treated by an ACE inhibitor causes BP to go out of control. In such patients amlodipine would appear to be a preferred choice to enalapril.\n[Drug-Disease]: amlodipine - hypertension"
    },
    {
        "pmid": "11083272",
        "target": "[]",
        "text": "[Title]: Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine.\n[Abstract]: OBJECTIVE: Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. METHODS: The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine. ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3). Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing. RESULTS: No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA. There were no findings suggestive of vasculitis in any of these patients. CONCLUSION: From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine. However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.\n[Drug-Disease]: minocycline - rheumatoid arthritis"
    },
    {
        "pmid": "11083272",
        "target": "[]",
        "text": "[Title]: Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine.\n[Abstract]: OBJECTIVE: Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. METHODS: The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine. ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3). Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing. RESULTS: No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA. There were no findings suggestive of vasculitis in any of these patients. CONCLUSION: From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine. However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.\n[Drug-Disease]: penicillamine - systemic sclerosis"
    },
    {
        "pmid": "11083272",
        "target": "[]",
        "text": "[Title]: Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine.\n[Abstract]: OBJECTIVE: Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. METHODS: The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine. ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3). Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing. RESULTS: No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA. There were no findings suggestive of vasculitis in any of these patients. CONCLUSION: From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine. However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.\n[Drug-Disease]: sulfasalazine - rheumatoid arthritis"
    },
    {
        "pmid": "11084061",
        "target": "[\"Span: 150 mg/d | Label: Dosage\"]",
        "text": "[Title]: An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy.\n[Abstract]: Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infection was limited until recently by poor graft and patient outcomes caused by recurrent HBV. Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) dramatically improved post-OLT survival, but recurrent HBV still occurred in up to 36% of the recipients. More recently, combination HBIG and lamivudine has been shown to effectively prevent HBV recurrence in patients post-OLT. The aim of the current study is to determine long-term outcome and cost-effectiveness of using combination HBIG and lamivudine compared with HBIG monotherapy in patients who undergo OLT for HBV. A retrospective chart review identified 59 patients administered combination HBIG and lamivudine and 12 patients administered HBIG monotherapy as primary prophylaxis against recurrent HBV. Lamivudine, 150 mg/d, was administered orally indefinitely. HBIG was administered under a standard protocol (10,000 IU intravenously during the anhepatic phase, then 10,000 IU/d intravenously for 7 days, then 10,000 IU intravenously monthly) indefinitely. A decision-analysis model was developed to evaluate the potential economic impact of prophylaxis against HBV with combination therapy compared with monotherapy. Recurrent HBV was defined as the reappearance of hepatitis B surface antigen (HBsAg) after its initial disappearance post-OLT. In the combination-therapy group, no patient redeveloped serum HBsAg or HBV DNA during mean follow-ups of 459 and 416 days, respectively. In the monotherapy group, 3 patients (25%) had reappearance of HBsAg in serum during a mean follow-up of 663 days. Combination therapy resulted in a dominant, cost-effective strategy with an average cost-effectiveness ratio of $252,111/recurrence prevented compared with $362,570/recurrence prevented in the monotherapy strategy. Combination prophylaxis with HBIG and lamivudine is highly effective in preventing recurrent HBV, may protect against the emergence of resistant mutants, and is significantly more cost-effective than HBIG monotherapy with its associated rate of recurrent HBV.\n[Drug-Disease]: lamivudine - hepatitis B"
    },
    {
        "pmid": "1108649",
        "target": "[]",
        "text": "[Title]: Amikacin therapy of infections in neutropenic patients.\n[Abstract]: Amikacin, a new aminoglycoside antibiotic, was utilized in the treatment of 49 cases of infection which occurred in 39 neutropenic cancer patients. Thirty-four patients (69 per cent) responded to this antibiotic. Pneumonia and septicemia were the most common types of infection treated and the response rates were 65 per cent and 75 per cent, respectively. Gram-negative bacili were responsible for 93 per cent of the identified infections and 74 per cent responded. E. coli, Ps. aeruginosa, and organisms of the Klebsiella-Enterobacter-Serratia group were the most common gram-negative bacilli causing infection. Responses were more frequent among patients who maintained higher serum concentrations of antibiotic, but the differences were not statistically significant. Patients with severe neutropenia (less than 100 neutrophils/mm3) had a response rate of 68 per cent. Toxicity was manifested as azotemia and hearing loss which occurred in 13 per cent and 6 per cent, respectively. However, toxicity was directly related to serum concentration and to the number of treatments with amikacin. This antibiotic is of potential importance because of its efficacy against gram-negative bacilli infections. Best results were obtained when sufficient drug was given as a continuous intravenous infusion to maintain serum concentrations of about 15 mu g/ml.\n[Drug-Disease]: amikacin - septicemia"
    },
    {
        "pmid": "11089368",
        "target": "[\"Span: 200 mg/1st day and then 100 mg/day | Label: Dosage\"]",
        "text": "[Title]: [Clinical use of tetracyclines in the treatment of periodontal diseases].\n[Abstract]: INTRODUCTION: There are a number of chemically different tetracycline homologues. The older group of tetracyclines, which was introduced in the 1950-60s, includes tetracycline, oxytetracycline, chlortetracycline and demeclocycline. The newer group of tetracyclines includes doxycycline, methacycline and minocycline. PHARMACOKINETICS: Elevated concentration of tetracycline in gingival fluid with respect to blood levels was an unexpected phenomenon. Patients given 250 mg every 6 hours had average crevicular fluid concentrations between 4 to 8 g/ml and blood concentrations between 2 to 2.5 g/ml after 48 hours. The levels in crevicular fluid and blood of volunteers who received 250 mg every 12 hours were 2 to 4 g/ml and 0.3 to 1.4 g/ml respectively after 48 hours. The concentration of doxycycline in gingival fluid after administration of 200 mg/1st day and then 100 mg/day achieved average level of 6 g/ml. Minocycline, a semisynthetic derivate of tetracycline, has shown to yield gingival fluid levels 5 times as high as serum levels after administration of 100 mg every 12 hours. MECHANISMS OF ACTION: Tetracycline and its derivates demonstrate high in vitro activity against most periodontal bacteria, including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Eikenella corrodens, Wolinella recta and Fusobacterium nucleatum. The study of in vitro susceptibility of these 6 bacterial strains showed that, in regard to blood level, minimal inhibitory concentration is higher and it is the concentration of the drug that can be expected in gingival fluid following oral administration of 100 mg per day (doxycycline) (Table 1). The anti-inflammatory effect of tetracyclines was demonstrated histologically not only by reducing the size of the infiltrated connective tissue, but qualitative changes were also observed. Golub and associates have presented evidence that tetracyclines inhibit collagenase activity in gingival fluid and in tissue cultures. Therapeutic concentrations of tetracycline inhibit chemotaxis, phagocytosis and random migration of neutrophils in vitro. ADVERSE EFFECTS: Great amounts of tetracyclines cause gastrointestinal disorders, nausea, vomiting and diarrhea. Tetracyclines suppress activity of the enzymes in the bowel and pancreas. During longlasting administration they can damage the liver and kidneys. Tetracyclines can cause photo-sensibilization. They make deposits with calcium in bones, specially during prenatal period and during growth, so they can cause permanent teeth discoloration and hypoplasia. INTERACTIONS: The most important interaction is with penicillin. These two kinds of antibiotics antagonize and decrease the therapeutic effect of each other, so their administration at the same time should be avoided. A significant interaction occurs between tetracyclines and metal ions. This interaction often has been observed in conjunction with use of various antacids. Tetracyclines can also influence the production and absorption of vitamin K. Nephrotoxicity has been reported when tetracyclines have been administrated in conjunction with methoxyflurane. INDICATIONS: Doxycycline, due to its advantages over tetracycline (Table 2), is indicated in treating destructive periodontal diseases including: juvenile periodontitis and refractory marginal periodontitis. Doxycycline therapy may be used for acute periodontal abscess and if the conditions are accompanied by general symptoms. Prophylactic application is recommended for implant placement procedures including membranes in guided tissue regeneration. RESULTS OF CLINICAL STUDY: ORAL APPLICATION: In spite of great number of published investigations this paper presents only the results of placebo-controlled, double-blind studies. There is evidence that therapy in localized juvenile periodontitis should eliminate Actinobacillus actinomycetemcomitans, since 95% of patients harbored this bacteria. (ABSTRACT TRUNCATED)\n[Drug-Disease]: Doxycycline - periodontitis"
    },
    {
        "pmid": "11089368",
        "target": "[\"Span: 250 mg every 6 hours | Label: Dosage\", \"Span: 250 mg every 12 hours | Label: Dosage\"]",
        "text": "[Title]: [Clinical use of tetracyclines in the treatment of periodontal diseases].\n[Abstract]: INTRODUCTION: There are a number of chemically different tetracycline homologues. The older group of tetracyclines, which was introduced in the 1950-60s, includes tetracycline, oxytetracycline, chlortetracycline and demeclocycline. The newer group of tetracyclines includes doxycycline, methacycline and minocycline. PHARMACOKINETICS: Elevated concentration of tetracycline in gingival fluid with respect to blood levels was an unexpected phenomenon. Patients given 250 mg every 6 hours had average crevicular fluid concentrations between 4 to 8 g/ml and blood concentrations between 2 to 2.5 g/ml after 48 hours. The levels in crevicular fluid and blood of volunteers who received 250 mg every 12 hours were 2 to 4 g/ml and 0.3 to 1.4 g/ml respectively after 48 hours. The concentration of doxycycline in gingival fluid after administration of 200 mg/1st day and then 100 mg/day achieved average level of 6 g/ml. Minocycline, a semisynthetic derivate of tetracycline, has shown to yield gingival fluid levels 5 times as high as serum levels after administration of 100 mg every 12 hours. MECHANISMS OF ACTION: Tetracycline and its derivates demonstrate high in vitro activity against most periodontal bacteria, including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Eikenella corrodens, Wolinella recta and Fusobacterium nucleatum. The study of in vitro susceptibility of these 6 bacterial strains showed that, in regard to blood level, minimal inhibitory concentration is higher and it is the concentration of the drug that can be expected in gingival fluid following oral administration of 100 mg per day (doxycycline) (Table 1). The anti-inflammatory effect of tetracyclines was demonstrated histologically not only by reducing the size of the infiltrated connective tissue, but qualitative changes were also observed. Golub and associates have presented evidence that tetracyclines inhibit collagenase activity in gingival fluid and in tissue cultures. Therapeutic concentrations of tetracycline inhibit chemotaxis, phagocytosis and random migration of neutrophils in vitro. ADVERSE EFFECTS: Great amounts of tetracyclines cause gastrointestinal disorders, nausea, vomiting and diarrhea. Tetracyclines suppress activity of the enzymes in the bowel and pancreas. During longlasting administration they can damage the liver and kidneys. Tetracyclines can cause photo-sensibilization. They make deposits with calcium in bones, specially during prenatal period and during growth, so they can cause permanent teeth discoloration and hypoplasia. INTERACTIONS: The most important interaction is with penicillin. These two kinds of antibiotics antagonize and decrease the therapeutic effect of each other, so their administration at the same time should be avoided. A significant interaction occurs between tetracyclines and metal ions. This interaction often has been observed in conjunction with use of various antacids. Tetracyclines can also influence the production and absorption of vitamin K. Nephrotoxicity has been reported when tetracyclines have been administrated in conjunction with methoxyflurane. INDICATIONS: Doxycycline, due to its advantages over tetracycline (Table 2), is indicated in treating destructive periodontal diseases including: juvenile periodontitis and refractory marginal periodontitis. Doxycycline therapy may be used for acute periodontal abscess and if the conditions are accompanied by general symptoms. Prophylactic application is recommended for implant placement procedures including membranes in guided tissue regeneration. RESULTS OF CLINICAL STUDY: ORAL APPLICATION: In spite of great number of published investigations this paper presents only the results of placebo-controlled, double-blind studies. There is evidence that therapy in localized juvenile periodontitis should eliminate Actinobacillus actinomycetemcomitans, since 95% of patients harbored this bacteria. (ABSTRACT TRUNCATED)\n[Drug-Disease]: tetracycline - periodontitis"
    },
    {
        "pmid": "11095261",
        "target": "[\"Span: BCL2 | Label: Gene\", \"Span: intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg | Label: Dosage\"]",
        "text": "[Title]: Chemosensitisation of malignant melanoma by BCL2 antisense therapy.\n[Abstract]: BACKGROUND: Chemoresistance of malignant melanoma has been linked to expression of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) and dacarbazine in patients with advanced malignant melanoma expressing BCL2. METHODS: In a within-patient dose-escalation protocol, 14 patients with advanced malignant melanoma were given augmerosen intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (total doses up to 1000 mg/m2 per cycle). Toxicity was scored by common toxicity criteria. Plasma augmerosen concentrations were assayed by high-performance liquid chromatography. In serial tumour biopsy samples, BCL2 protein concentrations were measured by western blotting and tumour-cell apoptosis was assessed. FINDINGS: The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia was common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abnormalities that resolved within 1 week. Steady-state plasma concentrations of augmerosen were attained within 24 h, and increased with administered dose. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment. Six patients have shown antitumour responses (one complete, two partial, three minor). The estimated median survival of all patients now exceeds 12 months. INTERPRETATION: Systemic administration of augmerosen downregulated the target BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment of patients with resistant neoplasms.\n[Drug-Disease]: augmerosen - melanoma"
    },
    {
        "pmid": "11099628",
        "target": "[\"Span: infants | Label: Age\", \"Span: 0.80 mg/kg/day | Label: Dosage\", \"Span: 0.72 mg/kg/day | Label: Dosage\"]",
        "text": "[Title]: Effects of cisapride on corrected QT interval, heart rate, and rhythm in infants undergoing polysomnography.\n[Abstract]: OBJECTIVE: To evaluate the effects of cisapride, a prokinetic gastrointestinal drug, on the electrocardiographic QT interval, heart rate, and rhythm in infants during routine 8-hour polysomnography. Reported electrocardiogram (ECG) and rhythm disturbances in a small number of patients with the use of cisapride provided the impetus for this prospective study. STUDY DESIGN: Two hundred fifty-two infants born at term were enrolled. Of these, 134 were on cisapride therapy for suspected gastroesophageal reflux and 118 were not on cisapride and served as controls. Cisapride-treated and control infants were from the outset divided into 3 age groups; group 1: under 3 months of age; group 2: between 3 and 6 months of age; and group 3: >6 months of age. Continuous ECG bipolar limb lead I recording, saturation monitoring, and electroencephalography were conducted. QT intervals and heart rate were measured at hourly intervals. RESULTS: Cisapride doses were: group 1 mean, 0.80 mg/kg/day (range: 0.38-1.55); group 2 mean, 0.80 mg/kg/day (range: 0. 23-1.38); and group 3 mean, 0.72 mg/kg/day (range: 0.32-1.41). Heart rate was higher in the younger infants, with a gradual decrease with age. No difference in heart rate was detected between the cisapride and control groups. The QTc interval in patients in group 1 was statistically longer than the controls, when applying both Bazett's and Hodges' formulae for QT correction. The other age groups did not differ. No arrhythmia or atrioventricular conduction abnormalities were observed. CONCLUSION: Infants under 3 months of age on cisapride treatment had significantly longer QTc intervals (with Bazett's formula, the 98th percentile was 504 ms in the cisapride group vs 447 ms in controls). The clinical significance and risk of the increased QTc interval in these infants are unclear and need further evaluation and risk stratification. Meanwhile, cisapride should be judiciously prescribed in infants <3 months of age.\n[Drug-Disease]: cisapride - gastroesophageal reflux"
    },
    {
        "pmid": "11101185",
        "target": "[\"Span: aerosol 88 microg BID | Label: Dosage\"]",
        "text": "[Title]: Fluticasone propionate versus zafirlukast: effect in patients previously receiving inhaled corticosteroid therapy.\n[Abstract]: BACKGROUND: The use of inhaled corticosteroids compared with leukotriene modifying drugs in the treatment of persistent asthma has not been extensively studied. OBJECTIVE: To compare the efficacy and safety of a low dose of fluticasone propionate (FP) and zafirlukast in patients previously maintained on inhaled corticosteroids. METHODS: Patients (> or = 12 years old; FEV1 = 60% to 85% of predicted) with persistent asthma who were previously treated with low doses of triamcinolone acetonide (TAA) 400 to 800 microg/day or beclomethasone dipropionate (BDP) 168 to 336 microg/day were randomized to treatment with FP aerosol 88 microg BID (FP, n = 221) or zafirlukast 20 mg BID (n = 216) over 6 weeks. RESULTS: Treatment with FP significantly increased the mean change at endpoint (the last post-baseline observation) in FEV1 (0.22 L versus 0.03 L, P < .001), morning PEF (17.8 versus 3.1 L/min, P = .004), evening PEF (16.7 versus 2.6 L/min, P = .002), the percentage of symptom-free days (16.2 versus 7.1%, P = .007), and the percentage of rescue-free days (23.4 versus 9.3%, P < .001), and significantly decreased rescue albuterol use (-0.66 puffs/day versus an increase of 0.27 puffs/day, P < .001) and combined symptom scores (-0.13 versus an increase of 0.08, P < .001) compared with zafirlukast. Treatment with FP maintained the percentage of awakening-free nights (-1.0 +/- 1.0); in contrast, treatment with zafirlukast reduced the percentage of awakening-free nights (-9.0 +/- 1.6, P < .001). A clinically meaningful difference (change of > or = 0.5; P < .001) was observed between FP and zafirlukast in the Asthma Quality of Life Questionnaire (AQLQ) global score and for each domain score except activity limitation (change of 0.3, P < .001). Significantly more patients in the zafirlukast group experienced an asthma exacerbation (n = 14) compared with FP-treated patients (n = 5, P = .035). Patients in the zafirlukast group were significantly more likely to be withdrawn due to lack of efficacy (P < .001). CONCLUSION: Switching patients from low doses of inhaled corticosteroids to a lower total microgram dose of FP improves pulmonary function, asthma symptoms, and quality of life, while switching to the leukotriene receptor antagonist zafirlukast may result in worsening of asthma control. This was indicated by the significant number of zafirlukast-treated patients who were dropped from the study due to lack of efficacy within 6 weeks of discontinuing inhaled corticosteroids.\n[Drug-Disease]: fluticasone propionate - asthma"
    },
    {
        "pmid": "16275125",
        "target": "[]",
        "text": "[Title]: Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study.\n[Abstract]: According to recent epidemiological data in Japan, stroke affects roughly 5.3 males and 3.9 females per 1000 person-years and is the third leading cause of mortality. At present, management strategies for secondary prevention of stroke include aggressive treatment of cardiovascular risk factors (i.e., hypertension, smoking cessation, etc.). Antiplatelet drugs in Japan, namely aspirin and cilostazol, are utilized regularly for the prevention of secondary stroke. While aspirin is beneficial for a wide range of cardiovascular endpoints, including total and ischemic strokes, it is also associated with significantly increased risks for hemorrhagic infarction. Cilostazol, by contrast, has been shown to significantly reduce the risk of recurrent strokes without affecting the occurrence of intracranial hemorrhage. In the Cilostazol Stroke Prevention Study, a randomized double-blind, placebo-controlled trial involving more than 1000 Japanese patients, cilostazol was found to reduce the risk of secondary stroke by 41.7% compared with placebo, a statistically significant reduction (P = 0.015). The greatest risk reduction (43.4% in cilostazol versus placebo, P = 0.0373) was found in patients who initially had a lacunar infarction, suggesting that cilostazol has a specific effect against small-vessel disease. In addition, cilostazol achieved significant risk reductions on a number of combined endpoints (e.g., cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death), and was associated with benefits in intent-to-treat analyses. These findings indicate that cilostazol may have a role as a vascular neuroprotectant, but the clinical implications are limited by the fact that patients were randomized to placebo instead of aspirin, which is the standard of care.\n[Drug-Disease]: aspirin - cerebral infarction"
    },
    {
        "pmid": "16288118",
        "target": "[\"Span: women | Label: Gender\"]",
        "text": "[Title]: Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.\n[Abstract]: BACKGROUND: Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings. METHODS: Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. RESULTS: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk. CONCLUSIONS: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.\n[Drug-Disease]: tamoxifen - breast cancer"
    },
    {
        "pmid": "16332718",
        "target": "[\"Span: 60 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer.\n[Abstract]: BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-naive patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-naive gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.\n[Drug-Disease]: cisplatin - gastric cancer"
    },
    {
        "pmid": "16332718",
        "target": "[\"Span: 145 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer.\n[Abstract]: BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-naive patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-naive gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.\n[Drug-Disease]: paclitaxel - gastric cancer"
    },
    {
        "pmid": "16460482",
        "target": "[\"Span: 300 mg/day | Label: Dosage\"]",
        "text": "[Title]: Effect of the non-steroidal anti-inflammatory drug sulindac on colorectal adenomas of uncolectomized familial adenomatous polyposis.\n[Abstract]: BACKGROUND: The aim of the present study was to elucidate the effect of sulindac on uncolectomized familial adenomatous polyposis (FAP). METHODS: Seven FAP patients (SU group) without proctocolectomy were given sulindac 300 mg/day orally for 12 months. Six FAP patients without sulindac (non-SU group) served as controls. Colorectal lesions were assessed by protrusion index (no. radiolucent areas/cm(2); PI) under barium enema examination and non-polypoid lesion were assessed under chromoscopy prior to and at the end of the observation period. In the SU group, germline adenomatous polyposis coli (APC) mutation was determined by protein truncation test. RESULTS: In the SU group, PI decreased significantly in the distal colon (from 3.0 +/- 1.1 to 1.1 +/- 0.8/cm(2), P &lt; 0.02) and in the proximal colon (from 3.4 +/- 2.4 to 0.9 +/- 1.3/cm(2), P &lt; 0.02). The PI in the non-SU group slightly but significantly increased in the distal colon (from 1.0 +/- 0.8 to 1.2 +/- 0.9/cm(2); P &lt; 0.05) and it remained unchanged in the proximal colon (from 0.6 +/- 0.3 to 0.7 +/- 0.3/cm(2); P &gt; 0.05). Chromoscopy at the end of observation identified non-polypoid lesions in five patients in the SU group, whereas such lesions were not found in the non-SU group (71% vs 0%, P = 0.016). Decrease in PI was not different among distal APC mutation (exons 1-9), proximal APC mutation (exons 10-15) and negative mutation. CONCLUSION: Sulindac reduces colorectal adenomas of protruding type in uncolectomized FAP. The effect of sulindac may be unrelated to genotype of FAP.\n[Drug-Disease]: sulindac - adenomatous polyposis coli"
    },
    {
        "pmid": "16478812",
        "target": "[\"Span: 42-year-old | Label: Age\", \"Span: white | Label: Body Type\", \"Span: man | Label: Gender\", \"Span: severe major depression | Label: Comorbidity\"]",
        "text": "[Title]: Quetiapine for insomnia associated with refractory depression exacerbated by phenelzine.\n[Abstract]: OBJECTIVE: To report the successful treatment of phenelzine-associated insomnia with low-dose quetiapine in a patient with refractory depression. CASE SUMMARY: A 42-year-old white man with severe major depression unresponsive to selective serotonin-reuptake inhibitors, bupropion, and tricyclic antidepressants improved following treatment with the monoamine oxidase inhibitor (MAOI) phenelzine. Insomnia, present to a moderate degree prior to antidepressant therapy, worsened markedly following phenelzine treatment and failed to respond to diphenhydramine, temazepam, triazolam, clonazepam, zolpidem, or trazodone given at high therapeutic doses. Sleep disturbance resolved with low-dose (50 mg) adjunctive quetiapine, with no adverse effects. DISCUSSION: Major depression refractory to standard therapy is a common and serious condition. Some cases respond to MAOIs; however, orthostatic hypotension and insomnia frequently occur. Potentially serious MAOI interactions with psychotropic drugs have raised concerns about combining these agents. In this case, a failure of a number of other medications known to treat MAOI-associated insomnia safely prompted a trial of quetiapine. Despite the possibility that enhanced serotonergic activity might have resulted in serotonin syndrome, no adverse interactions between phenelzine and quetiapine were noted. The use of low-dose, once-daily quetiapine, along with its unique binding properties, may account for its increased safety in combination with phenelzine. CONCLUSIONS: This case illustrates that low-dose quetiapine may be an alternative treatment for phenelzine-associated insomnia. Further case reports are needed to establish the safety and effectiveness of combining these agents.\n[Drug-Disease]: quetiapine - insomnia"
    },
    {
        "pmid": "16553533",
        "target": "[\"Span: 6-12 years | Label: Age\", \"Span: 13-18 years | Label: Age\", \"Span: 200 mg/day | Label: Dosage\"]",
        "text": "[Title]: Drug concentration monitoring with tolerability and efficacy assessments during open-label, long-term sertraline treatment of children and adolescents.\n[Abstract]: OBJECTIVE: The aim of this study was to evaluate the long-term pharmacokinetics, safety, and efficacy of sertraline in children and adolescents with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). METHOD: After 42-day initial treatment and 9-day withdrawal phases, children (6-12 years, n = 16) and adolescents (13-18 years, n = 27) entered a 24-week open-label phase, with sertraline titrated to 200 mg/day. Blood samples for plasma sertraline and N-desmethylsertraline levels were taken at the beginning of the 24-week phase and at weeks 1, 4, 8, 12, and 24. Efficacy and safety data were also collected. RESULTS: Mean maximum daily dose at endpoint was 157 +/- 49 mg. For female and male children, mean sertraline/N-desmethylsertraline concentrations normalized to a 200-mg dose were 85.0/160 ng/mL (n = 8) and 79.3/134 ng/mL (n = 8), respectively, and for female and male adolescents, 70.5/109 ng/mL (n = 16) and 76.3/120 ng/mL (n = 8). No significant age or gender effects or age-by-gender interactions were observed in sertraline values. Mean sertraline plasma concentrations normalized for dose and body weight did not differ significantly by age or gender. Three (3) patients (7%) discontinued owing to adverse events. In patients with OCD (n = 10), improvements were observed in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p = 0.029) and National Institute of Mental Health (NIMH) Global Obsessive Compulsive Scale (OCS) (p = 0.01). In MDD patients (n = 32), Clinical Global Impression (CGI) Severity (p = 0.002) and Improvement (p = 0.011) improved. CONCLUSIONS: Long-term treatment of MDD and OCD with sertraline up to 200 mg/day in children and adolescents results in dose-normalized plasma concentrations comparable to those seen in adults. Sertraline was generally well tolerated, and patients demonstrated clinical improvement over 24 weeks of treatment.\n[Drug-Disease]: Sertraline - MDD"
    },
    {
        "pmid": "16553533",
        "target": "[\"Span: 6-12 years | Label: Age\", \"Span: 13-18 years | Label: Age\", \"Span: 200 mg/day | Label: Dosage\"]",
        "text": "[Title]: Drug concentration monitoring with tolerability and efficacy assessments during open-label, long-term sertraline treatment of children and adolescents.\n[Abstract]: OBJECTIVE: The aim of this study was to evaluate the long-term pharmacokinetics, safety, and efficacy of sertraline in children and adolescents with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). METHOD: After 42-day initial treatment and 9-day withdrawal phases, children (6-12 years, n = 16) and adolescents (13-18 years, n = 27) entered a 24-week open-label phase, with sertraline titrated to 200 mg/day. Blood samples for plasma sertraline and N-desmethylsertraline levels were taken at the beginning of the 24-week phase and at weeks 1, 4, 8, 12, and 24. Efficacy and safety data were also collected. RESULTS: Mean maximum daily dose at endpoint was 157 +/- 49 mg. For female and male children, mean sertraline/N-desmethylsertraline concentrations normalized to a 200-mg dose were 85.0/160 ng/mL (n = 8) and 79.3/134 ng/mL (n = 8), respectively, and for female and male adolescents, 70.5/109 ng/mL (n = 16) and 76.3/120 ng/mL (n = 8). No significant age or gender effects or age-by-gender interactions were observed in sertraline values. Mean sertraline plasma concentrations normalized for dose and body weight did not differ significantly by age or gender. Three (3) patients (7%) discontinued owing to adverse events. In patients with OCD (n = 10), improvements were observed in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p = 0.029) and National Institute of Mental Health (NIMH) Global Obsessive Compulsive Scale (OCS) (p = 0.01). In MDD patients (n = 32), Clinical Global Impression (CGI) Severity (p = 0.002) and Improvement (p = 0.011) improved. CONCLUSIONS: Long-term treatment of MDD and OCD with sertraline up to 200 mg/day in children and adolescents results in dose-normalized plasma concentrations comparable to those seen in adults. Sertraline was generally well tolerated, and patients demonstrated clinical improvement over 24 weeks of treatment.\n[Drug-Disease]: Sertraline - OCD"
    },
    {
        "pmid": "16598518",
        "target": "[\"Span: aged between 30 and 70 | Label: Age\", \"Span: BMI = 25-30 kg/m2 | Label: Body Type\"]",
        "text": "[Title]: After myocardial infarction carvedilol improves insulin resistance compared to metoprolol.\n[Abstract]: PRINCIPLES: Both carvedilol and metoprolol have cardioprotective effects and decrease infarct size in myocardium. We compared effects of carvedilol and metoprolol on insulin resistance and serum lipid levels after myocardial infarction. METHODS: Fifty-nine patients aged between 30 and 70 and BMI = 25-30 kg/m2, who were diagnosed with myocardial infarction with ST segment elevation, were considered to be eligible for the study. Patients were randomly allocated to two different therapy protocols. Metoprolol 100 mg bid or carvedilol 25 mg bid was added to their standardized therapy regimen. Baseline to week 4 and 12, fasting blood glucose, serum lipid profile, BMI, C-peptide, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. RESULTS: After 12 weeks of metoprolol therapy HOMA-IR, insulin and C-peptide levels were significantly higher (p &lt; 0.05 for all) and total cholesterol and triglyceride levels decreased significantly (p &lt; 0.05 for all) compared to baseline. After 12 weeks of carvedilol therapy HOMA-IR, insulin and C-peptide (p &lt; 0.05 for all), total cholesterol and triglyceride (p = 0.001 for all) decreased significantly compared to baseline. Carvedilol provided more decrease in total cholesterol and LDL levels than metoprolol (p = 0.043 and p = 0.021, respectively). CONCLUSIONS: In patients after myocardial infarction, carvedilol added to background therapy improved insulin resistance and lipid profile.\n[Drug-Disease]: carvedilol - myocardial infarction"
    },
    {
        "pmid": "16598518",
        "target": "[\"Span: aged between 30 and 70 | Label: Age\", \"Span: BMI = 25-30 kg/m2 | Label: Body Type\"]",
        "text": "[Title]: After myocardial infarction carvedilol improves insulin resistance compared to metoprolol.\n[Abstract]: PRINCIPLES: Both carvedilol and metoprolol have cardioprotective effects and decrease infarct size in myocardium. We compared effects of carvedilol and metoprolol on insulin resistance and serum lipid levels after myocardial infarction. METHODS: Fifty-nine patients aged between 30 and 70 and BMI = 25-30 kg/m2, who were diagnosed with myocardial infarction with ST segment elevation, were considered to be eligible for the study. Patients were randomly allocated to two different therapy protocols. Metoprolol 100 mg bid or carvedilol 25 mg bid was added to their standardized therapy regimen. Baseline to week 4 and 12, fasting blood glucose, serum lipid profile, BMI, C-peptide, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. RESULTS: After 12 weeks of metoprolol therapy HOMA-IR, insulin and C-peptide levels were significantly higher (p &lt; 0.05 for all) and total cholesterol and triglyceride levels decreased significantly (p &lt; 0.05 for all) compared to baseline. After 12 weeks of carvedilol therapy HOMA-IR, insulin and C-peptide (p &lt; 0.05 for all), total cholesterol and triglyceride (p = 0.001 for all) decreased significantly compared to baseline. Carvedilol provided more decrease in total cholesterol and LDL levels than metoprolol (p = 0.043 and p = 0.021, respectively). CONCLUSIONS: In patients after myocardial infarction, carvedilol added to background therapy improved insulin resistance and lipid profile.\n[Drug-Disease]: metoprolol - myocardial infarction"
    },
    {
        "pmid": "1659980",
        "target": "[\"Span: 4 mg/kg | Label: Dosage\"]",
        "text": "[Title]: [Comparison of the antiemetic effectiveness of granisetron and alizapride plus dexamethasone in cytostatic therapy].\n[Abstract]: In a randomized single-blind international multicentre trial, two antiemetic regimens were compared in 115 oncology patients undergoing chemotherapy for the first time (cisplatin greater than 15 mg/m2, or ifosfamide greater than 1200 mg/m2 or etoposide greater than 120 mg/m2). One group received granisetron, a 5-hydroxytryptamine type-3-receptor antagonist, 40 micrograms/kg alone intravenously before chemotherapy, with, if necessary, up to two further doses daily of 40 micrograms/kg. The second group received a combination of alizapride plus dexamethasone (4 mg/kg alizapride and 8 mg/kg dexamethasone before chemotherapy, repeated, if necessary, after 4 and 8 hours up to two additional doses). There was good antiemetic efficacy (a maximum of one episode of vomiting in 24 hours = \"major efficacy\") in 50 of 62 patients (80.7%) in the granisetron group, and in 37 out of 53 (69.8%) of those treated with alizapride and dexamethasone; failure of antiemetic therapy occurred in 4.8% (granisetron) and 15.1% (combination) of patients. For the first day of each 5-day chemotherapy cycle, there was a higher rate of excellent antiemetic efficacy (no or only mild nausea, and no vomiting) with granisetron (90.3% vs 69.8%, P less than 0.006). The frequency (29% vs 32%) and nature of side effects (obstipation, diarrhoea, headaches, anxiety, vertigo), the causes of which were not differentiated, were similar. No extrapyramidal reactions occurred with granisetron. Of the 62 patients treated with granisetron, 47 did not require any further granisetron after the single daily prophylactic dose.\n[Drug-Disease]: alizapride - vomiting"
    },
    {
        "pmid": "1659980",
        "target": "[\"Span: 8 mg/kg | Label: Dosage\"]",
        "text": "[Title]: [Comparison of the antiemetic effectiveness of granisetron and alizapride plus dexamethasone in cytostatic therapy].\n[Abstract]: In a randomized single-blind international multicentre trial, two antiemetic regimens were compared in 115 oncology patients undergoing chemotherapy for the first time (cisplatin greater than 15 mg/m2, or ifosfamide greater than 1200 mg/m2 or etoposide greater than 120 mg/m2). One group received granisetron, a 5-hydroxytryptamine type-3-receptor antagonist, 40 micrograms/kg alone intravenously before chemotherapy, with, if necessary, up to two further doses daily of 40 micrograms/kg. The second group received a combination of alizapride plus dexamethasone (4 mg/kg alizapride and 8 mg/kg dexamethasone before chemotherapy, repeated, if necessary, after 4 and 8 hours up to two additional doses). There was good antiemetic efficacy (a maximum of one episode of vomiting in 24 hours = \"major efficacy\") in 50 of 62 patients (80.7%) in the granisetron group, and in 37 out of 53 (69.8%) of those treated with alizapride and dexamethasone; failure of antiemetic therapy occurred in 4.8% (granisetron) and 15.1% (combination) of patients. For the first day of each 5-day chemotherapy cycle, there was a higher rate of excellent antiemetic efficacy (no or only mild nausea, and no vomiting) with granisetron (90.3% vs 69.8%, P less than 0.006). The frequency (29% vs 32%) and nature of side effects (obstipation, diarrhoea, headaches, anxiety, vertigo), the causes of which were not differentiated, were similar. No extrapyramidal reactions occurred with granisetron. Of the 62 patients treated with granisetron, 47 did not require any further granisetron after the single daily prophylactic dose.\n[Drug-Disease]: dexamethasone - vomiting"
    },
    {
        "pmid": "1659980",
        "target": "[\"Span: 40 micrograms/kg | Label: Dosage\"]",
        "text": "[Title]: [Comparison of the antiemetic effectiveness of granisetron and alizapride plus dexamethasone in cytostatic therapy].\n[Abstract]: In a randomized single-blind international multicentre trial, two antiemetic regimens were compared in 115 oncology patients undergoing chemotherapy for the first time (cisplatin greater than 15 mg/m2, or ifosfamide greater than 1200 mg/m2 or etoposide greater than 120 mg/m2). One group received granisetron, a 5-hydroxytryptamine type-3-receptor antagonist, 40 micrograms/kg alone intravenously before chemotherapy, with, if necessary, up to two further doses daily of 40 micrograms/kg. The second group received a combination of alizapride plus dexamethasone (4 mg/kg alizapride and 8 mg/kg dexamethasone before chemotherapy, repeated, if necessary, after 4 and 8 hours up to two additional doses). There was good antiemetic efficacy (a maximum of one episode of vomiting in 24 hours = \"major efficacy\") in 50 of 62 patients (80.7%) in the granisetron group, and in 37 out of 53 (69.8%) of those treated with alizapride and dexamethasone; failure of antiemetic therapy occurred in 4.8% (granisetron) and 15.1% (combination) of patients. For the first day of each 5-day chemotherapy cycle, there was a higher rate of excellent antiemetic efficacy (no or only mild nausea, and no vomiting) with granisetron (90.3% vs 69.8%, P less than 0.006). The frequency (29% vs 32%) and nature of side effects (obstipation, diarrhoea, headaches, anxiety, vertigo), the causes of which were not differentiated, were similar. No extrapyramidal reactions occurred with granisetron. Of the 62 patients treated with granisetron, 47 did not require any further granisetron after the single daily prophylactic dose.\n[Drug-Disease]: granisetron - vomiting"
    },
    {
        "pmid": "1660550",
        "target": "[]",
        "text": "[Title]: Angiotensin II does not acutely reverse the reduction of proteinuria by long-term ACE inhibition.\n[Abstract]: Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II levels were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.\n[Drug-Disease]: lisinopril - proteinuria"
    },
    {
        "pmid": "16611451",
        "target": "[\"Span: children | Label: Age\"]",
        "text": "[Title]: Does long-term chloramphenicol cause anaemia in Malawi?\n[Abstract]: Common clinical practice in many tropical paediatric departments is that chloramphenicol courses are limited to 2 weeks due to concerns about anaemia. However, this approach is not supported by current research and animal models. We used chloramphenicol for 6 weeks in 146 children with septic arthritis. All the children improved clinically. Most children were anaemic on presentation (mean haemoglobin [Hb] 8.43 SD 1.9), but the anaemia improved rapidly with clinical resolution of the infection and was maintained at 6 months after presentation (mean Hb 10.57 SD 1.86).\n[Drug-Disease]: chloramphenicol - septic arthritis"
    },
    {
        "pmid": "16618834",
        "target": "[\"Span: 30+/-8 years | Label: Age\", \"Span: 80 mg daily | Label: Dosage\"]",
        "text": "[Title]: Effect of low-density lipoprotein cholesterol on angiotensin II sensitivity: a randomized trial with fluvastatin.\n[Abstract]: Increased angiotensin II (Ang II) sensitivity predisposes to hypertension and plaque instability. Raised low-density lipoprotein cholesterol (LDL-c) may increase Ang II sensitivity, but evidence in humans for this effect of LDL-c is limited. In 28, healthy, nonsmoking subjects, aged 30+/-8 years, with familial hypercholesterolemia, we determined the difference in infusion rate of Ang II and norepinephrine required to increase systolic blood pressure by 20 mm Hg (Pd-20) after 4 weeks of placebo and fluvastatin 80 mg daily in a randomized, double-blind, placebo-controlled, crossover study. Before infusions were started, fasting blood samples were taken to measure lipids. After 4 weeks of placebo, the mean LDL-c concentration was 6.3+/-1.4 mmol/L. The average decrease of LDL-c was 1.7+/-0.7 mmol/L after 4 weeks of fluvastatin (P&lt;0.001). The mean Pd-20 for Ang II increased by 1.28 ng/kg per minute (95% CI, 2.05 to 0.50; P=0.002) on fluvastatin, corresponding with a 26% decrease in Ang II sensitivity. Ang II sensitivity, however, remained increased compared with normocholesterolemic controls. The Pd-20 values for norepinephrine were unaffected by fluvastatin. The present study in healthy, young subjects with isolated hypercholesterolemia shows an increased sensitivity to Ang II that partly can be restored by LDL-c-lowering therapy. These findings indicate that LDL-c levels directly influence Ang II sensitivity.\n[Drug-Disease]: fluvastatin - hypercholesterolemia"
    },
    {
        "pmid": "16630771",
        "target": "[\"Span: 120 mg 3 times daily | Label: Dosage\", \"Span: mean age, 47.7 y | Label: Age\", \"Span: mean body mass index, 33 | Label: Body Type\"]",
        "text": "[Title]: A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.\n[Abstract]: BACKGROUND &amp; AIMS: Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease (NAFLD). We herein assessed the effect of orlistat in patients with NAFLD. METHODS: We performed a randomized, double-blind, placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients were randomized to receive either orlistat (120 mg 3 times daily for 6 months) or placebo. All patients participated in an identical behavioral weight loss program. All patients underwent monthly evaluation by abdominal US; liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters were monitored, and all patients underwent nutritional follow-up evaluation. Twenty-two patients underwent a second liver biopsy examination at the end of the study. RESULTS: Fifty-two patients were recruited and 44 (mean age, 47.7 y; mean body mass index, 33) completed the study. Serum glucose and insulin levels (P&lt;.03) were significantly higher in the orlistat group, which also presented a higher degree of fibrosis. Body mass index was reduced significantly in each group, with a nonsignificant difference between the groups. Serum alanine transaminase (ALT) levels decreased significantly in both groups, with an almost 2-fold reduction in the orlistat group (48% vs 26.4%). There was a statistically significant reversal of fatty liver by US only in the orlistat group (P&lt;.05). CONCLUSIONS: Orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction.\n[Drug-Disease]: orlistat - steatosis"
    },
    {
        "pmid": "16637862",
        "target": "[]",
        "text": "[Title]: Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.\n[Abstract]: Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b (n = 4) and pegylated interferon-alfa-2a (n = 2) for 24-48 weeks according to genotype with a dose of 50 or 135 mug/week respectively. All patients were given reduced ribavirin doses, initially 200-400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10-15 micromol/L. Interferon related side-effects were common, in one patient peg-alfa-2b was permanently reduced to 50 mug every 9-10 days with improvement in tolerance. Average ribavirin dose was 170-300 mg/day. Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood-transfusions were not needed. All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.\n[Drug-Disease]: iron - anaemia"
    },
    {
        "pmid": "16637862",
        "target": "[\"Span: 200-400 mg/day | Label: Dosage\"]",
        "text": "[Title]: Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.\n[Abstract]: Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b (n = 4) and pegylated interferon-alfa-2a (n = 2) for 24-48 weeks according to genotype with a dose of 50 or 135 mug/week respectively. All patients were given reduced ribavirin doses, initially 200-400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10-15 micromol/L. Interferon related side-effects were common, in one patient peg-alfa-2b was permanently reduced to 50 mug every 9-10 days with improvement in tolerance. Average ribavirin dose was 170-300 mg/day. Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood-transfusions were not needed. All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.\n[Drug-Disease]: ribavirin - chronic hepatitis C"
    },
    {
        "pmid": "16683970",
        "target": "[\"Span: Asian | Label: Body Type\"]",
        "text": "[Title]: Treatment with olanzapine, risperidone or typical antipsychotic drugs in Asian patients with schizophrenia.\n[Abstract]: OBJECTIVE: To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings. METHOD: In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline. RESULTS: At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p &lt; 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p &lt; 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p &lt; 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p &lt; 0.001). CONCLUSIONS: The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.\n[Drug-Disease]: olanzapine - schizophrenia"
    },
    {
        "pmid": "16683970",
        "target": "[\"Span: Asian | Label: Body Type\"]",
        "text": "[Title]: Treatment with olanzapine, risperidone or typical antipsychotic drugs in Asian patients with schizophrenia.\n[Abstract]: OBJECTIVE: To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings. METHOD: In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline. RESULTS: At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p &lt; 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p &lt; 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p &lt; 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p &lt; 0.001). CONCLUSIONS: The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.\n[Drug-Disease]: risperidone - schizophrenia"
    },
    {
        "pmid": "16763792",
        "target": "[\"Span: 1.2 mg/m2 | Label: Dosage\"]",
        "text": "[Title]: A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.\n[Abstract]: PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.\n[Drug-Disease]: bortezomib - malignancies"
    },
    {
        "pmid": "16763792",
        "target": "[\"Span: AUC = 6 | Label: Dosage\"]",
        "text": "[Title]: A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.\n[Abstract]: PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.\n[Drug-Disease]: carboplatin - malignancies"
    },
    {
        "pmid": "16763792",
        "target": "[\"Span: 135 mg/m2 | Label: Dosage\", \"Span: 175 mg/m2 | Label: Dosage\"]",
        "text": "[Title]: A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.\n[Abstract]: PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.\n[Drug-Disease]: paclitaxel - malignancies"
    },
    {
        "pmid": "16888694",
        "target": "[\"Span: young | Label: Age\"]",
        "text": "[Title]: [Side-effects of triamcinolone in young patients].\n[Abstract]: CASE REPORTS: Intravitreal triamcinolone is being increasingly employed for the treatment of macular diseases. We report two cases of intraocular pressure elevation and cataract formation after intravitreal triamcinolone therapy, and wonder if these complications are more likely when this agent is used in young patients. Intravitreal triamcinolone was injected into both eyes of the two young patients with chronic posterior and intermediate uveitis refractory to peribulbar and oral corticosteroid therapy. Chronic cystoid macular edema improved in both patients, however the intraocular pressure increased, requiring topical antihypertensive therapy, and this was followed by accelerated cataract formation. DISCUSSION: Young age and chronic inflammation could be associated with an intraocular pressure rise and subsequent cataract development after intravitreal triamcinolone.\n[Drug-Disease]: triamcinolone - Chronic cystoid macular edema"
    },
    {
        "pmid": "16888694",
        "target": "[\"Span: young | Label: Age\"]",
        "text": "[Title]: [Side-effects of triamcinolone in young patients].\n[Abstract]: CASE REPORTS: Intravitreal triamcinolone is being increasingly employed for the treatment of macular diseases. We report two cases of intraocular pressure elevation and cataract formation after intravitreal triamcinolone therapy, and wonder if these complications are more likely when this agent is used in young patients. Intravitreal triamcinolone was injected into both eyes of the two young patients with chronic posterior and intermediate uveitis refractory to peribulbar and oral corticosteroid therapy. Chronic cystoid macular edema improved in both patients, however the intraocular pressure increased, requiring topical antihypertensive therapy, and this was followed by accelerated cataract formation. DISCUSSION: Young age and chronic inflammation could be associated with an intraocular pressure rise and subsequent cataract development after intravitreal triamcinolone.\n[Drug-Disease]: triamcinolone - uveitis"
    },
    {
        "pmid": "16913436",
        "target": "[\"Span: male | Label: Gender\", \"Span: Lipidil Supra 160 mg/d | Label: Dosage\"]",
        "text": "[Title]: Effect of fenofibrate in combination with urate lowering agents in patients with gout.\n[Abstract]: BACKGROUND: To assess the efficacy of fenofibrate treatment in combination with urate lowering agents in patients with gout. METHODS: Fourteen male patients with chronic tophaceous or recurrent acute attacks of gout were evaluated in an open-label pilot study of the hypolipidemic agent, fenofibrate (Lipidil Supra 160 mg/d). Patients were stable on urate lowering agents (allopurinol or benzbromarone) for > or = three months without acute attack for the most recent one month before participating. All patients were being treated with established doses of urate lowering agents without modification throughout the study. Clinical and biochemical assessments including serum uric acid, creatinine, liver function test and fasting serum lipid were measured at (1) baseline (2) after two months of fenofibrate treatment and (3) two months after fenofibrate was withdrawn. RESULTS: Serum uric acid was lowered by 23% after two months of fenofibrate treatment (6.93 +/- 2.16 vs. 5.22 +/- 1.16 mg/dL; p = 0.016). Triglyceride levels were also reduced after fenofibrate treatment (p = 0.001). However, this effect was reversed after the withdrawal (p = 0.002) of the drug. Alkaline phosphatase was reduced after fenofibrate treatment (p = 0.006), but increased 21% after the withdrawal of the drug (p = 0.002). By contrast, serum levels of high density lipoprotein and creatinine were increased 9% (p = 0.018) and 12% (p = 0.006), respectively; however, both levels were significantly decreased to the baseline levels upon withdrawal of fenofibrate. CONCLUSIONS: Fenofibrate can effectively reduce uric acid levels in addition to its known hypolipidemic effect. Fenofibrate may be used as a potential urate lowering agent in patients with gout, especially in those with coexisting hyperlipidemia.\n[Drug-Disease]: Fenofibrate - gout"
    },
    {
        "pmid": "16913436",
        "target": "[\"Span: male | Label: Gender\", \"Span: Lipidil Supra 160 mg/d | Label: Dosage\"]",
        "text": "[Title]: Effect of fenofibrate in combination with urate lowering agents in patients with gout.\n[Abstract]: BACKGROUND: To assess the efficacy of fenofibrate treatment in combination with urate lowering agents in patients with gout. METHODS: Fourteen male patients with chronic tophaceous or recurrent acute attacks of gout were evaluated in an open-label pilot study of the hypolipidemic agent, fenofibrate (Lipidil Supra 160 mg/d). Patients were stable on urate lowering agents (allopurinol or benzbromarone) for > or = three months without acute attack for the most recent one month before participating. All patients were being treated with established doses of urate lowering agents without modification throughout the study. Clinical and biochemical assessments including serum uric acid, creatinine, liver function test and fasting serum lipid were measured at (1) baseline (2) after two months of fenofibrate treatment and (3) two months after fenofibrate was withdrawn. RESULTS: Serum uric acid was lowered by 23% after two months of fenofibrate treatment (6.93 +/- 2.16 vs. 5.22 +/- 1.16 mg/dL; p = 0.016). Triglyceride levels were also reduced after fenofibrate treatment (p = 0.001). However, this effect was reversed after the withdrawal (p = 0.002) of the drug. Alkaline phosphatase was reduced after fenofibrate treatment (p = 0.006), but increased 21% after the withdrawal of the drug (p = 0.002). By contrast, serum levels of high density lipoprotein and creatinine were increased 9% (p = 0.018) and 12% (p = 0.006), respectively; however, both levels were significantly decreased to the baseline levels upon withdrawal of fenofibrate. CONCLUSIONS: Fenofibrate can effectively reduce uric acid levels in addition to its known hypolipidemic effect. Fenofibrate may be used as a potential urate lowering agent in patients with gout, especially in those with coexisting hyperlipidemia.\n[Drug-Disease]: Fenofibrate - hyperlipidemia"
    },
    {
        "pmid": "1695298",
        "target": "[\"Span: 2.5-5.0 mg b.i.d. | Label: Dosage\", \"Span: men | Label: Gender\", \"Span: women | Label: Gender\", \"Span: 40 years and over | Label: Age\"]",
        "text": "[Title]: Multicenter study with isradipine and diuretics against atherosclerosis. US MIDAS Research Group.\n[Abstract]: Hypertension is a major risk factor for atherosclerosis. Although antihypertensive drug treatment can reduce morbidity and mortality from stroke, there is no consistent benefit on ischemic heart disease. It may be that subtle adverse effects of the drugs used in these clinical trials may have blunted the beneficial effects of treatment. Isradipine, a new calcium antagonist of the dihydropyridine class, is a potent antihypertensive drug with pronounced antiatherogenic properties, at least in animal studies. Thus, isradipine may be a suitable drug for assessing the efficacy of antihypertensive treatment in retarding the progression of atherosclerosis. The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a clinical trial to compare the efficacy of isradipine (2.5-5.0 mg b.i.d.) and hydrochlorothiazide (12.5-25 mg b.i.d.) in retarding atherosclerosis in carotid arteries. Carotid atherosclerosis will be monitored using B-mode ultrasonography. The sample size is 800 men and women aged 40 years and over. The power of the design is 90% to detect a 30% difference in the progression of plaque size between the isradipine- and hydrochlorothiazide-treated groups with a significance level of 5% (p = 0.05).\n[Drug-Disease]: isradipine - Hypertension"
    },
    {
        "pmid": "1695298",
        "target": "[\"Span: 2.5-5.0 mg b.i.d. | Label: Dosage\", \"Span: men | Label: Gender\", \"Span: women | Label: Gender\", \"Span: 40 years and over | Label: Age\"]",
        "text": "[Title]: Multicenter study with isradipine and diuretics against atherosclerosis. US MIDAS Research Group.\n[Abstract]: Hypertension is a major risk factor for atherosclerosis. Although antihypertensive drug treatment can reduce morbidity and mortality from stroke, there is no consistent benefit on ischemic heart disease. It may be that subtle adverse effects of the drugs used in these clinical trials may have blunted the beneficial effects of treatment. Isradipine, a new calcium antagonist of the dihydropyridine class, is a potent antihypertensive drug with pronounced antiatherogenic properties, at least in animal studies. Thus, isradipine may be a suitable drug for assessing the efficacy of antihypertensive treatment in retarding the progression of atherosclerosis. The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a clinical trial to compare the efficacy of isradipine (2.5-5.0 mg b.i.d.) and hydrochlorothiazide (12.5-25 mg b.i.d.) in retarding atherosclerosis in carotid arteries. Carotid atherosclerosis will be monitored using B-mode ultrasonography. The sample size is 800 men and women aged 40 years and over. The power of the design is 90% to detect a 30% difference in the progression of plaque size between the isradipine- and hydrochlorothiazide-treated groups with a significance level of 5% (p = 0.05).\n[Drug-Disease]: isradipine - retarding atherosclerosis"
    },
    {
        "pmid": "16960176",
        "target": "[\"Span: MBL-2 allele variants | Label: Gene\", \"Span: infants | Label: Age\"]",
        "text": "[Title]: Synergy between mannose-binding lectin gene polymorphisms and supplementation with vitamin A influences susceptibility to HIV infection in infants born to HIV-positive mothers.\n[Abstract]: BACKGROUND: Mannose-binding lectin (MBL-2) allele variants are associated with deficiencies in innate immunity and have been found to be correlated with HIV infection in adults and children. OBJECTIVE: We tested whether MBL-2 variants among infants born to HIV-positive mothers have an increased susceptibility to HIV. DESIGN: MBL-2 allele variants were measured among 225 infants born to HIV-positive mothers enrolled in a trial in Durban, South Africa. Mothers of 108 infants were randomly assigned to receive vitamin A and beta-carotene supplementation and 117 to receive placebo. Infants were followed with regular HIV tests to determine rates of mother-to-child HIV transmission. RESULTS: A high proportion of infants were either homozygous (10.7%) or heterozygous (32.4%) for MBL-2 variants. MBL-2 variants within the placebo arm were associated with an increased risk of HIV transmission (odds ratio: 3.09; 95% CI: 1.21, 7.86); however, MBL-2 variants within the supplementation arm were not associated with an increased risk of transmission (P = 0.04; test of interaction). Among infants with MBL-2 variants, supplementation was associated with a decreased risk of HIV transmission (odds ratio: 0.37; 95% CI: 0.15, 0.91). CONCLUSION: We observed what appears to be a gene-environment interaction between MBL-2 variants and an intervention with vitamin A plus beta-carotene that is relevant to mother-to-child HIV transmission.\n[Drug-Disease]: vitamin A - HIV infection"
    },
    {
        "pmid": "16960176",
        "target": "[\"Span: MBL-2 allele variants | Label: Gene\", \"Span: infants | Label: Age\"]",
        "text": "[Title]: Synergy between mannose-binding lectin gene polymorphisms and supplementation with vitamin A influences susceptibility to HIV infection in infants born to HIV-positive mothers.\n[Abstract]: BACKGROUND: Mannose-binding lectin (MBL-2) allele variants are associated with deficiencies in innate immunity and have been found to be correlated with HIV infection in adults and children. OBJECTIVE: We tested whether MBL-2 variants among infants born to HIV-positive mothers have an increased susceptibility to HIV. DESIGN: MBL-2 allele variants were measured among 225 infants born to HIV-positive mothers enrolled in a trial in Durban, South Africa. Mothers of 108 infants were randomly assigned to receive vitamin A and beta-carotene supplementation and 117 to receive placebo. Infants were followed with regular HIV tests to determine rates of mother-to-child HIV transmission. RESULTS: A high proportion of infants were either homozygous (10.7%) or heterozygous (32.4%) for MBL-2 variants. MBL-2 variants within the placebo arm were associated with an increased risk of HIV transmission (odds ratio: 3.09; 95% CI: 1.21, 7.86); however, MBL-2 variants within the supplementation arm were not associated with an increased risk of transmission (P = 0.04; test of interaction). Among infants with MBL-2 variants, supplementation was associated with a decreased risk of HIV transmission (odds ratio: 0.37; 95% CI: 0.15, 0.91). CONCLUSION: We observed what appears to be a gene-environment interaction between MBL-2 variants and an intervention with vitamin A plus beta-carotene that is relevant to mother-to-child HIV transmission.\n[Drug-Disease]: beta-carotene - HIV infection"
    },
    {
        "pmid": "16978400",
        "target": "[\"Span: 50 mg daily | Label: Dosage\"]",
        "text": "[Title]: Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.\n[Abstract]: BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for &gt; or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade &gt; or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.\n[Drug-Disease]: cyclophosphamide - breast cancer"
    },
    {
        "pmid": "16978400",
        "target": "[\"Span: 2.5 mg | Label: Dosage\"]",
        "text": "[Title]: Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.\n[Abstract]: BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for &gt; or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade &gt; or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.\n[Drug-Disease]: MTX - breast cancer"
    },
    {
        "pmid": "17008537",
        "target": "[\"Span: 71% were nonmutated for the immunoglobulin heavy-chain variable region gene | Label: Gene\", \"Span: young | Label: Age\", \"Span: older (&gt;70 years) | Label: Age\", \"Span: 600 mg/m2 | Label: Dosage\"]",
        "text": "[Title]: Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia.\n[Abstract]: Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (&gt;70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.\n[Drug-Disease]: cyclophosphamide - chronic lymphocytic leukemia"
    },
    {
        "pmid": "17008537",
        "target": "[\"Span: 71% were nonmutated for the immunoglobulin heavy-chain variable region gene | Label: Gene\", \"Span: young | Label: Age\", \"Span: older (&gt;70 years) | Label: Age\", \"Span: 2 mg/m2 | Label: Dosage\"]",
        "text": "[Title]: Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia.\n[Abstract]: Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (&gt;70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.\n[Drug-Disease]: pentostatin - chronic lymphocytic leukemia"
    },
    {
        "pmid": "17016601",
        "target": "[\"Span: Thymidylate synthase [TS, (EC 2.1.1.45)] | Label: Gene\"]",
        "text": "[Title]: Genotype of thymidylate synthase likely to affect efficacy of adjuvant 5-FU based chemotherapy in colon cancer.\n[Abstract]: Thymidylate synthase [TS, (EC 2.1.1.45)] is the target enzyme in 5-fluorouracil treatment. Recently, the DNA polymorphism of this gene has been found to affect TS protein (pTS) expression. However, no prospective studies have been performed to evaluate the influence of this polymorphism on the clinical efficacy of 5-FU-based adjuvant chemotherapy for colorectal cancer (CRC). In this study, we investigated the genotype of TS and immunopathological findings of pTS in 161 colon cancer specimens from patients who were registered in a prospective adjuvant immunochemotherapy clinical trial. The clinical course and prognosis of these patients were checked after the study had been completed. This study comprised 11 (6.8%) cases of 2R/2R, 40 (24.8%) of 2R/3R, and 110 (68.3%) of 3R/3R genotypes. All of the 2R/2R cases were still alive at the time of analysis although this finding was not statistically significant. In this prospective examination on a randomized controlled trial, the patients with colon cancer of the 2R/2R TS genotype may be good responders to 5-FU-based adjuvant chemotherapy. Furthermore, differences in the proportions of the TS genotypes can account for the interracial differences in the adverse effects of 5-FU-based chemotherapy.\n[Drug-Disease]: 5-FU - colon cancer"
    },
    {
        "pmid": "17054409",
        "target": "[\"Span: P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene | Label: Gene\", \"Span: Chinese | Label: Body Type\"]",
        "text": "[Title]: Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients.\n[Abstract]: P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene, plays an important role in absorption and distribution of drugs. The brain entry of risperidone and 9-OH-risperidone is greatly limited by P-glycoprotein, which implies that the functional polymorphisms of ABCB1 in humans may be a factor contributing to the variability in response to risperidone. The present study was therefore designed to examine whether polymorphisms of the ABCB1 gene are related to therapeutic response. For this purpose, 130 Chinese schizophrenia patients undergoing risperidone treatment were recruited. Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 8 weeks after the treatment. Association tests between genotypes and percentage improvement in total BPRS scores were performed using analyses of variance. Our results show that genotyping C1236T may help to predict the efficacy of risperidone treatment on the basis that patients with the TT genotype showed greater improvement than those with other genotypes on the overall BPRS (F = 3.967, p = 0.021), while other polymorphisms, including rs13233308, G2677T/A and C3435T polymorphism, did not show any association with the response to risperidone. These results showed suggestive evidence that genetic variation in the ABCB1 gene may influence the individual response to risperidone.\n[Drug-Disease]: risperidone - schizophrenia"
    },
    {
        "pmid": "17060545",
        "target": "[\"Span: adult | Label: Age\", \"Span: 2 microg/mL | Label: Dosage\", \"Span: 15 microg/mL | Label: Dosage\"]",
        "text": "[Title]: High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.\n[Abstract]: BACKGROUND: Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 microg/mL. METHODS: A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC (>=2 vs <2 microg/mL) for efficacy and high vs low trough (>=15 vs <15 microg/mL) for nephrotoxicity analyses. RESULTS: Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents. CONCLUSIONS: High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 microg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 microg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.\n[Drug-Disease]: vancomycin - pneumonia"
    },
    {
        "pmid": "17060545",
        "target": "[\"Span: adult | Label: Age\", \"Span: 2 microg/mL | Label: Dosage\", \"Span: 15 microg/mL | Label: Dosage\"]",
        "text": "[Title]: High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.\n[Abstract]: BACKGROUND: Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 microg/mL. METHODS: A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC (>=2 vs <2 microg/mL) for efficacy and high vs low trough (>=15 vs <15 microg/mL) for nephrotoxicity analyses. RESULTS: Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents. CONCLUSIONS: High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 microg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 microg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.\n[Drug-Disease]: vancomycin - Staphylococcus aureus infections"
    },
    {
        "pmid": "17060545",
        "target": "[\"Span: adult | Label: Age\", \"Span: 2 microg/mL | Label: Dosage\", \"Span: 15 microg/mL | Label: Dosage\"]",
        "text": "[Title]: High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity.\n[Abstract]: BACKGROUND: Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 microg/mL. METHODS: A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC (>=2 vs <2 microg/mL) for efficacy and high vs low trough (>=15 vs <15 microg/mL) for nephrotoxicity analyses. RESULTS: Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents. CONCLUSIONS: High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 microg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 microg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.\n[Drug-Disease]: vancomycin - bacteremia"
    },
    {
        "pmid": "17069549",
        "target": "[\"Span: aged 6-14 years | Label: Age\"]",
        "text": "[Title]: Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study.\n[Abstract]: OBJECTIVE: This pilot study examined the effects of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with pervasive developmental disorders (PDD). METHOD: Twelve children (aged 6-14 years) with PDD accompanied by ADHD symptoms entered a 10-week open-label study with atomoxetine (1.19 +/- 0.41 mg/kg/day). Response was assessed by using parent and clinician rating scales with change in the ADHD-Rating Scale (ADHDRS) as primary outcome measure. RESULTS: Atomoxetine reduced ADHD-symptoms as measured by the ADHDRS (44% decrease vs. baseline, p &lt; 0.003), the Conners' Parent Rating Scale-R:S (CPRS-R) (25% in the subscale \"Cognitive Problems,\" p &lt; 0.028; 32% in \"Hyperactivity,\" p &lt; 0.030; and 23% in \"ADHD index,\" p &lt; 0.023). We found a reduction of 21% (p = 0.071) for changes in the subscale \"Hyperactivity\" of the Aberrant Behavior Checklist (ABC). No change was found in any of the other ABC subscales, nor in the subscale \"Oppositional\" of the CPRS-R. Five patients (42%) discontinued because of side effects. Gastrointestinal symptoms, irritability, sleep problems, and fatigue were the most frequent side effects. CONCLUSIONS: These preliminary findings indicate that atomoxetine may be a promising new agent in the treatment of ADHD symptoms in children with PDD. However, children with PDD may have a higher vulnerability for some of the known side-effects of atomoxetine.\n[Drug-Disease]: atomoxetine - ADHD"
    },
    {
        "pmid": "17069549",
        "target": "[\"Span: aged 6-14 years | Label: Age\"]",
        "text": "[Title]: Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study.\n[Abstract]: OBJECTIVE: This pilot study examined the effects of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with pervasive developmental disorders (PDD). METHOD: Twelve children (aged 6-14 years) with PDD accompanied by ADHD symptoms entered a 10-week open-label study with atomoxetine (1.19 +/- 0.41 mg/kg/day). Response was assessed by using parent and clinician rating scales with change in the ADHD-Rating Scale (ADHDRS) as primary outcome measure. RESULTS: Atomoxetine reduced ADHD-symptoms as measured by the ADHDRS (44% decrease vs. baseline, p &lt; 0.003), the Conners' Parent Rating Scale-R:S (CPRS-R) (25% in the subscale \"Cognitive Problems,\" p &lt; 0.028; 32% in \"Hyperactivity,\" p &lt; 0.030; and 23% in \"ADHD index,\" p &lt; 0.023). We found a reduction of 21% (p = 0.071) for changes in the subscale \"Hyperactivity\" of the Aberrant Behavior Checklist (ABC). No change was found in any of the other ABC subscales, nor in the subscale \"Oppositional\" of the CPRS-R. Five patients (42%) discontinued because of side effects. Gastrointestinal symptoms, irritability, sleep problems, and fatigue were the most frequent side effects. CONCLUSIONS: These preliminary findings indicate that atomoxetine may be a promising new agent in the treatment of ADHD symptoms in children with PDD. However, children with PDD may have a higher vulnerability for some of the known side-effects of atomoxetine.\n[Drug-Disease]: atomoxetine - developmental disorders"
    },
    {
        "pmid": "17069551",
        "target": "[\"Span: autistic disorder | Label: Comorbidity\", \"Span: ages 7 and 18 years | Label: Age\", \"Span: 4-8 mg | Label: Dosage\"]",
        "text": "[Title]: Ramelteon for insomnia in two youths with autistic disorder.\n[Abstract]: OBJECTIVE: The aim of this study was to report preliminary data on the effectiveness and tolerability of ramelteon for the treatment of insomnia in youth with autistic disorder (autism). METHOD: Two youths, ages 7 and 18 years, with autism and significant insomnia characterized by problems with sleep onset and maintenance received an open-label trial of ramelteon (4-8 mg) over a duration of 16-18 weeks. RESULTS: Target symptoms of delayed sleep onset and/or frequent nocturnal awakening improved significantly, as determined by Clinical Global Impressions-Improvement (CGI-I) scale ratings of either \"much improved\" or \"very much improved.\" Ramelteon was well tolerated. No daytime sedation was reported. CONCLUSIONS: This case report illustrates the potential effectiveness and tolerability of ramelteon for sleep disturbances in 2 patients with autism. Further research is needed to verify its safety, tolerability, and efficacy in children and adolescents with autism.\n[Drug-Disease]: ramelteon - insomnia"
    },
    {
        "pmid": "17111685",
        "target": "[]",
        "text": "[Title]: [The effectiveness of carvedilol in heart failure].\n[Abstract]: BACKGROUND: The third generation beta-blocker (carvedilol) is effective in reduction of hypertension, and of mortality and morbidity as a supplement to conventional drugs of heart failure therapies (diuretics, ACE inhibitors), based on randomized controlled trials and retrospective analysis. OBJECTIVE: To analyse the efficacy of carvedilol in the treatment of heart failure with special focused on morbidity, mortality endpoints. METHODS: We assessed the multicenter, randomised, double-blind studies involving more than 150 patients (1995-2005) from MEDLINE database, in which carvedilol was used in the case of moderate to severe heart failure. We also present the results of health-economic publications (2000-2005). RESULTS: In U.S. Carvedilol Heart Failure Study (n 1096) the mortality declined by 65% (3.2% vs. 7.8%; p &lt;0.001) with carvedilol vs. placebo, while the cardiovascular hospitalization decline was 27% (14.1% vs. 19.6%; p = 0.036) in heart failure (LVEF &lt; or = 5%) applied together with the basic therapy (diuretic and ACE-inhibitor). In the COPERNICUS trial the efficacy of carvedilol was compared to placebo in the case of severe HF patients (LVEF &lt; 25%, n = 2889). The annual mortality risk declined by 35% (19.7% vs. 12.8%, 95% CI 19-48%, p = 0.00013) while the risk of mortality or any risk of hospitalisation by 24% (p = 0.00004) in the active group. The CAPRICORN study (LVEF &lt; or = 0%, n=1959) showed that carvedilol is efficacious in reduction of total (HR: 0.77; 95% CI 0.60-0.98; p = 0.031) and cardiovascular mortality (HR: 0.75; 95% CI 0.58-0.96; p = 0.024) as far as high-risk patients are concerned. CONCLUSION: The effectiveness of carvedilol is certified in reduction of mortality and hospitalization in the treatment of moderate-severe heart-failure as part of the combination therapy. The benefits of use of the drug are well measurable not only on the level of patients but on the suppliers and the financer as well, thanks to the decline of resource utilization.\n[Drug-Disease]: carvedilol - heart-failure"
    },
    {
        "pmid": "17175572",
        "target": "[\"Span: children | Label: Age\"]",
        "text": "[Title]: A placebo double-blind pilot study of dextromethorphan for problematic behaviors in children with autism.\n[Abstract]: We used a mixed group/single-case, double-blind, placebo-controlled, ABAB design to examine the safety and efficacy of the glutamate antagonist dextromethorphan for the treatment of problematic behaviors and core symptoms in eight children diagnosed with autism. All participants had increased levels of irritability at baseline as measured by the Aberrant Behavior Checklist, and demonstrated a wide variety of problematic behaviors. Group analyses revealed that dextromethorphan was equivalent to placebo in the treatment of problem behaviors and core symptoms. Analyses at the single-subject level demonstrated that three of the eight participants who had a behavioral profile consistent with attention-deficit hyperactivity disorder responded positively to dextromethorphan. Future research that employs a larger, more homogeneous sample is necessary to replicate the findings from this study.\n[Drug-Disease]: dextromethorphan - attention-deficit hyperactivity disorder"
    },
    {
        "pmid": "1725031",
        "target": "[]",
        "text": "[Title]: The effects of ramipril on glucose tolerance, insulin secretion, and insulin sensitivity in patients with hypertension.\n[Abstract]: To evaluate a possible influence of the angiotensin-converting enzyme inhibitor ramipril on glucose tolerance and insulin sensitivity, an oral glucose tolerance test (oGTT) and an euglycemic clamp were performed in 10 nonobese, nondiabetic patients with mild hypertension before and after treatment with ramipril for 14 days. Following ramipril treatment, systolic and diastolic blood pressures were significantly lower (152.5 +/- 10.6/97.5 +/- 4.3 vs. 136.5 +/- 18.9/79.5 +/- 16.4 mm Hg). Therapy with ramipril showed no influence on glucose tolerance (serum glucose of 106.8 +/- 32.8 vs. 109.1 +/- 33.9 mg/dl at 120 min during the oGTT), insulin secretion (53.0 +/- 45.7 vs. 41.1 +/- 10.6 microU/ml at 120 min), and insulin sensitivity (glucose infusion rate of 180.8 +/- 60.7 vs. 199.8 +/- 77.5 mg/m2/min after 3 h of clamp). In conclusion, short-term treatment of hypertension with ramipril has no influence on glucose metabolism in nondiabetic patients.\n[Drug-Disease]: ramipril - hypertension"
    },
    {
        "pmid": "17269997",
        "target": "[\"Span: children | Label: Age\", \"Span: young adults | Label: Age\", \"Span: 1.5-2.5 mg/kg/day | Label: Dosage\"]",
        "text": "[Title]: Efficacy and safety of thalidomide in children and young adults with intractable inflammatory bowel disease: long-term results.\n[Abstract]: BACKGROUND: Anti-tumour necrosis factor-alpha antibodies are useful for the treatment of refractory Crohn's disease and ulcerative colitis. Thalidomide is another agent with tumour necrosis factor-alpha suppressive properties. AIM: To investigate the long-term efficacy and safety of thalidomide in a group of children and young adults with refractory inflammatory bowel disease. METHODS: Twenty-eight patients with refractory moderate-severe inflammatory bowel disease (19 Crohn's disease, 9 ulcerative colitis) received thalidomide 1.5-2.5 mg/kg/day. Patients were assessed at baseline, at weeks 2, 4, 8 and 12, and then every 12 weeks by patient's diary, physical examinations, laboratory analyses and scoring on activity indexes. Primary outcomes were: (i) efficacy in inducing remission; and (ii) efficacy in maintaining remission. RESULTS: Remission was achieved with thalidomide in 21 of 28 (75%) patients (17 with Crohn's disease, 4 with ulcerative colitis). Mean duration of remission was 34.5 months. Sixteen of 20 (80%) patients suspended steroids. Reversible neuropathy occurred in seven of 28 (25%) patients, but only with cumulative doses over 28 g. Other side effects requiring thalidomide suspension were vertigo/somnolence (one of 28), and agitation/hallucinations (one of 28). CONCLUSIONS: Thalidomide seems to be effective in inducing long-term remission in children and adolescents with intractable inflammatory bowel disease. Neuropathy is the main adverse effect, but appears to be cumulative dose-dependent, thus allowing long-term remission before drug suspension.\n[Drug-Disease]: Thalidomide - ulcerative colitis"
    },
    {
        "pmid": "17269997",
        "target": "[\"Span: children | Label: Age\", \"Span: young adults | Label: Age\", \"Span: 1.5-2.5 mg/kg/day | Label: Dosage\"]",
        "text": "[Title]: Efficacy and safety of thalidomide in children and young adults with intractable inflammatory bowel disease: long-term results.\n[Abstract]: BACKGROUND: Anti-tumour necrosis factor-alpha antibodies are useful for the treatment of refractory Crohn's disease and ulcerative colitis. Thalidomide is another agent with tumour necrosis factor-alpha suppressive properties. AIM: To investigate the long-term efficacy and safety of thalidomide in a group of children and young adults with refractory inflammatory bowel disease. METHODS: Twenty-eight patients with refractory moderate-severe inflammatory bowel disease (19 Crohn's disease, 9 ulcerative colitis) received thalidomide 1.5-2.5 mg/kg/day. Patients were assessed at baseline, at weeks 2, 4, 8 and 12, and then every 12 weeks by patient's diary, physical examinations, laboratory analyses and scoring on activity indexes. Primary outcomes were: (i) efficacy in inducing remission; and (ii) efficacy in maintaining remission. RESULTS: Remission was achieved with thalidomide in 21 of 28 (75%) patients (17 with Crohn's disease, 4 with ulcerative colitis). Mean duration of remission was 34.5 months. Sixteen of 20 (80%) patients suspended steroids. Reversible neuropathy occurred in seven of 28 (25%) patients, but only with cumulative doses over 28 g. Other side effects requiring thalidomide suspension were vertigo/somnolence (one of 28), and agitation/hallucinations (one of 28). CONCLUSIONS: Thalidomide seems to be effective in inducing long-term remission in children and adolescents with intractable inflammatory bowel disease. Neuropathy is the main adverse effect, but appears to be cumulative dose-dependent, thus allowing long-term remission before drug suspension.\n[Drug-Disease]: Thalidomide - Crohn's disease"
    },
    {
        "pmid": "15965573",
        "target": "[]",
        "text": "[Title]: A review of carvedilol arrhythmia data in clinical trials.\n[Abstract]: beta-Blockers are currently being evaluated more intensively to define their role in clinical use as antiarrhythmic agents. beta-Adrenergic blockade has been studied in relation to atrial fibrillation, ventricular arrhythmias, and sudden death; however, it is apparent from a number of studies that not all beta-blockers are equally effective. Randomized clinical trial data, both in heart failure and post-myocardial infarction (MI) patients, have shown differences in mortality benefits in addition to a variable effect on arrhythmias and sudden death. Carvedilol, a third-generation beta-blocker with proven clinical benefit in the management of heart failure and post-MI patients, has properties that may make it an effective antiarrhythmic agent. This paper reviews the current clinical arrhythmia data available for carvedilol from large-scale clinical trials and small studies. The trial evidence demonstrates that carvedilol therapy can be an effective adjunctive rate-control therapy in patients with atrial fibrillation, prevent mortality in patients with heart failure or post-MI with left ventricular dysfunction, with or without atrial fibrillation, and reduce its onset and the incidence of ventricular arrhythmia and sudden death.\n[Drug-Disease]: carvedilol - heart failure and post-myocardial infarction"
    },
    {
        "pmid": "15978306",
        "target": "[\"Span: mean age, 61 years | Label: Age\", \"Span: 82% white | Label: Body Type\", \"Span: 53% women | Label: Gender\", \"Span: 160 mg OD | Label: Dosage\"]",
        "text": "[Title]: Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study.\n[Abstract]: BACKGROUND: Recent antihypertensive treatment guidelines recommend greater use of combination therapies. OBJECTIVES: The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. METHODS: This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP &lt;140 mm Hg or a reduction in mean sitting SBP of &gt; or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP &lt;90 mm Hg or a reduction in mean sitting DBP of &gt; or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). RESULTS: The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged &gt; or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P &lt; 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P &lt; 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P &lt; 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P &lt; 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P &lt; 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P &lt; 0.05). CONCLUSION: In this group of patients with moderate hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.\n[Drug-Disease]: valsartan - hypertension"
    },
    {
        "pmid": "15978306",
        "target": "[\"Span: mean age, 61 years | Label: Age\", \"Span: 82% white | Label: Body Type\", \"Span: 53% women | Label: Gender\", \"Span: 12.5 mg | Label: Dosage\", \"Span: 25 mg | Label: Dosage\"]",
        "text": "[Title]: Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study.\n[Abstract]: BACKGROUND: Recent antihypertensive treatment guidelines recommend greater use of combination therapies. OBJECTIVES: The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. METHODS: This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP &lt;140 mm Hg or a reduction in mean sitting SBP of &gt; or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP &lt;90 mm Hg or a reduction in mean sitting DBP of &gt; or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). RESULTS: The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged &gt; or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P &lt; 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P &lt; 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P &lt; 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P &lt; 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P &lt; 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P &lt; 0.05). CONCLUSION: In this group of patients with moderate hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.\n[Drug-Disease]: HCTZ - hypertension"
    },
    {
        "pmid": "15978306",
        "target": "[\"Span: mean age, 61 years | Label: Age\", \"Span: 82% white | Label: Body Type\", \"Span: 53% women | Label: Gender\", \"Span: 5 mg | Label: Dosage\", \"Span: 10 mg | Label: Dosage\"]",
        "text": "[Title]: Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study.\n[Abstract]: BACKGROUND: Recent antihypertensive treatment guidelines recommend greater use of combination therapies. OBJECTIVES: The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. METHODS: This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP &lt;140 mm Hg or a reduction in mean sitting SBP of &gt; or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP &lt;90 mm Hg or a reduction in mean sitting DBP of &gt; or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). RESULTS: The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged &gt; or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P &lt; 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P &lt; 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P &lt; 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P &lt; 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P &lt; 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P &lt; 0.05). CONCLUSION: In this group of patients with moderate hypertension and &gt; or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.\n[Drug-Disease]: amlodipine - hypertension"
    },
    {
        "pmid": "16012280",
        "target": "[\"Span: 15 mg/d | Label: Dosage\", \"Span: male | Label: Gender\"]",
        "text": "[Title]: Aripiprazole in schizophrenia with cocaine dependence: a pilot study.\n[Abstract]: The debilitation of schizophrenia (SCHZ) worsens markedly with comorbid cocaine dependence (CD) and alcohol abuse. To date, no medications have conclusively demonstrated effects against both SCHZ and CD (SCHZ + CD) simultaneously. Because of its dopamine-modulating properties, we hypothesized that aripiprazole would alleviate cocaine craving in patients with SCHZ + CD. We conducted a prospective, 8-week, open-label trial in poorly compliant SCHZ + CD subjects. Each received aripiprazole as their sole neuroleptic agent at a maximum dose of 15 mg/d. The Brief Psychiatric Rating Scale (BPRS) and the Brief Substance Craving Scale (BSCS) measured psychosis and subjective cocaine and alcohol cravings. Urine tests for cocaine provided data on actual use. Of 10 male subjects entered, 6 (60%) completed the 8-week trial. In those cases, positive urine tests dropped significantly (P &lt; 0.001) after 2 weeks, when aripiprazole had reached steady state. Mean cocaine craving scores declined significantly (P = 0.026) as did mean alcohol craving scores (P = 0.006). Declining psychosis scores were associated with declining cocaine craving (r = 0.87, P &lt; 0.01) and alcohol craving (r = 0.88, P &lt; 0.01), respectively. This experience suggests possible aripiprazole effects in lowering both desire for and the use of cocaine in comorbid SCHZ subjects. These data suggest double-blind, randomized, comparison study in this severely ill, comorbid patient group.\n[Drug-Disease]: aripiprazole - alcohol abuse"
    },
    {
        "pmid": "16012280",
        "target": "[\"Span: 15 mg/d | Label: Dosage\", \"Span: male | Label: Gender\"]",
        "text": "[Title]: Aripiprazole in schizophrenia with cocaine dependence: a pilot study.\n[Abstract]: The debilitation of schizophrenia (SCHZ) worsens markedly with comorbid cocaine dependence (CD) and alcohol abuse. To date, no medications have conclusively demonstrated effects against both SCHZ and CD (SCHZ + CD) simultaneously. Because of its dopamine-modulating properties, we hypothesized that aripiprazole would alleviate cocaine craving in patients with SCHZ + CD. We conducted a prospective, 8-week, open-label trial in poorly compliant SCHZ + CD subjects. Each received aripiprazole as their sole neuroleptic agent at a maximum dose of 15 mg/d. The Brief Psychiatric Rating Scale (BPRS) and the Brief Substance Craving Scale (BSCS) measured psychosis and subjective cocaine and alcohol cravings. Urine tests for cocaine provided data on actual use. Of 10 male subjects entered, 6 (60%) completed the 8-week trial. In those cases, positive urine tests dropped significantly (P &lt; 0.001) after 2 weeks, when aripiprazole had reached steady state. Mean cocaine craving scores declined significantly (P = 0.026) as did mean alcohol craving scores (P = 0.006). Declining psychosis scores were associated with declining cocaine craving (r = 0.87, P &lt; 0.01) and alcohol craving (r = 0.88, P &lt; 0.01), respectively. This experience suggests possible aripiprazole effects in lowering both desire for and the use of cocaine in comorbid SCHZ subjects. These data suggest double-blind, randomized, comparison study in this severely ill, comorbid patient group.\n[Drug-Disease]: aripiprazole - cocaine dependence"
    },
    {
        "pmid": "16077267",
        "target": "[\"Span: 40 mg | Label: Dosage\", \"Span: 80 mg | Label: Dosage\", \"Span: 45 men | Label: Gender\", \"Span: 47 women | Label: Gender\", \"Span: type 2 disease | Label: Comorbidity\"]",
        "text": "[Title]: Effect of telmisartan on blood pressure control and kidney function in hypertensive, proteinuric patients with chronic kidney disease.\n[Abstract]: OBJECTIVES: To assess the antihypertensive and antiproteinuric efficacy and safety of the angiotensin II type 1 receptor blocker telmisartan in patients with hypertension and chronic kidney disease. METHODS: A multicenter, prospective trial was performed in adults with hypertension [systolic blood pressure (SBP)/diastolic blood pressure (DBP) &gt;130/85 mmHg), chronic renal insufficiency (serum creatinine &lt;4.0 mg/dl), and proteinuria (&gt;1 g/24 h). In addition to existing antihypertensive therapy, the nature and doses of which remained unchanged throughout the study, patients received once-daily telmisartan 40 mg for the first 3 months followed by forced titration to telmisartan 80 mg for the subsequent 3 months to achieve a target SBP/DBP of &lt;130/85 mmHg. The rationale for using telmisartan was its long half-life efficacy, greater antihypertensive effect compared with valsartan or losartan, and newly discovered potential antidiabetic effect. RESULTS: The study was conducted in 92 patients (45 men, 47 women), of whom 60 had diabetes mellitus (54 patients with type 2 disease). Five patients discontinued prematurely: two because of hyperkalemia, two because of protocol violation, and one because of lack of efficacy. After 6 months' telmisartan treatment, office trough seated SBP was reduced by 19.6 mmHg (P&lt;0.001) from 154.9+/-14.6 mmHg and DBP by 11.8 mmHg (P&lt;0.001) from 91.7+/-8.1 mmHg. Seated trough SBP/DBP of &lt;130/85 mmHg was achieved at 6 months in 34.8% of patients. Ambulatory blood pressure monitoring also demonstrated significant reductions in mean daytime SBP of 10.9 mmHg (P=0.01), night-time SBP of 12.1 mmHg (P=0.05), daytime DBP of 3.1 mmHg (P=0.05), and night-time DBP of 6.5 mmHg (P=0.05). Proteinuria decreased significantly from 3.6+/-3.4 to 2.8+/-2.8 g/24 h (P=0.01). A decrease in proteinuria depended significantly on a decrease in SBP at the end of the study (P=0.044). Each decrease in SBP of about 10 mmHg led to a decrease in proteinuria of about 0.79 g/24 h (95% CI 0.02-1.56 g/24 h). Serum creatinine increased from 1.96+/-0.79 to 2.08+/-0.89 mg/dl (P=0.01), whereas creatinine clearance did not change significantly. CONCLUSIONS: Telmisartan effectively and safely reduced blood pressure and brought about regression of proteinuria in diabetic and nondiabetic, hypertensive, proteinuric patients with chronic kidney disease, even in those with mild-to-moderate chronic renal failure.\n[Drug-Disease]: telmisartan - hypertensive"
    },
    {
        "pmid": "16077267",
        "target": "[\"Span: 40 mg | Label: Dosage\", \"Span: 80 mg | Label: Dosage\", \"Span: 45 men | Label: Gender\", \"Span: 47 women | Label: Gender\", \"Span: type 2 disease | Label: Comorbidity\"]",
        "text": "[Title]: Effect of telmisartan on blood pressure control and kidney function in hypertensive, proteinuric patients with chronic kidney disease.\n[Abstract]: OBJECTIVES: To assess the antihypertensive and antiproteinuric efficacy and safety of the angiotensin II type 1 receptor blocker telmisartan in patients with hypertension and chronic kidney disease. METHODS: A multicenter, prospective trial was performed in adults with hypertension [systolic blood pressure (SBP)/diastolic blood pressure (DBP) &gt;130/85 mmHg), chronic renal insufficiency (serum creatinine &lt;4.0 mg/dl), and proteinuria (&gt;1 g/24 h). In addition to existing antihypertensive therapy, the nature and doses of which remained unchanged throughout the study, patients received once-daily telmisartan 40 mg for the first 3 months followed by forced titration to telmisartan 80 mg for the subsequent 3 months to achieve a target SBP/DBP of &lt;130/85 mmHg. The rationale for using telmisartan was its long half-life efficacy, greater antihypertensive effect compared with valsartan or losartan, and newly discovered potential antidiabetic effect. RESULTS: The study was conducted in 92 patients (45 men, 47 women), of whom 60 had diabetes mellitus (54 patients with type 2 disease). Five patients discontinued prematurely: two because of hyperkalemia, two because of protocol violation, and one because of lack of efficacy. After 6 months' telmisartan treatment, office trough seated SBP was reduced by 19.6 mmHg (P&lt;0.001) from 154.9+/-14.6 mmHg and DBP by 11.8 mmHg (P&lt;0.001) from 91.7+/-8.1 mmHg. Seated trough SBP/DBP of &lt;130/85 mmHg was achieved at 6 months in 34.8% of patients. Ambulatory blood pressure monitoring also demonstrated significant reductions in mean daytime SBP of 10.9 mmHg (P=0.01), night-time SBP of 12.1 mmHg (P=0.05), daytime DBP of 3.1 mmHg (P=0.05), and night-time DBP of 6.5 mmHg (P=0.05). Proteinuria decreased significantly from 3.6+/-3.4 to 2.8+/-2.8 g/24 h (P=0.01). A decrease in proteinuria depended significantly on a decrease in SBP at the end of the study (P=0.044). Each decrease in SBP of about 10 mmHg led to a decrease in proteinuria of about 0.79 g/24 h (95% CI 0.02-1.56 g/24 h). Serum creatinine increased from 1.96+/-0.79 to 2.08+/-0.89 mg/dl (P=0.01), whereas creatinine clearance did not change significantly. CONCLUSIONS: Telmisartan effectively and safely reduced blood pressure and brought about regression of proteinuria in diabetic and nondiabetic, hypertensive, proteinuric patients with chronic kidney disease, even in those with mild-to-moderate chronic renal failure.\n[Drug-Disease]: telmisartan - proteinuric"
    },
    {
        "pmid": "16168501",
        "target": "[\"Span: men | Label: Gender\", \"Span: aged 15-35 | Label: Age\", \"Span: Nanog | Label: Gene\", \"Span: CD9 | Label: Gene\", \"Span: EDR1 (PHC1) | Label: Gene\", \"Span: SCNN1A | Label: Gene\", \"Span: GDF3 | Label: Gene\", \"Span:  | Label: Gene\", \"Span: Glut3 | Label: Gene\", \"Span: Stella | Label: Gene\"]",
        "text": "[Title]: Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity.\n[Abstract]: Testicular germ cell tumors (TGCTs) are the most common carcinomas of young men aged 15-35. The molecular events involved in TGCT genesis are poorly understood. TGCTs have near universal amplification of the short arm of chromosome 12, however positional cloning efforts have not identified causative genes on 12p involved in formation or progression of TGCTs. Human embryonal carcinoma (EC) are the stem cells of TGCTs and are pluripotent. EC cells terminally differentiate toward a neuronal lineage with all-trans retinoic acid (RA) treatment resulting in a concomitant G1 cell cycle arrest and loss of tumorigenicity. Our efforts to define the molecular mechanisms of RA-mediated tumor cell differentiation at a critical \"commitment to differentiate\" window has identified a cassette of genes on 12p that are repressed with RA precisely as EC cells lose tumorigenic potential. These are Nanog, CD9, EDR1 (PHC1), SCNN1A, GDF3, Glut3 and Stella. The master pluripotency regulator Oct4 is located on chromosome 6 and is also repressed by RA. Notably, knockdown of Oct4 with siRNA results in repression of basal Nanog, EDR1, GDF3 and Stella gene expression. Nanog has recently been identified to play a role in maintenance of the pluripotency of mouse embryonic stem cells and CD9, EDR1, GDF3, and Stella have each been implicated as stem cell markers. Since RA suppresses the tumorigenicity of EC cells, these genes may have a critical role in the etiology of TGCTs, suggesting a link between enforced pluripotency and transformation.\n[Drug-Disease]: RA - embryonal carcinoma"
    },
    {
        "pmid": "16238680",
        "target": "[\"Span: HDL-bound paraoxonase-1 (PON1) | Label: Gene\", \"Span: PON1 -107C>T | Label: Gene\", \"Span: 192Q>R genotype | Label: Gene\"]",
        "text": "[Title]: The effect of statin therapy on plasma high-density lipoprotein cholesterol levels is modified by paraoxonase-1 in patients with familial hypercholesterolaemia.\n[Abstract]: OBJECTIVES: Statins reduce low-density lipoprotein cholesterol (LDL-C) and can raise high-density lipoprotein cholesterol (HDL-C). HDL-bound paraoxonase-1 (PON1) is associated with variations in plasma HDL-C, and may, therefore, contribute to changes of HDL-C during statin therapy. DESIGN: The effects of baseline PON1 status to HDL-C changes because of statin therapy were investigated. PON1 status was determined with (i) PON1 -107C>T and 192Q>R genotype, (ii) PON1 levels and (iii) PON1 paraoxonase, diazoxonase and arylesterase activity. SETTING: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. SUBJECTS: A total of 134 familial hypercholesterolaemia (FH) patients undergoing atorvastatin or simvastatin therapy. RESULTS: PON1 levels and activities significantly modified the HDL-C increment (P=0.002 for PON1 levels and arylesterase activity and P=0.001 for diazoxonase activity). The effects were even more evident amongst subgroup classifications based on PON1 status and baseline HDL-C concentrations: the HDL-C increment was more pronounced in subgroups of -107CT/TT or 192QR/RR genotype combined with low baseline HDL-C (+13.9%, P<0.001, respectively+15.4%, P<0.001). In contrast, the -107CC or 192QQ genotype in combination with high baseline HDL-C, did not show a significant increase of HDL-C. CONCLUSIONS: PON1 status in conjunction with baseline HDL-C levels predicts HDL-C increment during statin therapy in FH patients.\n[Drug-Disease]: atorvastatin - FH"
    },
    {
        "pmid": "16238680",
        "target": "[\"Span: HDL-bound paraoxonase-1 (PON1) | Label: Gene\", \"Span: PON1 -107C>T | Label: Gene\", \"Span: 192Q>R genotype | Label: Gene\"]",
        "text": "[Title]: The effect of statin therapy on plasma high-density lipoprotein cholesterol levels is modified by paraoxonase-1 in patients with familial hypercholesterolaemia.\n[Abstract]: OBJECTIVES: Statins reduce low-density lipoprotein cholesterol (LDL-C) and can raise high-density lipoprotein cholesterol (HDL-C). HDL-bound paraoxonase-1 (PON1) is associated with variations in plasma HDL-C, and may, therefore, contribute to changes of HDL-C during statin therapy. DESIGN: The effects of baseline PON1 status to HDL-C changes because of statin therapy were investigated. PON1 status was determined with (i) PON1 -107C>T and 192Q>R genotype, (ii) PON1 levels and (iii) PON1 paraoxonase, diazoxonase and arylesterase activity. SETTING: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. SUBJECTS: A total of 134 familial hypercholesterolaemia (FH) patients undergoing atorvastatin or simvastatin therapy. RESULTS: PON1 levels and activities significantly modified the HDL-C increment (P=0.002 for PON1 levels and arylesterase activity and P=0.001 for diazoxonase activity). The effects were even more evident amongst subgroup classifications based on PON1 status and baseline HDL-C concentrations: the HDL-C increment was more pronounced in subgroups of -107CT/TT or 192QR/RR genotype combined with low baseline HDL-C (+13.9%, P<0.001, respectively+15.4%, P<0.001). In contrast, the -107CC or 192QQ genotype in combination with high baseline HDL-C, did not show a significant increase of HDL-C. CONCLUSIONS: PON1 status in conjunction with baseline HDL-C levels predicts HDL-C increment during statin therapy in FH patients.\n[Drug-Disease]: simvastatin - FH"
    },
    {
        "pmid": "16243814",
        "target": "[\"Span: 0.4 to 21 years old | Label: Age\"]",
        "text": "[Title]: Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors.\n[Abstract]: PURPOSE: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy. EXPERIMENTAL DESIGN: Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP). RESULTS: Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P &lt; or = 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair. CONCLUSIONS: Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.\n[Drug-Disease]: temozolomide - medulloblastomas"
    },
    {
        "pmid": "16274835",
        "target": "[\"Span: 10 mg once-daily | Label: Dosage\"]",
        "text": "[Title]: Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1.\n[Abstract]: BACKGROUND/AIMS: Adefovir dipivoxil (10 mg once-daily) was added to antiretroviral therapy including lamivudine in 35 HIV/HBV co-infected patients. METHODS: Parameters evaluated included alanine aminotransferase (ALT), HBV DNA and serological markers, HIV-1 RNA, and CD4+ cell count. RESULTS: Twenty-nine patients (83%) completed 144 weeks. Serum HBV DNA declined from a baseline 9.76 log10 copies/mL (median) to 4.68, 5.24, and 5.90 log10 copies/mL at weeks 48, 96, and 144, respectively (P&lt;0.0001 at all time points). Seven patients (25%) achieved HBV DNA&lt;2.3 log10 copies/mL. No adefovir-associated resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were detected. ALT declined from 81 IU/L (median) at baseline by -16.0, -44.5, and -46.0 IU/L at week 48, 96 and 144, respectively (P=&lt;0.05, respectively), and normalized in 71% of patients (20 of 28) by week 144. Two patients developed antibodies against HB 'e' antigen by week 48. No serious adverse events related to adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable. CONCLUSIONS: Treatment with adefovir dipivoxil for 144 weeks was well tolerated and resulted in significant and sustained reductions in HBV DNA and ALT in HIV/HBV co-infected patients. Efficacy increased with treatment duration, with no loss of viral suppression.\n[Drug-Disease]: adefovir dipivoxil - HIV/HBV co-infected"
    },
    {
        "pmid": "16294345",
        "target": "[\"Span: 45 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia.\n[Abstract]: BACKGROUND: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML. METHODS: VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS: Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS: Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.\n[Drug-Disease]: ATRA - AML"
    },
    {
        "pmid": "16294345",
        "target": "[\"Span: 5-10 mg/kg starting dose | Label: Dosage\"]",
        "text": "[Title]: Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia.\n[Abstract]: BACKGROUND: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML. METHODS: VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS: Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS: Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.\n[Drug-Disease]: VPA - AML"
    },
    {
        "pmid": "16303861",
        "target": "[\"Span: 80 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.\n[Abstract]: BACKGROUND: To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d. RESULTS: Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received &gt;80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received &lt; or =80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined. CONCLUSIONS: Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.\n[Drug-Disease]: irinotecan - colorectal cancer"
    },
    {
        "pmid": "16303861",
        "target": "[\"Span: 500 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.\n[Abstract]: BACKGROUND: To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d. RESULTS: Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received &gt;80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received &lt; or =80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined. CONCLUSIONS: Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.\n[Drug-Disease]: folinic acid - colorectal cancer"
    },
    {
        "pmid": "16303861",
        "target": "[\"Span: 1500 mg/m(2) | Label: Dosage\", \"Span: 2000 mg/m(2) | Label: Dosage\"]",
        "text": "[Title]: Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.\n[Abstract]: BACKGROUND: To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d. RESULTS: Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received &gt;80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received &lt; or =80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined. CONCLUSIONS: Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.\n[Drug-Disease]: 5-fluorouracil - colorectal cancer"
    },
    {
        "pmid": "16330438",
        "target": "[\"Span: 40 mg daily | Label: Dosage\", \"Span: 66 years (range 36-78) | Label: Age\"]",
        "text": "[Title]: Combination therapy with thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma not undergoing upfront autologous stem cell transplantation: a phase II trial.\n[Abstract]: BACKGROUND AND OBJECTIVES: Thalidomide plus dexamethasone (Thal/Dex) has emerged as an effective alternative to vincristine, doxorubicin and dexamethasone as a pre-transplant induction therapy for newly diagnosed multiple myeloma. However, many patients treated initially with Thal/Dex do not proceed to autologous stem cell transplantation (ASCT) and the time to progression and other outcome measures with Thal/Dex as primary therapy for multiple myeloma are not known. We present the first data on the outcome of patients with newly diagnosed multiple myeloma treated with Thal/Dex who did not undergo upfront ASCT. DESIGN AND METHODS: We identified 21 patients with newly diagnosed multiple myeloma treated with Thal/Dex on a phase II clinical trial who did not undergo ASCT due to age, comorbidity or the patient's refusal. Patients received thalidomide at a dose of 200 mg/day orally and dexamethasone 40 mg daily on days 1-4, 9-12, 17-20 (odd months) and days 1-4 (even months). Cycles were repeated every 28 days. RESULTS: The median age was 66 years (range 36-78). The median duration of follow-up was 21 months (range 1-52). One (5%) patient achieved a complete response, and 9 (43%) had a partial response, so the overall response rate was 48%. Of the remaining patients, 7 (33.3%) had stable disease, one patient did not respond, and three died while on therapy prior to response assessment. The median overall survival and time to progression were 21 months and 18 months, respectively. INTERPRETATION AND CONCLUSIONS: The median time to disease progression in patients with multiple myeloma who receive initial therapy with Thal/Dex and who do not undergo ASCT is 18 months.\n[Drug-Disease]: dexamethasone - multiple myeloma"
    },
    {
        "pmid": "16330438",
        "target": "[\"Span: 200 mg/day | Label: Dosage\", \"Span: 66 years (range 36-78) | Label: Age\"]",
        "text": "[Title]: Combination therapy with thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma not undergoing upfront autologous stem cell transplantation: a phase II trial.\n[Abstract]: BACKGROUND AND OBJECTIVES: Thalidomide plus dexamethasone (Thal/Dex) has emerged as an effective alternative to vincristine, doxorubicin and dexamethasone as a pre-transplant induction therapy for newly diagnosed multiple myeloma. However, many patients treated initially with Thal/Dex do not proceed to autologous stem cell transplantation (ASCT) and the time to progression and other outcome measures with Thal/Dex as primary therapy for multiple myeloma are not known. We present the first data on the outcome of patients with newly diagnosed multiple myeloma treated with Thal/Dex who did not undergo upfront ASCT. DESIGN AND METHODS: We identified 21 patients with newly diagnosed multiple myeloma treated with Thal/Dex on a phase II clinical trial who did not undergo ASCT due to age, comorbidity or the patient's refusal. Patients received thalidomide at a dose of 200 mg/day orally and dexamethasone 40 mg daily on days 1-4, 9-12, 17-20 (odd months) and days 1-4 (even months). Cycles were repeated every 28 days. RESULTS: The median age was 66 years (range 36-78). The median duration of follow-up was 21 months (range 1-52). One (5%) patient achieved a complete response, and 9 (43%) had a partial response, so the overall response rate was 48%. Of the remaining patients, 7 (33.3%) had stable disease, one patient did not respond, and three died while on therapy prior to response assessment. The median overall survival and time to progression were 21 months and 18 months, respectively. INTERPRETATION AND CONCLUSIONS: The median time to disease progression in patients with multiple myeloma who receive initial therapy with Thal/Dex and who do not undergo ASCT is 18 months.\n[Drug-Disease]: Thal - multiple myeloma"
    },
    {
        "pmid": "16386596",
        "target": "[\"Span: 54.8% HCV-coinfected | Label: Comorbidity\", \"Span: 10 mg | Label: Dosage\"]",
        "text": "[Title]: Study on the efficacy and safety of adefovir dipivoxil treatment in post-liver transplant patients with hepatitis B virus infection and lamivudine-resistant hepatitis B virus.\n[Abstract]: Hepatitis B virus (HBV) recurrence and de novo HBV infection are frequent events in liver transplantation recipients. Treatment with lamivudine is initially efficient in both infections but the incidence of lamivudine-resistant HBV emergence increases over time. Adefovir appears to be promising in post-liver transplantation patients with recurrent HBV infection and lamivudine-resistant HBV. This study analyzed adefovir treatment in 42 post-liver transplantation patients who developed recurrent HBV or de novo HBV infection with lamivudine-resistant HBV (54.8% HCV-coinfected). Patients received 10 mg of oral adefovir once daily for a mean period of time of 21.5 months (range from 12 to 31 months). In 62.9% of patients, ALT levels decreased significantly. Serum HBV-DNA was undetectable in 64% of the cases. Twenty percent of patients lost HBeAg marker and 13.3% of them developed anti-HBe. In 9.5% of recipients, HBsAg became negative. There was no significant change in serum creatinine levels. In only one patient was worsening of the renal function detected, making dose adjustment necessary. No other side effects were reported. Our results confirm the efficacy and safety of adefovir treatment in post-liver transplantation patients with lamivudine-resistant HBV, neither were adefovir-resistant mutations identified in patients after 21 months of therapy, nor were there adverse events, especially renal toxicity.\n[Drug-Disease]: adefovir dipivoxil - HBV infection"
    },
    {
        "pmid": "16396707",
        "target": "[\"Span: Thiopurine S-methyltransferase polymorphisms | Label: Gene\", \"Span: Korean | Label: Body Type\", \"Span: heterozygous for the TPMT*6 allele | Label: Gene\", \"Span: heterozygous for the TPMT*3C allele | Label: Gene\"]",
        "text": "[Title]: Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine.\n[Abstract]: OBJECTIVE: The present study sought to elucidate the genetic basis of thiopurine methyltransferase (TPMT) polymorphism and subsequently to investigate the relationship between mutant TPMT and an adverse response observed in Korean patients with systemic lupus erythematosus (SLE) taking azathioprine (AZA). METHODS: The TPMT genotype of 342 patients with SLE was determined by MALDI-TOF mass spectrometry and correlated with the effects of clinical exposure to AZA. RESULTS: TPMT polymorphism was detected in 17 of the 342 study subjects (5.0%), 12 heterozygous for the TPMT*3C allele and 5 heterozygous for the TPMT*6 allele. Numerous patients taking AZA demonstrated adverse drug responses. Severe nausea occurred in 4 patients with the TPMT*3C allele, while 1 patient with the TPMT*6 allele suffered severe bone marrow toxicity. Leucopenia (n = 17), nausea (n = 4), and abnormal liver function (n = 1) were suspected in 23 of the 94 lupus patients taking AZA. AZA was relatively well tolerated by the remainder of the patients. The heterozygous genotype for the TPMT*3C and *6 alleles was frequently detected in Korean SLE patients. CONCLUSION: Contrary to previous hypotheses, this study identified no statistical correlation between TPMT genotype and AZA toxicity. We thus conclude that TMPT genotyping cannot replace regular blood monitoring in SLE patients receiving AZA treatment.\n[Drug-Disease]: AZA - SLE"
    },
    {
        "pmid": "16415698",
        "target": "[]",
        "text": "[Title]: The efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence: a preliminary report.\n[Abstract]: OBJECTIVE: Although a growing body of research suggests that atypical neuroleptic medications are efficacious in the treatment of cocaine addiction among individuals with schizophrenia, more rigorously controlled trials are needed. To extend this research, we performed a 6-week double-blind study comparing olanzapine to haloperidol with the primary objective of reducing cue-elicited cocaine craving and the secondary aims of decreasing substance use, improving psychiatric symptoms, and determining an effect size for future studies. METHODS: Thirty-one subjects with cocaine dependence and schizophrenia were randomized to olanzapine or haloperidol, underwent a cue-exposure procedure, and completed psychiatric and substance abuse ratings. RESULTS: Individuals in the olanzapine group who completed the study had a significant reduction on the energy subscale of the Voris Cocaine Craving Scale at study completion compared with individuals in the haloperidol group. The olanzapine-treated group also had lower, but not statistically significant, PANSS General Psychopathology Subscale scores and fewer positive urine toxicology screens compared with those in the haloperidol group. CONCLUSION: This small, but rigorously controlled, pilot trial provides additional evidence for the use of atypical antipsychotics for the treatment of individuals with co-occurring schizophrenia and cocaine dependence. Reductions in craving were associated with medium to large effect sizes.\n[Drug-Disease]: olanzapine - cocaine addiction"
    },
    {
        "pmid": "16446752",
        "target": "[\"Span: 8 mg | Label: Dosage\", \"Span: apolipoprotein E (APOE) genotype | Label: Gene\", \"Span: APOE epsilon4-positive | Label: Gene\"]",
        "text": "[Title]: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.\n[Abstract]: Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.\n[Drug-Disease]: RSG - AD"
    },
    {
        "pmid": "16461866",
        "target": "[\"Span: 300 mg/d | Label: Dosage\"]",
        "text": "[Title]: Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population.\n[Abstract]: CONTEXT: No effective pharmacotherapies exist for cocaine dependence, although contingency management (CM) has demonstrated efficacy. OBJECTIVE: To compare the efficacy of bupropion hydrochloride and CM for reducing cocaine use in methadone hydrochloride-maintained individuals. DESIGN: This 25-week, placebo-controlled, double-blind trial randomly assigned participants to 1 of 4 treatment conditions: CM and placebo (CMP), CM and 300 mg/d of bupropion hydrochloride (CMB), voucher control and placebo (VCP), or voucher control and bupropion (VCB). SETTING: Outpatient clinic at the Veterans Affairs Connecticut Healthcare System. PARTICIPANTS: A total of 106 opiate-dependent, cocaine-abusing individuals. INTERVENTIONS: All study participants received methadone hydrochloride (range, 60-120 mg). Participants receiving bupropion hydrochloride were given 300 mg/d beginning at week 3. In the CM conditions, each urine sample negative for both opioids and cocaine resulted in a monetary-based voucher that increased for consecutively drug-free urine samples during weeks 1 to 13. Completion of abstinence-related activities also resulted in a voucher. During weeks 14 to 25, only completion of activities was reinforced in the CM group, regardless of sample results. The voucher control groups received vouchers for submitting urine samples, regardless of results, throughout the study. MAIN OUTCOME MEASURE: Thrice-weekly urine toxicologic test results for cocaine and heroin. RESULTS: Groups did not differ in baseline characteristics or retention rates. Opiate use decreased significantly, with all treatment groups attaining equivalent amounts of opiate use at the end of the study. In the CMB group, the proportion of cocaine-positive samples significantly decreased during weeks 3 to 13 (P&lt;.001) relative to week 3 and remained low during weeks 14 to 25. In the CMP group, cocaine use significantly increased during weeks 3 to 13 (P&lt;.001) relative to week 3, but then cocaine use significantly decreased relative to the initial slope during weeks 14 to 25 (P&lt;.001). In contrast, by treatment end, the VCB and VCP groups showed no significant improvement in cocaine use. CONCLUSION: These findings suggest that combining CM with bupropion for the treatment of cocaine addiction may significantly improve outcomes relative to bupropion alone.\n[Drug-Disease]: bupropion - cocaine addiction"
    },
    {
        "pmid": "16467208",
        "target": "[\"Span: p53 | Label: Gene\", \"Span: p73 | Label: Gene\"]",
        "text": "[Title]: MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis.\n[Abstract]: We found that MEK1 inhibitor PD184352 strikingly increased apoptosis induced by arsenic trioxide (ATO) in 21 of 25 patients with primary acute myelogenous leukemia (AML). Isobologram analysis confirmed the synergistic (13 of 25 patients) or additive (8 of 25 patients) nature of this interaction. Moreover, we demonstrated that the p53-related gene p73 is a molecular target of the combined treatment in AML blasts. Indeed, ATO modulates the expression of the p73 gene by inducing the proapoptotic and antiproliferative TAp73 and the antiapoptotic and proproliferative DeltaNp73 isoforms, thereby failing to elevate the TA/DeltaNp73 ratio. Conversely, treatment with PD184352 reduces the level of DeltaNp73 and blunts the arsenic-mediated up-regulation of DeltaNp73, thus causing an increase in the TA/DeltaNp73 ratio of dual-treated cells. High doses of ATO induced p53 accumulation in 11 of 21 patients. Combined treatment resulted in the induction of the proapoptotic p53/p73 target gene p53AIP1 (p53-regulated apoptosis-inducing protein 1) and greatly enhanced the apoptosis of treated cells.\n[Drug-Disease]: PD184352 - AML"
    },
    {
        "pmid": "16467208",
        "target": "[\"Span: p53 | Label: Gene\", \"Span: p73 | Label: Gene\"]",
        "text": "[Title]: MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis.\n[Abstract]: We found that MEK1 inhibitor PD184352 strikingly increased apoptosis induced by arsenic trioxide (ATO) in 21 of 25 patients with primary acute myelogenous leukemia (AML). Isobologram analysis confirmed the synergistic (13 of 25 patients) or additive (8 of 25 patients) nature of this interaction. Moreover, we demonstrated that the p53-related gene p73 is a molecular target of the combined treatment in AML blasts. Indeed, ATO modulates the expression of the p73 gene by inducing the proapoptotic and antiproliferative TAp73 and the antiapoptotic and proproliferative DeltaNp73 isoforms, thereby failing to elevate the TA/DeltaNp73 ratio. Conversely, treatment with PD184352 reduces the level of DeltaNp73 and blunts the arsenic-mediated up-regulation of DeltaNp73, thus causing an increase in the TA/DeltaNp73 ratio of dual-treated cells. High doses of ATO induced p53 accumulation in 11 of 21 patients. Combined treatment resulted in the induction of the proapoptotic p53/p73 target gene p53AIP1 (p53-regulated apoptosis-inducing protein 1) and greatly enhanced the apoptosis of treated cells.\n[Drug-Disease]: ATO - AML"
    },
    {
        "pmid": "16519947",
        "target": "[]",
        "text": "[Title]: Lamotrigine for bipolar disorder and comorbid cocaine dependence: a replication and extension study.\n[Abstract]: BACKGROUND: Bipolar disorder (BPD) is associated with high rates of substance abuse. We previously reported favorable results with lamotrigine in 30 patients with BPD and cocaine dependence. This report examines lamotrigine therapy in an additional 32 cocaine dependent patients. Data on these 32 participants are presented as a replication study. In addition, we extend the previous findings by combining data from both groups, and by exploring predictors of response. METHOD: Participants received a baseline evaluation and assessment for up to 36weeks with the 17-item Hamilton Rating Scale for Depression (HRSD(17)), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS(18)), and Cocaine Craving Questionnaire (CCQ). Urine samples were obtained, and participants reported drug use during the previous week. RESULTS: In the replication sample (n=32), significant improvements were observed in HRSD(17), YMRS, BPRS(18), and CCQ (baseline to exit), as well as on dollars/week spent on cocaine. In the extension study, the original sample (n=30) and the replication sample (n=32) were combined for a total of 62 participants in the intent-to-treat sample. HRSD(17), YMRS, BPRS(18), and CCQ scores, as well as dollars spent on cocaine, decreased significantly. LIMITATIONS: The study has an open-label, uncontrolled design. CONCLUSION: Lamotrigine treatment was associated with significant improvements in mood, drug craving, and drug use. Controlled trials are needed.\n[Drug-Disease]: Lamotrigine - Bipolar disorder"
    },
    {
        "pmid": "16519947",
        "target": "[]",
        "text": "[Title]: Lamotrigine for bipolar disorder and comorbid cocaine dependence: a replication and extension study.\n[Abstract]: BACKGROUND: Bipolar disorder (BPD) is associated with high rates of substance abuse. We previously reported favorable results with lamotrigine in 30 patients with BPD and cocaine dependence. This report examines lamotrigine therapy in an additional 32 cocaine dependent patients. Data on these 32 participants are presented as a replication study. In addition, we extend the previous findings by combining data from both groups, and by exploring predictors of response. METHOD: Participants received a baseline evaluation and assessment for up to 36weeks with the 17-item Hamilton Rating Scale for Depression (HRSD(17)), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS(18)), and Cocaine Craving Questionnaire (CCQ). Urine samples were obtained, and participants reported drug use during the previous week. RESULTS: In the replication sample (n=32), significant improvements were observed in HRSD(17), YMRS, BPRS(18), and CCQ (baseline to exit), as well as on dollars/week spent on cocaine. In the extension study, the original sample (n=30) and the replication sample (n=32) were combined for a total of 62 participants in the intent-to-treat sample. HRSD(17), YMRS, BPRS(18), and CCQ scores, as well as dollars spent on cocaine, decreased significantly. LIMITATIONS: The study has an open-label, uncontrolled design. CONCLUSION: Lamotrigine treatment was associated with significant improvements in mood, drug craving, and drug use. Controlled trials are needed.\n[Drug-Disease]: Lamotrigine - cocaine dependence"
    },
    {
        "pmid": "16525670",
        "target": "[\"Span: 30-40 mg/m2/day | Label: Dosage\"]",
        "text": "[Title]: Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer.\n[Abstract]: A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) &lt;1.25 m2:80 mg/day, 1.25&lt;or= BSA &lt;1.50 m2: 100 mg/day, 1.50 m2&lt;or= BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m2/day. Initially, patients were administered S-1 and 40 mg/m2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day.\n[Drug-Disease]: DOC - anorexia"
    },
    {
        "pmid": "16525670",
        "target": "[\"Span: 30-40 mg/m2/day | Label: Dosage\"]",
        "text": "[Title]: Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer.\n[Abstract]: A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) &lt;1.25 m2:80 mg/day, 1.25&lt;or= BSA &lt;1.50 m2: 100 mg/day, 1.50 m2&lt;or= BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m2/day. Initially, patients were administered S-1 and 40 mg/m2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day.\n[Drug-Disease]: DOC - diarrhea"
    },
    {
        "pmid": "16525670",
        "target": "[\"Span: 30-40 mg/m2/day | Label: Dosage\"]",
        "text": "[Title]: Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer.\n[Abstract]: A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) &lt;1.25 m2:80 mg/day, 1.25&lt;or= BSA &lt;1.50 m2: 100 mg/day, 1.50 m2&lt;or= BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m2/day. Initially, patients were administered S-1 and 40 mg/m2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day.\n[Drug-Disease]: DOC - neutropenia"
    },
    {
        "pmid": "16525670",
        "target": "[\"Span: 30-40 mg/m2/day | Label: Dosage\"]",
        "text": "[Title]: Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer.\n[Abstract]: A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) &lt;1.25 m2:80 mg/day, 1.25&lt;or= BSA &lt;1.50 m2: 100 mg/day, 1.50 m2&lt;or= BSA; 120 mg/day, orally, day 1-14) and DOC (30-40 mg/m2/day, intravenously, day 1 and 15], which were repeated as often as possible every four weeks. Pharmacokinetic analysis was done at DOC 40 mg/m2/day. Initially, patients were administered S-1 and 40 mg/m2/day of DOC, and DOC 40 mg/m2/day was considered as MTD. In detail, one patient developed neutropenia (grade 4, G4), and two other patients had no day 15 DOC administration because of neutropenia (grade 3, G3). When S-1 and 35 mg/m2/day of DOC were administered to three patients, no adverse reactions were noted. In six patients treated with S-1 and 30 mg/m2/day of DOC, one patient developed neutropenia (G4), and another patient developed diarrhea (G3) and anorexia (G3). The rest of this cohort showed no adverse reactions. Although 5-fluorouracil and gimeracil concentrations remained high under impaired renal function, no pharmacokinetic interactions appeared between S-1 and DOC under normal renal function. The dose limiting toxicity of a combination of S-1 and biweekly DOC was leukopenia and neutropenia. The recommended dose for this combination in phase II study is DOC 35 mg/m2/day.\n[Drug-Disease]: DOC - gastric cancer"
    },
    {
        "pmid": "16563328",
        "target": "[\"Span: 2% lidocaine (6-2-2 mixture) | Label: Dosage\"]",
        "text": "[Title]: A novel mixture of propofol, alfentanil, and lidocaine for regional block with monitored anesthesia care in ophthalmic surgery.\n[Abstract]: STUDY OBJECTIVE: The purpose of this study is to determine the efficacy and safety of sedation/analgesia using a mixture of propofol, alfentanil, and lidocaine. DESIGN: A retrospective case review was undertaken. SETTING: This study took place at a university medical center. PATIENTS: Eighty-nine American Society of Anesthesiologists physical status 1, 2, and 3 adult patients undergoing ophthalmic surgery with regional block and monitored anesthesia care were studied. INTERVENTION: Six milliliters of propofol, 2 mL of alfentanil, and 2 mL of 2% lidocaine (6-2-2 mixture) were freshly mixed. The bolus dose was determined based on the patients' age: 5 microg/kg of alfentanil (and 0.3 mg/kg of propofol) for patients older than 75 years; the dose increased 1 mug/kg per 10-year decrease in age; and up to 9 microg/kg of alfentanil (0.54 mg/kg of propofol) for patients younger than 45 years. Regional block was performed at 1 minute after bolus completion. Blood pressure (BP), Sa(O2), electrocardiogram, capnography, clinical signs of sedation, responses to block, need for airway support, nausea and vomiting (N/V), pain due to propofol infusion, recall, and patient and surgeon satisfaction were recorded. MEASUREMENTS AND MAIN RESULTS: Seventy-eight percent of patients achieved analgesia and sedation without adverse response to the block. Twelve percent achieved good analgesia and sedation with only eyebrow movement upon needle insertion. Twenty-seven percent had respiratory depression but were able to follow commands and maintain adequate ventilation. Two percent had brief apnea alleviated by chin lift or jaw thrust. None had pain because of propofol infusion or N/V. Before sedation, average systolic BP was significantly increased (P &lt; 0.0001) compared with baseline. After sedation and block, systolic BP decreased 6% from baseline (P &lt; 0.005). CONCLUSION: Adjusted for age and weight, the dose of the 6-2-2 mixture met the sedation requirements for most patients. With a low incidence of need for airway support, no pain during infusion, and no N/V, this novel mixture of propofol, alfentanil, and lidocaine provided adequate analgesia and sedation as well as hemodynamic stability for ophthalmic surgery under regional block.\n[Drug-Disease]: lidocaine - pain"
    },
    {
        "pmid": "16563328",
        "target": "[\"Span: 5 microg/kg | Label: Dosage\", \"Span: up to 9 microg/kg | Label: Dosage\"]",
        "text": "[Title]: A novel mixture of propofol, alfentanil, and lidocaine for regional block with monitored anesthesia care in ophthalmic surgery.\n[Abstract]: STUDY OBJECTIVE: The purpose of this study is to determine the efficacy and safety of sedation/analgesia using a mixture of propofol, alfentanil, and lidocaine. DESIGN: A retrospective case review was undertaken. SETTING: This study took place at a university medical center. PATIENTS: Eighty-nine American Society of Anesthesiologists physical status 1, 2, and 3 adult patients undergoing ophthalmic surgery with regional block and monitored anesthesia care were studied. INTERVENTION: Six milliliters of propofol, 2 mL of alfentanil, and 2 mL of 2% lidocaine (6-2-2 mixture) were freshly mixed. The bolus dose was determined based on the patients' age: 5 microg/kg of alfentanil (and 0.3 mg/kg of propofol) for patients older than 75 years; the dose increased 1 mug/kg per 10-year decrease in age; and up to 9 microg/kg of alfentanil (0.54 mg/kg of propofol) for patients younger than 45 years. Regional block was performed at 1 minute after bolus completion. Blood pressure (BP), Sa(O2), electrocardiogram, capnography, clinical signs of sedation, responses to block, need for airway support, nausea and vomiting (N/V), pain due to propofol infusion, recall, and patient and surgeon satisfaction were recorded. MEASUREMENTS AND MAIN RESULTS: Seventy-eight percent of patients achieved analgesia and sedation without adverse response to the block. Twelve percent achieved good analgesia and sedation with only eyebrow movement upon needle insertion. Twenty-seven percent had respiratory depression but were able to follow commands and maintain adequate ventilation. Two percent had brief apnea alleviated by chin lift or jaw thrust. None had pain because of propofol infusion or N/V. Before sedation, average systolic BP was significantly increased (P &lt; 0.0001) compared with baseline. After sedation and block, systolic BP decreased 6% from baseline (P &lt; 0.005). CONCLUSION: Adjusted for age and weight, the dose of the 6-2-2 mixture met the sedation requirements for most patients. With a low incidence of need for airway support, no pain during infusion, and no N/V, this novel mixture of propofol, alfentanil, and lidocaine provided adequate analgesia and sedation as well as hemodynamic stability for ophthalmic surgery under regional block.\n[Drug-Disease]: alfentanil - pain"
    },
    {
        "pmid": "16636934",
        "target": "[\"Span: 2 mg/kg | Label: Dosage\", \"Span: T/C substitution at position -889 of the IL-1alpha promoter gene (T-889C) | Label: Gene\"]",
        "text": "[Title]: T-889C IL-1alpha promoter polymorphism influences the response to oral cyclophosphamide in scleroderma patients with alveolitis.\n[Abstract]: Cyclophosphamide (CYC) is the cornerstone of the treatment of systemic sclerosis (SSc)-associated fibrosing alveolitis (FAS). Despite treatment with CYC, in a not negligible proportion of SSc-FAS patients, deterioration in lung function can be observed. Interleukin-1 (IL-1) cluster gene single nucleotide polymorphisms (SNPs) were implicated in the pathogenesis of some interstitial lung diseases and may favor the progression of restrictive lung disease in SSc. The present retrospective case-control study was conducted on 18 SSc patients previously treated with oral CYC (2 mg/kg) and medium-dose steroids (prednisone 25 mg for 3 months and then tapered to 5 mg/day) for the presence of FAS-defined as the presence of areas of ground-glass attenuation on high-resolution computed tomography (HRCT) and a recent deterioration in lung function. The T/C substitution at position -889 of the IL-1alpha promoter gene (T-889C) was determined by polymerase chain reaction and restriction length fragment analysis. Patients carrying the T allele showed a significant decrease in forced vital capacity (FVC) values after 12 months of therapy (2.46+/-1.09 vs 2.59+/-1.17 l), while wild-type patients showed an increase in FVC values (2.73+/-0.54 vs 2.54+/-0.5 l) (p=0.005 between the two groups, analysis of variance for repeated measures). Patients with the T-889C polymorphism presented higher baseline erythrocyte sedimentation rates (ESR) compared to wild-type patients (50.3+/-25.4 vs 23.3+/-17.7 mm/h). Baseline ESR inversely correlated with the variation of FVC (DeltaFVC) after 12 months of therapy (r=-0.50 and p&lt;0.05). The two groups were otherwise similar with respect to autoantibodies, age, disease duration, disease subset, radiological HRCT grade, and baseline lung physiology. The T-889C polymorphism represents a marker for worse functional responses to CYC in SSc-FAS. The mechanisms by which this SNP may negatively influence the response to CYC therapy are unknown, but might be linked to increased inflammatory responses in the lungs.\n[Drug-Disease]: CYC - alveolitis"
    },
    {
        "pmid": "16636934",
        "target": "[\"Span: 2 mg/kg | Label: Dosage\", \"Span: T/C substitution at position -889 of the IL-1alpha promoter gene (T-889C) | Label: Gene\"]",
        "text": "[Title]: T-889C IL-1alpha promoter polymorphism influences the response to oral cyclophosphamide in scleroderma patients with alveolitis.\n[Abstract]: Cyclophosphamide (CYC) is the cornerstone of the treatment of systemic sclerosis (SSc)-associated fibrosing alveolitis (FAS). Despite treatment with CYC, in a not negligible proportion of SSc-FAS patients, deterioration in lung function can be observed. Interleukin-1 (IL-1) cluster gene single nucleotide polymorphisms (SNPs) were implicated in the pathogenesis of some interstitial lung diseases and may favor the progression of restrictive lung disease in SSc. The present retrospective case-control study was conducted on 18 SSc patients previously treated with oral CYC (2 mg/kg) and medium-dose steroids (prednisone 25 mg for 3 months and then tapered to 5 mg/day) for the presence of FAS-defined as the presence of areas of ground-glass attenuation on high-resolution computed tomography (HRCT) and a recent deterioration in lung function. The T/C substitution at position -889 of the IL-1alpha promoter gene (T-889C) was determined by polymerase chain reaction and restriction length fragment analysis. Patients carrying the T allele showed a significant decrease in forced vital capacity (FVC) values after 12 months of therapy (2.46+/-1.09 vs 2.59+/-1.17 l), while wild-type patients showed an increase in FVC values (2.73+/-0.54 vs 2.54+/-0.5 l) (p=0.005 between the two groups, analysis of variance for repeated measures). Patients with the T-889C polymorphism presented higher baseline erythrocyte sedimentation rates (ESR) compared to wild-type patients (50.3+/-25.4 vs 23.3+/-17.7 mm/h). Baseline ESR inversely correlated with the variation of FVC (DeltaFVC) after 12 months of therapy (r=-0.50 and p&lt;0.05). The two groups were otherwise similar with respect to autoantibodies, age, disease duration, disease subset, radiological HRCT grade, and baseline lung physiology. The T-889C polymorphism represents a marker for worse functional responses to CYC in SSc-FAS. The mechanisms by which this SNP may negatively influence the response to CYC therapy are unknown, but might be linked to increased inflammatory responses in the lungs.\n[Drug-Disease]: CYC - systemic sclerosis"
    },
    {
        "pmid": "16730335",
        "target": "[\"Span: 5-17 years of age | Label: Age\", \"Span: dopamine type-2 receptor (DRD2) polymorphisms | Label: Gene\", \"Span: DRD2 alleles (Taq1A, -141C Ins/Del, C957T) | Label: Gene\"]",
        "text": "[Title]: Effects of short- and long-term risperidone treatment on prolactin levels in children with autism.\n[Abstract]: BACKGROUND: The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS: Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS: Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p &lt; .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p &lt; .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p &lt; .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS: Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.\n[Drug-Disease]: risperidone - autism"
    },
    {
        "pmid": "16740843",
        "target": "[\"Span: 5- to 13-year-old | Label: Age\", \"Span: iron-deficient | Label: Comorbidity\", \"Span: approximately 15 mg of iron per day | Label: Dosage\"]",
        "text": "[Title]: Iron fortification reduces blood lead levels in children in Bangalore, India.\n[Abstract]: OBJECTIVE: Chronic lead poisoning and iron deficiency are concentrated in urban children from lower socioeconomic strata, and both impair neurocognitive development. Our study objective was to determine if iron fortification reduces blood lead levels in urban, lead-exposed, iron-deficient children in Bangalore, India. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, controlled school-based feeding trial was done in 5- to 13-year-old iron-deficient children (n = 186). At baseline, a high prevalence of lead poisoning was found in the younger children. Subsequently, all 5- to 9-year-old children participating in the trial (n = 134) were followed to determine if iron fortification would affect their blood lead levels. INTERVENTION: Children were dewormed and fed 6 days/week for 16 weeks either an iron-fortified rice meal (approximately 15 mg of iron per day as ferric pyrophosphate) or an identical control meal without added iron. Feeding was directly supervised and compliance monitored. OUTCOME MEASURES: Hemoglobin, serum ferritin, C-reactive protein, transferrin receptor, zinc protoporphyrin, and blood lead concentrations were measured. RESULTS: The prevalence of iron deficiency was significantly reduced in the iron group (from 70% to 28%) compared with the control group (76% to 55%). There was a significant decrease in median blood lead concentration in the iron group compared with the control group. The prevalence of blood lead levels &gt; or =10 microg/dL was significantly reduced in the iron group (from 65% to 29%) compared with the control group (68% to 55%). CONCLUSIONS: Our findings suggest providing iron in a fortified food to lead-exposed children may reduce chronic lead intoxication. Iron fortification may be an effective and sustainable strategy to accompany environmental lead abatement.\n[Drug-Disease]: ferric pyrophosphate - lead poisoning"
    },
    {
        "pmid": "16837676",
        "target": "[\"Span: postmenopausal | Label: Body Type\", \"Span: women | Label: Gender\", \"Span: mean age, 67.5 years | Label: Age\", \"Span: CHD | Label: Comorbidity\", \"Span: multiple risk factors for CHD | Label: Comorbidity\", \"Span: 60 mg | Label: Dosage\"]",
        "text": "[Title]: Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.\n[Abstract]: BACKGROUND: The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established. METHODS: We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer. RESULTS: As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000). CONCLUSIONS: Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).\n[Drug-Disease]: raloxifene - invasive breast cancer"
    },
    {
        "pmid": "16855456",
        "target": "[\"Span: 10 men | Label: Gender\", \"Span: 10 women | Label: Gender\", \"Span: aged 38.1 +/- 8.81 years | Label: Age\", \"Span: mean dose of 222.5 +/- 85.1 mg/d | Label: Dosage\"]",
        "text": "[Title]: An open prospective study of zonisamide in acute bipolar depression.\n[Abstract]: OBJECTIVE: To examine the effectiveness and safety of zonisamide in the treatment of acute bipolar depression. METHODS: An open-label, prospective, nonrandomized, 8-week study conducted in bipolar outpatients (type I, type II, or not otherwise specified) with depressive symptoms. No patient was manic or mixed at study entry. Previous treatments were continued unchanged, but no new treatments were allowed. Montgomery Asberg Depression Rating Scale and the Mania Rating Scale from the Schedule of Affective Disorders and Schizophrenia-Change Version were used. RESULTS: Twenty patients (10 men, 10 women) with bipolar disorder (17 type I, 2 type II, 1 NOS), aged 38.1 +/- 8.81 years, received zonisamide at mean dose of 222.5 +/- 85.1 mg/d. Mean Montgomery Asberg Depression Rating Scale scores improved significantly from baseline to endpoint (mean difference = -8.4, 95% confidence interval [4.1, 12.6], P = 0.001). Ten patients (50%) terminated early due to adverse effects, mostly side effects including nausea/vomiting, cognitive impairment, and sedation. One patient experienced increased suicidal ideation, and one patient experienced hypomania. CONCLUSIONS: This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment.\n[Drug-Disease]: zonisamide - hypomania"
    },
    {
        "pmid": "16897403",
        "target": "[\"Span: aged 2.6-9.6 years | Label: Age\", \"Span: autism | Label: Comorbidity\"]",
        "text": "[Title]: An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism.\n[Abstract]: Long-term effectiveness of controlled-release melatonin in 25 children, aged 2.6-9.6 years with autism without other coexistent pathologies was evaluated openly. Sleep patterns were studied using Children's Sleep Habits Questionnaire (CSHQ) and sleep diaries at baseline, after 1-3-6 months melatonin treatment and 1 month after discontinuation. Sleep diary and CSHQ showed a more problematic sleep in autistic children compared with controls. During treatment sleep patterns of all children improved. After discontinuation 16 children returned to pre-treatment score, readministration of melatonin was again effective. Treatment gains were maintained at 12 and 24-month follow-ups. No adverse side effects were reported. In conclusion, controlled-release melatonin may provide an effective and well-tolerated treatment for autistic children with chronic sleep disorders.\n[Drug-Disease]: melatonin - sleep disorders"
    },
    {
        "pmid": "1691407",
        "target": "[\"Span: greater than or equal to 65 years | Label: Age\"]",
        "text": "[Title]: The safety and tolerability of quinapril.\n[Abstract]: Quinapril, a new angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action, has been extensively studied in patients with hypertension and congestive heart failure (CHF) during a worldwide clinical development program. A comprehensive safety data base was established to allow appropriate analyses of the extensive patient safety data. The safety of quinapril has been evaluated in 2,697 patients with hypertension and CHF, including 451 elderly patients (greater than or equal to 65 years), and has been compared with safety data from a total of 1,058 patients receiving a comparative therapy. A comparison of the double-blind studies demonstrated that quinapril has a lower incidence of adverse events and/or withdrawals than reported for captopril or enalapril. An analysis of the onset of adverse events did not show either an increase with time on quinapril therapy or a dose relationship. The proportion of patients who experienced orthostatic hypotension or hypotension was less than that of patients who were treated with captopril or enalapril. An analysis of all events (from both double-blind and long-term, open-label studies) showed no increase in the incidence of events reported in patients with CHF compared with hypertensive patients. When the data for all studies were combined, an age analysis showed no increase in the total reporting of adverse events in elderly patients compared with the younger patients studied. The incidence of adverse events was lower in those patients not receiving concomitant diuretic therapy. An overall analysis of clinical laboratory data indicated that quinapril did not have significant adverse effects on clinical laboratory parameters when compared with captopril, enalapril, or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)\n[Drug-Disease]: quinapril - CHF"
    },
    {
        "pmid": "1691407",
        "target": "[\"Span: greater than or equal to 65 years | Label: Age\"]",
        "text": "[Title]: The safety and tolerability of quinapril.\n[Abstract]: Quinapril, a new angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action, has been extensively studied in patients with hypertension and congestive heart failure (CHF) during a worldwide clinical development program. A comprehensive safety data base was established to allow appropriate analyses of the extensive patient safety data. The safety of quinapril has been evaluated in 2,697 patients with hypertension and CHF, including 451 elderly patients (greater than or equal to 65 years), and has been compared with safety data from a total of 1,058 patients receiving a comparative therapy. A comparison of the double-blind studies demonstrated that quinapril has a lower incidence of adverse events and/or withdrawals than reported for captopril or enalapril. An analysis of the onset of adverse events did not show either an increase with time on quinapril therapy or a dose relationship. The proportion of patients who experienced orthostatic hypotension or hypotension was less than that of patients who were treated with captopril or enalapril. An analysis of all events (from both double-blind and long-term, open-label studies) showed no increase in the incidence of events reported in patients with CHF compared with hypertensive patients. When the data for all studies were combined, an age analysis showed no increase in the total reporting of adverse events in elderly patients compared with the younger patients studied. The incidence of adverse events was lower in those patients not receiving concomitant diuretic therapy. An overall analysis of clinical laboratory data indicated that quinapril did not have significant adverse effects on clinical laboratory parameters when compared with captopril, enalapril, or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)\n[Drug-Disease]: quinapril - hypertensive"
    },
    {
        "pmid": "16942935",
        "target": "[]",
        "text": "[Title]: Tissue velocity echocardiography shows early improvement in diastolic function with irbesartan and atenolol therapy in patients with hypertensive left ventricular hypertrophy. Results form the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).\n[Abstract]: BACKGROUND: Abnormal diastolic function is common in hypertensive left ventricular hypertrophy (LVH). Early identification and treatment may prevent future cardiovascular events. METHODS: We examined 58 hypertensive patients with LVH, 38 with hypertension but no LVH, and 38 normotensive subjects. The effects of the AT1 receptor blocker irbesartan and the beta1 blocker atenolol on diastolic function during 48 weeks of treatment were evaluated in the LVH group by tissue velocity echocardiography (TVE). We measured basal septal and lateral wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). For comparison, diastolic function was assessed by conventional mitral pulse wave Doppler echocardiography. RESULTS: Diastolic function was impaired in both hypertensive groups. Irbesartan and atenolol (week 48, septal wall) improved IVRTm (-44%, P&lt;.001, and -19%, P&lt;.001; P&lt;or=.001 between groups), E-decm (+56%, P&lt;.001, and +53%, P&lt;.001), and Em/Am (+11%, P=.396, and +20%, P=.010). Only irbesartan improved E/Em (-4%, P=.052 v +2%, P=.041). For irbesartan, relative changes in IVRTm and in septum thickness were related (P=.017), whereas relative changes in the Em/Am ratio and in heart rate were related for atenolol (P=.027). Alterations in diastolic dysfunction were greater and detected earlier with TVE than with conventional echocardiography. CONCLUSIONS: The TVE is more sensitive than conventional echocardiography in detecting alterations in diastolic function. Both irbesartan and atenolol improve diastolic function, but through different mechanisms. The improvement in IVRTm was greater with irbesartan, and only irbesartan improved E/Em. This may have implications on the treatment of high risk hypertensive patients.\n[Drug-Disease]: irbesartan - hypertensive"
    },
    {
        "pmid": "16942935",
        "target": "[]",
        "text": "[Title]: Tissue velocity echocardiography shows early improvement in diastolic function with irbesartan and atenolol therapy in patients with hypertensive left ventricular hypertrophy. Results form the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).\n[Abstract]: BACKGROUND: Abnormal diastolic function is common in hypertensive left ventricular hypertrophy (LVH). Early identification and treatment may prevent future cardiovascular events. METHODS: We examined 58 hypertensive patients with LVH, 38 with hypertension but no LVH, and 38 normotensive subjects. The effects of the AT1 receptor blocker irbesartan and the beta1 blocker atenolol on diastolic function during 48 weeks of treatment were evaluated in the LVH group by tissue velocity echocardiography (TVE). We measured basal septal and lateral wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). For comparison, diastolic function was assessed by conventional mitral pulse wave Doppler echocardiography. RESULTS: Diastolic function was impaired in both hypertensive groups. Irbesartan and atenolol (week 48, septal wall) improved IVRTm (-44%, P&lt;.001, and -19%, P&lt;.001; P&lt;or=.001 between groups), E-decm (+56%, P&lt;.001, and +53%, P&lt;.001), and Em/Am (+11%, P=.396, and +20%, P=.010). Only irbesartan improved E/Em (-4%, P=.052 v +2%, P=.041). For irbesartan, relative changes in IVRTm and in septum thickness were related (P=.017), whereas relative changes in the Em/Am ratio and in heart rate were related for atenolol (P=.027). Alterations in diastolic dysfunction were greater and detected earlier with TVE than with conventional echocardiography. CONCLUSIONS: The TVE is more sensitive than conventional echocardiography in detecting alterations in diastolic function. Both irbesartan and atenolol improve diastolic function, but through different mechanisms. The improvement in IVRTm was greater with irbesartan, and only irbesartan improved E/Em. This may have implications on the treatment of high risk hypertensive patients.\n[Drug-Disease]: irbesartan - hypertensive left ventricular hypertrophy"
    },
    {
        "pmid": "16942935",
        "target": "[]",
        "text": "[Title]: Tissue velocity echocardiography shows early improvement in diastolic function with irbesartan and atenolol therapy in patients with hypertensive left ventricular hypertrophy. Results form the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).\n[Abstract]: BACKGROUND: Abnormal diastolic function is common in hypertensive left ventricular hypertrophy (LVH). Early identification and treatment may prevent future cardiovascular events. METHODS: We examined 58 hypertensive patients with LVH, 38 with hypertension but no LVH, and 38 normotensive subjects. The effects of the AT1 receptor blocker irbesartan and the beta1 blocker atenolol on diastolic function during 48 weeks of treatment were evaluated in the LVH group by tissue velocity echocardiography (TVE). We measured basal septal and lateral wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). For comparison, diastolic function was assessed by conventional mitral pulse wave Doppler echocardiography. RESULTS: Diastolic function was impaired in both hypertensive groups. Irbesartan and atenolol (week 48, septal wall) improved IVRTm (-44%, P&lt;.001, and -19%, P&lt;.001; P&lt;or=.001 between groups), E-decm (+56%, P&lt;.001, and +53%, P&lt;.001), and Em/Am (+11%, P=.396, and +20%, P=.010). Only irbesartan improved E/Em (-4%, P=.052 v +2%, P=.041). For irbesartan, relative changes in IVRTm and in septum thickness were related (P=.017), whereas relative changes in the Em/Am ratio and in heart rate were related for atenolol (P=.027). Alterations in diastolic dysfunction were greater and detected earlier with TVE than with conventional echocardiography. CONCLUSIONS: The TVE is more sensitive than conventional echocardiography in detecting alterations in diastolic function. Both irbesartan and atenolol improve diastolic function, but through different mechanisms. The improvement in IVRTm was greater with irbesartan, and only irbesartan improved E/Em. This may have implications on the treatment of high risk hypertensive patients.\n[Drug-Disease]: atenolol - hypertensive"
    },
    {
        "pmid": "16942935",
        "target": "[]",
        "text": "[Title]: Tissue velocity echocardiography shows early improvement in diastolic function with irbesartan and atenolol therapy in patients with hypertensive left ventricular hypertrophy. Results form the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).\n[Abstract]: BACKGROUND: Abnormal diastolic function is common in hypertensive left ventricular hypertrophy (LVH). Early identification and treatment may prevent future cardiovascular events. METHODS: We examined 58 hypertensive patients with LVH, 38 with hypertension but no LVH, and 38 normotensive subjects. The effects of the AT1 receptor blocker irbesartan and the beta1 blocker atenolol on diastolic function during 48 weeks of treatment were evaluated in the LVH group by tissue velocity echocardiography (TVE). We measured basal septal and lateral wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). For comparison, diastolic function was assessed by conventional mitral pulse wave Doppler echocardiography. RESULTS: Diastolic function was impaired in both hypertensive groups. Irbesartan and atenolol (week 48, septal wall) improved IVRTm (-44%, P&lt;.001, and -19%, P&lt;.001; P&lt;or=.001 between groups), E-decm (+56%, P&lt;.001, and +53%, P&lt;.001), and Em/Am (+11%, P=.396, and +20%, P=.010). Only irbesartan improved E/Em (-4%, P=.052 v +2%, P=.041). For irbesartan, relative changes in IVRTm and in septum thickness were related (P=.017), whereas relative changes in the Em/Am ratio and in heart rate were related for atenolol (P=.027). Alterations in diastolic dysfunction were greater and detected earlier with TVE than with conventional echocardiography. CONCLUSIONS: The TVE is more sensitive than conventional echocardiography in detecting alterations in diastolic function. Both irbesartan and atenolol improve diastolic function, but through different mechanisms. The improvement in IVRTm was greater with irbesartan, and only irbesartan improved E/Em. This may have implications on the treatment of high risk hypertensive patients.\n[Drug-Disease]: atenolol - hypertensive left ventricular hypertrophy"
    },
    {
        "pmid": "17003665",
        "target": "[\"Span: 4 girls | Label: Gender\", \"Span: 12 boys | Label: Gender\"]",
        "text": "[Title]: Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial.\n[Abstract]: OBJECTIVE: To explore placebo-controlled efficacy and safety of atomoxetine (ATX) for attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorders (ASD). METHOD: Children ages 5 to 15 with ASD and prominent ADHD symptoms were randomly assigned to order in a crossover of clinically titrated ATX and placebo, 6 weeks each, separated by 1-week washout. Slopes for each condition were compared by paired t test. RESULTS: In 2004-2005, 12 boys and 4 girls (7 with autistic disorder, 1 Asperger's, 8 pervasive developmental disorder not otherwise specified) all completed at least 3 weeks of each condition. On the primary outcome, the Hyperactivity subscale of the Aberrant Behavior Checklist, ATX was superior to placebo (p =.043, effect size d = 0.90). It was also superior on a 0 to 3 rating of nine DSM-IV ADHD hyperactive/impulsive symptoms (p =.005, d = 1.27), but missed significance on nine inattentive symptoms (p =.053, d= 0.89). Nine subjects responded to ATX, four to placebo (25% improvement on the Hyperactivity subscale plus Clinical Global Impressions-Improvement of 1-2. One was rehospitalized for recurrent violence on ATX. Adverse events were otherwise tolerable, with no tendency to stereotypy. CONCLUSIONS: ATX appears safe and effective for treating hyperactivity in some children with autism spectrum disorders. The effect appears as large as in a multisite methylphenidate trial in the same population, with fewer intolerable side effects. Further study in autism spectrum disorders is indicated.\n[Drug-Disease]: ATX - ADHD hyperactive/impulsive symptoms"
    },
    {
        "pmid": "17023870",
        "target": "[\"Span: preschool-age children | Label: Age\"]",
        "text": "[Title]: Pharmacogenetics of methylphenidate response in preschoolers with ADHD.\n[Abstract]: OBJECTIVE: The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHOD: DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped. RESULTS: Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p=.05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p=.03) andT1069C (p=.05). SNAP25 variants were also associated with tics (p=.02), buccal-lingual movements (p=.01), and irritability (p=04). DRD4 variants were also associated with picking (p=.03). Increasing dose predicted irritability (p=.05) and social withdrawal (p=.03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1). CONCLUSIONS: Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility.\n[Drug-Disease]: methylphenidate - ADHD"
    }
]