Instruction: Extract chemical and disease entities from the following text.

Input: Hypothalamic prolactin receptor messenger ribonucleic acid levels, prolactin signaling, and hyperprolactinemic inhibition of pulsatile luteinizing hormone secretion are dependent on estradiol. Hyperprolactinemia can reduce fertility and libido. Although central prolactin actions are thought to contribute to this, the mechanisms are poorly understood. We first tested whether chronic hyperprolactinemia inhibited two neuroendocrine parameters necessary for female fertility: pulsatile LH secretion and the estrogen-induced LH surge. Chronic hyperprolactinemia induced by the dopamine antagonist sulpiride caused a 40% reduction LH pulse frequency in ovariectomized rats, but only in the presence of chronic low levels of estradiol. Sulpiride did not affect the magnitude of a steroid-induced LH surge or the percentage of GnRH neurons activated during the surge. Estradiol is known to influence expression of the long form of prolactin receptors (PRL-R) and components of prolactin's signaling pathway. To test the hypothesis that estrogen increases PRL-R expression and sensitivity to prolactin, we next demonstrated that estradiol greatly augments prolactin-induced STAT5 activation. Lastly, we measured PRL-R and suppressor of cytokine signaling (SOCS-1 and -3 and CIS, which reflect the level of prolactin signaling) mRNAs in response to sulpiride and estradiol. Sulpiride induced only SOCS-1 in the medial preoptic area, where GnRH neurons are regulated, but in the arcuate nucleus and choroid plexus, PRL-R, SOCS-3, and CIS mRNA levels were also induced. Estradiol enhanced these effects on SOCS-3 and CIS. Interestingly, estradiol also induced PRL-R, SOCS-3, and CIS mRNA levels independently. These data show that GnRH pulse frequency is inhibited by chronic hyperprolactinemia in a steroid-dependent manner. They also provide evidence for estradiol-dependent and brain region-specific regulation of PRL-R expression and signaling responses by prolactin.

Output: Chemical/Disease Entities: ribonucleic acid (Chemical), hyperprolactinemic (Disease), estradiol (Chemical), Hyperprolactinemia (Disease), hyperprolactinemia (Disease), estrogen (Chemical), hyperprolactinemia (Disease), dopamine (Chemical), sulpiride (Chemical), estradiol (Chemical), Sulpiride (Chemical), steroid (Chemical), Estradiol (Chemical), estrogen (Chemical), estradiol (Chemical), sulpiride (Chemical), estradiol (Chemical), Sulpiride (Chemical), Estradiol (Chemical), estradiol (Chemical), hyperprolactinemia (Disease), steroid (Chemical), estradiol (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Estrogen prevents cholesteryl ester accumulation in macrophages induced by the HIV protease inhibitor ritonavir. Individuals with HIV can now live long lives with drug therapy that often includes protease inhibitors such as ritonavir. Many patients, however, develop negative long-term side effects such as premature atherosclerosis. We have previously demonstrated that ritonavir treatment increases atherosclerotic lesion formation in male mice to a greater extent than in female mice. Furthermore, peripheral blood monocytes isolated from ritonavir-treated females had less cholesteryl ester accumulation. In the present study, we have investigated the molecular mechanisms by which female hormones influence cholesterol metabolism in macrophages in response to the HIV protease inhibitor ritonavir. We have utilized the human monocyte cell line, THP-1 as a model to address this question. Briefly, cells were differentiated for 72 h with 100 nM PMA to obtain a macrophage-like phenotype in the presence or absence of 1 nM 17beta-estradiol (E2), 100 nM progesterone or vehicle (0.01% ethanol). Cells were then treated with 30 ng/ml ritonavir or vehicle in the presence of aggregated LDL for 24 h. Cell extracts were harvested, and lipid or total RNA was isolated. E2 decreased the accumulation of cholesteryl esters in macrophages following ritonavir treatment. Ritonavir increased the expression of the scavenger receptor, CD36 mRNA, responsible for the uptake of LDL. Additionally, ritonavir treatment selectively increased the relative levels of PPARgamma mRNA, a transcription factor responsible for the regulation of CD36 mRNA expression. Treatment with E2, however, failed to prevent these increases at the mRNA level. E2 did, however, significantly suppress CD36 protein levels as measured by fluorescent immunocytochemistry. This data suggests that E2 modifies the expression of CD36 at the level of protein expression in monocyte-derived macrophages resulting in reduced cholesteryl ester accumulation following ritonavir treatment.

Output: Chemical/Disease Entities: cholesteryl ester (Chemical), ritonavir (Chemical), ritonavir (Chemical), premature atherosclerosis (Disease), ritonavir (Chemical), atherosclerotic lesion (Disease), ritonavir (Chemical), cholesteryl ester (Chemical), cholesterol (Chemical), ritonavir (Chemical), 17beta-estradiol (Chemical), E2 (Chemical), progesterone (Chemical), ethanol (Chemical), ritonavir (Chemical), E2 (Chemical), cholesteryl esters (Chemical), ritonavir (Chemical), Ritonavir (Chemical), ritonavir (Chemical), E2 (Chemical), E2 (Chemical), E2 (Chemical), cholesteryl ester (Chemical), ritonavir (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Upregulation of brain expression of P-glycoprotein in MRP2-deficient TR(-) rats resembles seizure-induced up-regulation of this drug efflux transporter in normal rats. PURPOSE: The multidrug resistance protein 2 (MRP2) is a drug efflux transporter that is expressed predominantly at the apical domain of hepatocytes but seems also to be expressed at the apical membrane of brain capillary endothelial cells that form the blood-brain barrier (BBB). MRP2 is absent in the transport-deficient (TR(-)) Wistar rat mutant, so that this rat strain was very helpful in defining substrates of MRP2 by comparing tissue concentrations or functional activities of compounds in MRP2-deficient rats with those in transport-competent Wistar rats. By using this strategy to study the involvement of MRP2 in brain access of antiepileptic drugs (AEDs), we recently reported that phenytoin is a substrate for MRP2 in the BBB. However, one drawback of such studies in genetically deficient rats is the fact that compensatory changes with upregulation of other transporters can occur. This prompted us to study the brain expression of P-glycoprotein (Pgp), a major drug efflux transporter in many tissues, including the BBB, in TR(-) rats compared with nonmutant (wild-type) Wistar rats. METHODS: The expression of MRP2 and Pgp in brain and liver sections of TR(-) rats and normal Wistar rats was determined with immunohistochemistry, by using a novel, highly selective monoclonal MRP2 antibody and the monoclonal Pgp antibody C219, respectively. RESULTS: Immunofluorescence staining with the MRP2 antibody was found to label a high number of microvessels throughout the brain in normal Wistar rats, whereas such labeling was absent in TR(-) rats. TR(-) rats exhibited a significant up-regulation of Pgp in brain capillary endothelial cells compared with wild-type controls. No such obvious upregulation of Pgp was observed in liver sections. A comparable overexpression of Pgp in the BBB was obtained after pilocarpine-induced seizures in wild-type Wistar rats. Experiments with systemic administration of the Pgp substrate phenobarbital and the selective Pgp inhibitor tariquidar in TR(-) rats substantiated that Pgp is functional and compensates for the lack of MRP2 in the BBB. CONCLUSIONS: The data on TR(-) rats indicate that Pgp plays an important role in the compensation of MRP2 deficiency in the BBB. Because such a compensatory mechanism most likely occurs to reduce injury to the brain from cytotoxic compounds, the present data substantiate the concept that MRP2 performs a protective role in the BBB. Furthermore, our data suggest that TR(-) rats are an interesting tool to study consequences of overexpression of Pgp in the BBB on access of drugs in the brain, without the need of inducing seizures or other Pgp-enhancing events for this purpose.

Output: Chemical/Disease Entities: seizure (Disease), phenytoin (Chemical), pilocarpine (Chemical), seizures (Disease), phenobarbital (Chemical), tariquidar (Chemical), injury to the brain (Disease), seizures (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Use of chromosome substitution strains to identify seizure susceptibility loci in mice. Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) x A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.

Output: Chemical/Disease Entities: seizure (Disease), Seizure (Disease), seizure (Disease), pilocarpine (Chemical), seizures (Disease), temporal lobe epilepsy (Disease), seizure (Disease), pilocarpine (Chemical), seizures (Disease), pilocarpine (Chemical), seizures (Disease), seizures (Disease), seizure (Disease), temporal lobe epilepsy (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Investigation of mitochondrial involvement in the experimental model of epilepsy induced by pilocarpine. Mitochondrial abnormalities have been associated with several aspects of epileptogenesis, such as energy generation, control of cell death, neurotransmitter synthesis, and free radical (FR) production. Increased production of FRs may cause mtDNA damage leading to decreased activities of oxidative phosphorylation complexes containing mtDNA-encoded subunits. In this study, we investigated whether increased generation of FR during status epilepticus would be sufficient to provoke abnormalities in mtDNA and in the expression and activity of cytochrome c oxidase (CCO), complex IV of the respiratory chain, in the chronic phase of the pilocarpine model of temporal lobe epilepsy. DNA analysis revealed low amounts of a 4.8 kb mtDNA deletion but with no differences in frequency or quantity in the control and experimental groups. We did not find abnormalities in the expression and distribution of an mtDNA-encoded subunit of CCO (CCO-I) or a relative decrease in CCO-I when compared with nuclear-encoded subunits (CCO-IV and SDH-fp). No abnormality in CCO activity was observed through histochemistry. Although evidences of mitochondrial abnormalities were found in previously published studies, our results do not suggest that the FRs, generated during the acute phase, determined important abnormalities in mtDNA, in expression of CCO-I, and in CCO activity.

Output: Chemical/Disease Entities: epilepsy (Disease), pilocarpine (Chemical), Mitochondrial abnormalities (Disease), death (Disease), status epilepticus (Disease), pilocarpine (Chemical), temporal lobe epilepsy (Disease), mitochondrial abnormalities (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Causes of acute thrombotic microangiopathy in patients receiving kidney transplantation. OBJECTIVES: Thrombotic microangiopathy is a well-known problem in patients following renal transplantation. In postrenal transplantation, thrombotic microangiopathy is often a reflection of hemolytic uremic syndrome. We aimed to determine the causes of thrombotic microangiopathy in a population of renal transplantation recipients and discuss the literature. MATERIALS AND METHODS: We investigated the causes of thrombotic microangiopathy during a 1-year period, from June 2003 to June 2004, at the King Fahad National Guard Hospital in Riyadh, Saudi Arabia, by reviewing the slides of all transplant biopsies (n=25) performed during this interval. Pre- and posttransplant crossmatching was done when possible. RESULTS: Five cases of thrombotic microangiopathy were found. Three of these cases were from the 25 transplantations performed at King Fahad National Guard Hospital, while the other 2 transplantations had been performed abroad and were referred to us for follow-up. Three cases were related to cyclosporine, and 1 case was secondary to both cyclosporine and tacrolimus. The fifth case had features of thrombotic microangiopathy related to an antiphospholipid syndrome in a patient with systemic lupus erythematosus. CONCLUSIONS: In the literature, the most-frequent cause of hemolytic uremic syndrome in patients following renal transplantation is recurrence of the hemolytic uremic syndrome. Other causes include drug-related (cyclosporine, tacrolimus) toxicity, procoagulant status, and antibody-mediated rejection. We found that the most-frequent cause of thrombotic microangiopathy was drug related, secondary mainly to cyclosporine. In the current study, the frequency of thrombotic microangiopathy was similar to the percentage reported in the literature (20%).

Output: Chemical/Disease Entities: thrombotic microangiopathy (Disease), Thrombotic microangiopathy (Disease), thrombotic microangiopathy (Disease), hemolytic uremic syndrome (Disease), thrombotic microangiopathy (Disease), thrombotic microangiopathy (Disease), thrombotic microangiopathy (Disease), cyclosporine (Chemical), cyclosporine (Chemical), tacrolimus (Chemical), thrombotic microangiopathy (Disease), antiphospholipid syndrome (Disease), systemic lupus erythematosus (Disease), hemolytic uremic syndrome (Disease), hemolytic uremic syndrome (Disease), cyclosporine (Chemical), tacrolimus (Chemical), toxicity (Disease), thrombotic microangiopathy (Disease), cyclosporine (Chemical), thrombotic microangiopathy (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose. Catecholamine-induced cardiomyopathy due to chronic excess of endogenous catecholamines has been recognized for decades as a clinical phenomenon. In contrast, reports of myocardial dysfunction due to acute iatrogenic overdose are rare. A 35-year-old woman whose cervix uteri was inadvertently injected with 8 mg of epinephrine developed myocardial stunning that was characterized by severe hemodynamic compromise, profound, albeit transient, left ventricular systolic and diastolic dysfunction, and only modestly elevated biochemical markers of myocardial necrosis. Our case illustrates the serious consequences of medical errors that can be avoided through improved medication labeling and staff supervision.

Output: Chemical/Disease Entities: left ventricular systolic and diastolic dysfunction (Disease), epinephrine (Chemical), overdose (Disease), Catecholamine (Chemical), cardiomyopathy (Disease), catecholamines (Chemical), myocardial dysfunction (Disease), overdose (Disease), epinephrine (Chemical), myocardial stunning (Disease), left ventricular systolic and diastolic dysfunction (Disease), myocardial necrosis (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.

Output: Chemical/Disease Entities: Urinary bladder cancer (Disease), Wegener's granulomatosis (Disease), cyclophosphamide (Chemical), bladder cancer (Disease), cyclophosphamide (Chemical), Wegener's granulomatosis (Disease), Wegener's granulomatosis (Disease), Cancer (Disease), bladder cancer (Disease), cyclophosphamide (Chemical), bladder cancer (Disease), bladder cancer (Disease), Wegener's granulomatosis (Disease), bladder cancer (Disease), Wegener's granulomatosis (Disease), cyclophosphamide (Chemical), bladder cancer (Disease), cyclophosphamide (Chemical), bladder cancer (Disease), Wegener's granulomatosis (Disease), bladder cancer (Disease), Wegener's granulomatosis (Disease), cyclophosphamide (Chemical), bladder cancer (Disease), Wegener's granulomatosis (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: L-arginine transport in humans with cortisol-induced hypertension. A deficient L-arginine-nitric oxide system is implicated in cortisol-induced hypertension. We investigate whether abnormalities in L-arginine uptake contribute to this deficiency. Eight healthy men were recruited. Hydrocortisone acetate (50 mg) was given orally every 6 hours for 24 hours after a 5-day fixed-salt diet (150 mmol/d). Crossover studies were performed 2 weeks apart. Thirty milliliters of blood was obtained for isolation of peripheral blood mononuclear cells after each treatment period. L-arginine uptake was assessed in mononuclear cells incubated with L-arginine (1 to 300 micromol/L), incorporating 100 nmol/L [3H]-l-arginine for a period of 5 minutes at 37 degrees C. Forearm [3H]-L-arginine extraction was calculated after infusion of [3H]-L-arginine into the brachial artery at a rate of 100 nCi/min for 80 minutes. Deep forearm venous samples were collected for determination of L-arginine extraction. Plasma cortisol concentrations were significantly raised during the active phase (323+/-43 to 1082+/-245 mmol/L, P<0.05). Systolic blood pressure was elevated by an average of 7 mm Hg. Neither L-arginine transport into mononuclear cells (placebo vs active, 26.3+/-3.6 vs 29.0+/-2.1 pmol/10 000 cells per 5 minutes, respectively, at an l-arginine concentration of 300 micromol/L) nor L-arginine extraction in the forearm (at 80 minutes, placebo vs active, 1 868 904+/-434 962 vs 2 013 910+/-770 619 disintegrations per minute) was affected by cortisol treatment; ie, that L-arginine uptake is not affected by short-term cortisol treatment. We conclude that cortisol-induced increases in blood pressure are not associated with abnormalities in the l-arginine transport system.

Output: Chemical/Disease Entities: L-arginine (Chemical), cortisol (Chemical), hypertension (Disease), L-arginine (Chemical), nitric oxide (Chemical), cortisol (Chemical), hypertension (Disease), L-arginine (Chemical), Hydrocortisone acetate (Chemical), L-arginine (Chemical), L-arginine (Chemical), [3H]-l-arginine (Chemical), [3H]-L-arginine (Chemical), [3H]-L-arginine (Chemical), L-arginine (Chemical), cortisol (Chemical), L-arginine (Chemical), l-arginine (Chemical), L-arginine (Chemical), cortisol (Chemical), L-arginine (Chemical), cortisol (Chemical), cortisol (Chemical), increases in blood pressure (Disease), l-arginine (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: MR imaging with quantitative diffusion mapping of tacrolimus-induced neurotoxicity in organ transplant patients. Our objective was to investigate brain MR imaging findings and the utility of diffusion-weighted (DW) imaging in organ transplant patients who developed neurologic symptoms during tacrolimus therapy. Brain MR studies, including DW imaging, were prospectively performed in 14 organ transplant patients receiving tacrolimus who developed neurologic complications. In each patient who had abnormalities on the initial MR study, a follow-up MR study was performed 1 month later. Apparent diffusion coefficient (ADC) values on the initial MR study were correlated with reversibility of the lesions. Of the 14 patients, 5 (35.7%) had white matter abnormalities, 1 (7.1%) had putaminal hemorrhage, and 8 (57.1%) had normal findings on initial MR images. Among the 5 patients with white matter abnormalities, 4 patients (80.0%) showed higher than normal ADC values on initial MR images, and all showed complete resolution on follow-up images. The remaining 1 patient (20.0%) showed lower than normal ADC value and showed incomplete resolution with cortical laminar necrosis. Diffusion-weighted imaging may be useful in predicting the outcomes of the lesions of tacrolimus-induced neurotoxicity.

Output: Chemical/Disease Entities: tacrolimus (Chemical), neurotoxicity (Disease), tacrolimus (Chemical), tacrolimus (Chemical), neurologic complications (Disease), white matter abnormalities (Disease), putaminal hemorrhage (Disease), white matter abnormalities (Disease), cortical laminar necrosis (Disease), tacrolimus (Chemical), neurotoxicity (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Octreotide-induced hypoxemia and pulmonary hypertension in premature neonates. The authors report 2 cases of premature neonates who had enterocutaneous fistula complicating necrotizing enterocolitis. Pulmonary hypertension developed after administration of a somatostatin analogue, octreotide, to enhance resolution of the fistula. The authors discuss the mechanism of the occurrence of this complication and recommend caution of its use in high-risk premature neonates.

Output: Chemical/Disease Entities: Octreotide (Chemical), hypoxemia (Disease), pulmonary hypertension (Disease), fistula (Disease), necrotizing enterocolitis (Disease), Pulmonary hypertension (Disease), octreotide (Chemical), fistula (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Sequential observations of exencephaly and subsequent morphological changes by mouse exo utero development system: analysis of the mechanism of transformation from exencephaly to anencephaly. Anencephaly has been suggested to develop from exencephaly; however, there is little direct experimental evidence to support this, and the mechanism of transformation remains unclear. We examined this theory using the exo utero development system that allows direct and sequential observations of mid- to late-gestation mouse embryos. We observed the exencephaly induced by 5-azacytidine at embryonic day 13.5 (E13.5), let the embryos develop exo utero until E18.5, and re-observed the same embryos at E18.5. We confirmed several cases of transformation from exencephaly to anencephaly. However, in many cases, the exencephalic brain tissue was preserved with more or less reduction during this period. To analyze the transformation patterns, we classified the exencephaly by size and shape of the exencephalic tissue into several types at E13.5 and E18.5. It was found that the transformation of exencephalic tissue was not simply size-dependent, and all cases of anencephaly at E18.5 resulted from embryos with a large amount of exencephalic tissue at E13.5. Microscopic observation showed the configuration of exencephaly at E13.5, frequent hemorrhaging and detachment of the neural plate from surface ectoderm in the exencephalic head at E15.5, and multiple modes of reduction in the exencephalic tissue at E18.5. From observations of the vasculature, altered distribution patterns of vessels were identified in the exencephalic head. These findings suggest that overgrowth of the exencephalic neural tissue causes the altered distribution patterns of vessels, subsequent peripheral circulatory failure and/or hemorrhaging in various parts of the exencephalic head, leading to the multiple modes of tissue reduction during transformation from exencephaly to anencephaly.

Output: Chemical/Disease Entities: exencephaly (Disease), exencephaly (Disease), anencephaly (Disease), Anencephaly (Disease), exencephaly (Disease), exencephaly (Disease), 5-azacytidine (Chemical), exencephaly (Disease), anencephaly (Disease), exencephalic (Disease), exencephaly (Disease), exencephalic (Disease), exencephalic (Disease), anencephaly (Disease), exencephalic (Disease), exencephaly (Disease), hemorrhaging (Disease), exencephalic (Disease), exencephalic (Disease), exencephalic (Disease), exencephalic (Disease), circulatory failure (Disease), hemorrhaging (Disease), exencephalic (Disease), exencephaly (Disease), anencephaly (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Acute cocaine-induced seizures: differential sensitivity of six inbred mouse strains. Mature male and female mice from six inbred stains were tested for susceptibility to behavioral seizures induced by a single injection of cocaine. Cocaine was injected ip over a range of doses (50-100 mg/kg) and behavior was monitored for 20 minutes. Seizure end points included latency to forelimb or hindlimb clonus, latency to clonic running seizure and latency to jumping bouncing seizure. A range of strain specific sensitivities was documented with A/J and SJL mice being most sensitive and C57BL/6J most resistant. DBA/2J, BALB/cByJ and NZW/LacJ strains exhibited intermediate sensitivity. EEG recordings were made in SJL, A/J and C57BL/6J mice revealing a close correspondence between electrical activity and behavior. Additionally, levels of cocaine determined in hippocampus and cortex were not different between sensitive and resistant strains. Additional studies of these murine strains may be useful for investigating genetic influences on cocaine-induced seizures.

Output: Chemical/Disease Entities: cocaine (Chemical), seizures (Disease), seizures (Disease), cocaine (Chemical), Cocaine (Chemical), Seizure (Disease), seizure (Disease), seizure (Disease), cocaine (Chemical), cocaine (Chemical), seizures (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy. We describe 3 episodes of microangiopathic hemolytic anemia (MAHA) in 2 solid organ recipients under FK506 (tacrolimus) therapy. In both cases, discontinuation of FK506 and treatment with plasma exchange, fresh frozen plasma replacement, corticosteroids, aspirin, and dipyridamole led to resolution of MAHA. In one patient, reintroduction of FK506 led to rapid recurrence of MAHA. FK506-associated MAHA is probably rare but physicians must be aware of this severe complication. In our experience and according to the literature, FK506 does not seem to cross-react with cyclosporin A (CyA), an immuno-suppressive drug already known to induce MAHA.

Output: Chemical/Disease Entities: Microangiopathic hemolytic anemia (Disease), FK506 (Chemical), tacrolimus (Chemical), microangiopathic hemolytic anemia (Disease), MAHA (Disease), FK506 (Chemical), tacrolimus (Chemical), FK506 (Chemical), corticosteroids (Chemical), aspirin (Chemical), dipyridamole (Chemical), MAHA (Disease), FK506 (Chemical), MAHA (Disease), FK506 (Chemical), MAHA (Disease), FK506 (Chemical), cyclosporin A (Chemical), CyA (Chemical), MAHA (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Variant ventricular tachycardia in desipramine toxicity. We report a case of variant ventricular tachycardia induced by desipramine toxicity. Unusual features of the arrhythmia are repetitive group beating, progressive shortening of the R-R interval, progressive widening of the QRS complex with eventual failure of intraventricular conduction, and changes in direction of the QRS axis. Recognition of variant ventricular tachycardia is important because therapy differs from that of classic ventricular tachycardia.

Output: Chemical/Disease Entities: ventricular tachycardia (Disease), desipramine (Chemical), toxicity (Disease), ventricular tachycardia (Disease), desipramine (Chemical), toxicity (Disease), arrhythmia (Disease), ventricular tachycardia (Disease), ventricular tachycardia (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Desipramine-induced delirium at "subtherapeutic" concentrations: a case report. An elderly patient treated with low dose Desipramine developed a delirium while her plasma level was in the "subtherapeutic" range. Delirium, which may be induced by tricyclic drug therapy in the elderly, can be caused by tricyclics with low anticholinergic potency. Therapeutic ranges for antidepressants that have been derived from general adult population studies may not be appropriate for the elderly. Further studies of specifically elderly patients are now required to establish safer and more appropriate guidelines for drug therapy.

Output: Chemical/Disease Entities: Desipramine (Chemical), delirium (Disease), Desipramine (Chemical), delirium (Disease), Delirium (Disease), antidepressants (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Mouse strain-dependent effect of amantadine on motility and brain biogenic amines. The effect of amantadine hydrochloride, injected i.p. in 6 increments of 100 mg/kg each over 30 hr, on mouse motility and whole brain content of selected biogenic amines and major metabolites was studied in 4 strains of mice. These were the albino Sprague-Dawley ICR and BALB/C, the black C57BL/6 and the brown CDF-I mouse strains. Amantadine treatment produced a biphasic effect on mouse motility. The initial dose of amantadine depressed locomotor activity in all mouse strains studied with the BALB/C mice being the most sensitive. Subsequent amantadine treatments produced enhancement of motility from corresponding control in all mouse strains with the BALB/C mice being the least sensitive. The locomotor activity was decreased from corresponding controls in all strains studied, except for the ICR mice, during an overnight drug-free period following the fourth amantadine treatment. Readministration of amantadine, after a drug-free overnight period, increased motility from respective saline control in all strains with exception of the BALB/C mice where suppression of motility occurred. Treatment with amantadine did not alter whole brain dopamine levels but decreased the amounts of 3,4-dihydroxyphenylacetic acid in the BALB/C mice compared to saline control. Conversely, brain normetanephrine concentration was increased from saline control by amantadine in the BALB/C mice. The results suggest a strain-dependent effect of amantadine on motility and indicate a differential response to the acute and multiple dose regimens used. The BALB/C mouse was the most sensitive strain and could serve as the strain of choice for evaluating the side effects of amantadine. The biochemical results of brain biogenic amines of BALB/C mouse strain suggest a probable decrease of catecholamine turnover rate and/or metabolism by monoamine oxidase and a resulting increase in O-methylation of norepinephrine which may account for a behavioral depression caused by amantadine in the BALB/C mice.

Output: Chemical/Disease Entities: amantadine (Chemical), amines (Chemical), amantadine hydrochloride (Chemical), amines (Chemical), Amantadine (Chemical), amantadine (Chemical), depressed (Disease), amantadine (Chemical), amantadine (Chemical), amantadine (Chemical), suppression of motility (Disease), amantadine (Chemical), dopamine (Chemical), 3,4-dihydroxyphenylacetic acid (Chemical), normetanephrine (Chemical), amantadine (Chemical), amantadine (Chemical), amantadine (Chemical), amines (Chemical), catecholamine (Chemical), norepinephrine (Chemical), behavioral depression (Disease), amantadine (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: No enhancement by phenobarbital of the hepatocarcinogenicity of a choline-devoid diet in the rat. An experiment was performed to test whether inclusion of phenobarbital in a choline-devoid diet would increase the hepatocarcinogenicity of the diet. Groups of 5-week old male Fischer-344 rats were fed for 7-25 months semipurified choline-devoid or choline-supplemented diets, containing or not 0.06% phenobarbital. No hepatic preneoplastic nodules or hepatocellular carcinomas developed in rats fed the plain choline-supplemented diet, while one preneoplastic nodule and one hepatocellular carcinoma developed in two rats fed the same diet containing phenobarbital. The incidence of preneoplastic nodules and of hepatocellular carcinomas was 10% and 37%, respectively, in rats fed the plain choline-devoid diet, and 17% and 30%, in rats fed the phenobarbital-containing choline-devoid diet. The results evinced no enhancement of the hepatocarcinogenicity of the choline-devoid diet by phenobarbital. Sporadic neoplastic lesions were observed in organs other than the liver of some of the animals, irrespective of the diet fed.

Output: Chemical/Disease Entities: phenobarbital (Chemical), choline (Chemical), phenobarbital (Chemical), choline (Chemical), choline (Chemical), choline (Chemical), phenobarbital (Chemical), hepatocellular carcinomas (Disease), choline (Chemical), hepatocellular carcinoma (Disease), phenobarbital (Chemical), hepatocellular carcinomas (Disease), choline (Chemical), phenobarbital (Chemical), choline (Chemical), choline (Chemical), phenobarbital (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Effect of direct intracoronary administration of methylergonovine in patients with and without variant angina. The effects of intracoronary administration of methylergonovine were studied in 21 patients with variant angina and 22 patients with atypical chest pain and in others without angina pectoris (control group). Methylergonovine was administered continuously at a rate of 10 micrograms/min up to 50 micrograms. In all patients with variant angina, coronary spasm was provoked at a mean dose of 28 +/- 13 micrograms (mean +/- SD). In the control group neither ischemic ST change nor localized spasm occurred. The basal tone of the right coronary artery was significantly lower than that of the left coronary artery. The percentage of vasoconstriction of the right coronary artery was significantly higher than that of the left coronary artery. These results suggest that spasm provocation tests, which use an intracoronary injection of a relatively low dose of methylergonovine, have a high sensitivity in variant angina and the vasoreactivity of the right coronary artery may be greater than that of the other coronary arteries.

Output: Chemical/Disease Entities: methylergonovine (Chemical), variant angina (Disease), methylergonovine (Chemical), variant angina (Disease), chest pain (Disease), angina pectoris (Disease), Methylergonovine (Chemical), variant angina (Disease), coronary spasm (Disease), spasm (Disease), spasm (Disease), methylergonovine (Chemical), variant angina (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer. Doxorubicin is an effective anticancer chemotherapeutic agent known to cause acute and chronic cardiomyopathy. To develop a more sensitive echocardiographic screening test for cardiac damage due to doxorubicin, a cohort study was performed using dobutamine infusion to differentiate asymptomatic long-term survivors of childhood cancer treated with doxorubicin from healthy control subjects. Echocardiographic data from the experimental group of 21 patients (mean age 16 +/- 5 years) treated from 1.6 to 14.3 years (median 5.3) before this study with 27 to 532 mg/m2 of doxorubicin (mean 196) were compared with echocardiographic data from 12 normal age-matched control subjects. Graded dobutamine infusions of 0.5, 2.5, 5 and 10 micrograms/kg per min were administered. Echocardiographic Doppler studies were performed before infusion and after 15 min of infusion at each rate. Dobutamine infusion at 10 micrograms/kg per min was discontinued after six studies secondary to a 50% incidence rate of adverse symptoms. The most important findings were that compared with values in control subjects, end-systolic left ventricular posterior wall dimension and percent of left ventricular posterior wall thickening in doxorubicin-treated patients were decreased at baseline study and these findings were more clearly delineated with dobutamine stimulation. End-systolic left ventricular posterior wall dimension at baseline for the doxorubicin-treated group was 11 +/- 1.9 mm versus 13.1 +/- 1.5 mm for control subjects (p less than 0.01). End-systolic left ventricular posterior wall dimension at the 5-micrograms/kg per min dobutamine infusion for the doxorubicin-treated group was 14.1 +/- 2.4 mm versus 19.3 +/- 2.6 mm for control subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Output: Chemical/Disease Entities: Dobutamine (Chemical), doxorubicin (Chemical), cancer (Disease), Doxorubicin (Chemical), cardiomyopathy (Disease), cardiac damage (Disease), doxorubicin (Chemical), dobutamine (Chemical), cancer (Disease), doxorubicin (Chemical), doxorubicin (Chemical), dobutamine (Chemical), Dobutamine (Chemical), doxorubicin (Chemical), dobutamine (Chemical), doxorubicin (Chemical), dobutamine (Chemical), doxorubicin (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Effects of aminophylline on the threshold for initiating ventricular fibrillation during respiratory failure. Cardiac arrhythmias have frequently been reported in association with respiratory failure. The possible additive role of pharmacologic agents in precipitating cardiac disturbances in patients with respiratory failure has only recently been emphasized. The effects of aminophylline on the ventricular fibrillation threshold during normal acid-base conditions and during respiratory failure were studied in anesthetized open chest dogs. The ventricular fibrillation threshold was measured by passing a gated train of 12 constant current pulses through the ventricular myocardium during the vulnerable period of the cardiac cycle. During the infusion of aminophylline, the ventricular fibrillation threshold was reduced by 30 to 40 percent of the control when pH and partial pressures of oxygen (PO2) and carbon dioxide (CO2) were kept within normal limits. When respiratory failure was produced by hypoventilation (pH 7.05 to 7.25; PC02 70 to 100 mm Hg: P02 20 to 40 mm Hg), infusion of aminophylline resulted in an even greater decrease in ventricular fibrillation threshold to 60 percent of the control level. These experiments suggest that although many factors may contribute to the increased incidence of ventricular arrhythmias in respiratory failure, pharmacologic agents, particularly aminophylline, may play a significant role.

Output: Chemical/Disease Entities: aminophylline (Chemical), ventricular fibrillation (Disease), respiratory failure (Disease), Cardiac arrhythmias (Disease), respiratory failure (Disease), cardiac disturbances (Disease), respiratory failure (Disease), aminophylline (Chemical), ventricular fibrillation (Disease), respiratory failure (Disease), ventricular fibrillation (Disease), aminophylline (Chemical), ventricular fibrillation (Disease), oxygen (Chemical), PO2 (Chemical), carbon dioxide (Chemical), CO2 (Chemical), respiratory failure (Disease), hypoventilation (Disease), aminophylline (Chemical), ventricular fibrillation (Disease), ventricular arrhythmias (Disease), respiratory failure (Disease), aminophylline (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Case report: acute unintentional carbachol intoxication. INTRODUCTION: Intoxications with carbachol, a muscarinic cholinergic receptor agonist are rare. We report an interesting case investigating a (near) fatal poisoning. METHODS: The son of an 84-year-old male discovered a newspaper report stating clinical success with plant extracts in Alzheimer's disease. The mode of action was said to be comparable to that of the synthetic compound 'carbamylcholin'; that is, carbachol. He bought 25 g of carbachol as pure substance in a pharmacy, and the father was administered 400 to 500 mg. Carbachol concentrations in serum and urine on day 1 and 2 of hospital admission were analysed by HPLC-mass spectrometry. RESULTS: Minutes after oral administration, the patient developed nausea, sweating and hypotension, and finally collapsed. Bradycardia, cholinergic symptoms and asystole occurred. Initial cardiopulmonary resuscitation and immediate treatment with adrenaline (epinephrine), atropine and furosemide was successful. On hospital admission, blood pressure of the intubated, bradyarrhythmic patient was 100/65 mmHg. Further signs were hyperhidrosis, hypersalivation, bronchorrhoea, and severe miosis; the electrocardiographic finding was atrio-ventricular dissociation. High doses of atropine (up to 50 mg per 24 hours), adrenaline and dopamine were necessary. The patient was extubated 1 week later. However, increased dyspnoea and bronchospasm necessitated reintubation. Respiratory insufficiency was further worsened by Proteus mirabilis infection and severe bronchoconstriction. One week later, the patient was again extubated and 3 days later was transferred to a peripheral ward. On the next day he died, probably as a result of heart failure. Serum samples from the first and second days contained 3.6 and 1.9 mg/l carbachol, respectively. The corresponding urine concentrations amounted to 374 and 554 mg/l. CONCLUSION: This case started with a media report in a popular newspaper, initiated by published, peer-reviewed research on herbals, and involved human failure in a case history, medical examination and clinical treatment. For the first time, an analytical method for the determination of carbachol in plasma and urine has been developed. The analysed carbachol concentration exceeded the supposed serum level resulting from a therapeutic dose by a factor of 130 to 260. Especially in old patients, intensivists should consider intoxications (with cholinergics) as a cause of acute cardiovascular failure.

Output: Chemical/Disease Entities: carbachol (Chemical), carbachol (Chemical), poisoning (Disease), Alzheimer's disease (Disease), carbamylcholin (Chemical), carbachol (Chemical), carbachol (Chemical), Carbachol (Chemical), nausea (Disease), hypotension (Disease), Bradycardia (Disease), asystole (Disease), adrenaline (Chemical), epinephrine (Chemical), atropine (Chemical), furosemide (Chemical), hyperhidrosis (Disease), hypersalivation (Disease), bronchorrhoea (Disease), miosis (Disease), atrio-ventricular dissociation (Disease), atropine (Chemical), adrenaline (Chemical), dopamine (Chemical), dyspnoea (Disease), bronchospasm (Disease), Respiratory insufficiency (Disease), Proteus mirabilis infection (Disease), heart failure (Disease), carbachol (Chemical), carbachol (Chemical), carbachol (Chemical), acute cardiovascular failure (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Crossover comparison of efficacy and preference for rizatriptan 10 mg versus ergotamine/caffeine in migraine. Rizatriptan is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This randomized double- blind crossover outpatient study assessed the preference for 1 rizatriptan 10 mg tablet to 2 ergotamine 1 mg/caffeine 100 mg tablets in 439 patients treating a single migraine attack with each therapy. Of patients expressing a preference (89.1%), more than twice as many preferred rizatriptan to ergotamine/caffeine (69.9 vs. 30.1%, p < or = 0.001). Faster relief of headache was the most important reason for preference, cited by 67.3% of patients preferring rizatriptan and 54.2% of patients who preferred ergotamine/caffeine. The co-primary endpoint of being pain free at 2 h was also in favor of rizatriptan. Forty-nine percent of patients were pain free 2 h after rizatriptan, compared with 24.3% treated with ergotamine/caffeine (p < or = 0.001), rizatriptan being superior within 1 h of treatment. Headache relief at 2 h was 75.9% for rizatriptan and 47.3% for ergotamine/caffeine (p < or = 0.001), with rizatriptan being superior to ergotamine/caffeine within 30 min of dosing. Almost 36% of patients taking rizatriptan were pain free at 2 h and had no recurrence or need for additional medication within 24 h, compared to 20% of patients on ergotamine/caffeine (p < or = 0.001). Rizatriptan was also superior to ergotamine/caffeine in the proportions of patients with no nausea, vomiting, phonophobia or photophobia and for patients with normal function 2 h after drug intake (p < or = 0.001). More patients were (completely, very or somewhat) satisfied 2 h after treatment with rizatriptan (69.8%) than at 2 h after treatment with ergotamine/caffeine (38.6%, p < or = 0.001). Recurrence rates were 31.4% with rizatriptan and 15.3% with ergotamine/caffeine. Both active treatments were well tolerated. The most common adverse events (incidence > or = 5% in one group) after rizatriptan and ergotamine/caffeine, respectively, were dizziness (6.7 and 5.3%), nausea (4.2 and 8.5%) and somnolence (5.5 and 2.3%).

Output: Chemical/Disease Entities: rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), migraine (Disease), Rizatriptan (Chemical), 5-HT (Chemical), migraine (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), migraine (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), headache (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), pain (Disease), rizatriptan (Chemical), pain (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), rizatriptan (Chemical), Headache (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), rizatriptan (Chemical), pain (Disease), ergotamine (Chemical), caffeine (Chemical), Rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), nausea (Disease), vomiting (Disease), phonophobia (Disease), photophobia (Disease), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), rizatriptan (Chemical), ergotamine (Chemical), caffeine (Chemical), dizziness (Disease), nausea (Disease), somnolence (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Five patients with carcinoma developed thrombotic microangiopathy (characterized by renal insufficiency, microangiopathic hemolytic anemia, and usually thrombocytopenia) after treatment with cisplatin, bleomycin, and a vinca alkaloid. One patient had thrombotic thrombocytopenic purpura, three the hemolytic-uremic syndrome, and one an apparent forme fruste of one of these disorders. Histologic examination of the renal tissue showed evidence of intravascular coagulation, primarily affecting the small arteries, arterioles, and glomeruli. Because each patient was tumor-free or had only a small tumor at the onset of this syndrome, the thrombotic microangiopathy may have been induced by chemotherapy. Diagnosis of this potentially fatal complication may be delayed or missed if renal tissue or the peripheral blood smear is not examined, because renal failure may be ascribed to cisplatin nephrotoxicity and the anemia and thrombocytopenia to drug-induced bone marrow suppression.

Output: Chemical/Disease Entities: Thrombotic microangiopathy (Disease), renal failure (Disease), carcinoma (Disease), thrombotic microangiopathy (Disease), renal insufficiency (Disease), microangiopathic hemolytic anemia (Disease), thrombocytopenia (Disease), cisplatin (Chemical), bleomycin (Chemical), vinca alkaloid (Chemical), thrombotic thrombocytopenic purpura (Disease), hemolytic-uremic syndrome (Disease), intravascular coagulation (Disease), tumor (Disease), tumor (Disease), thrombotic microangiopathy (Disease), renal failure (Disease), cisplatin (Chemical), nephrotoxicity (Disease), anemia (Disease), thrombocytopenia (Disease), bone marrow suppression (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. A combination of 5 d of nelarabine (AraG) with 5 d of etoposide (VP) and cyclophosphamide (CPM) and prophylactic intrathecal chemotherapy was used as salvage therapy in seven children with refractory or relapsed T-cell leukaemia or lymphoma. The most common side effects attributable to the AraG included Grade 2 and 3 sensory and motor neuropathy and musculoskeletal pain. Haematological toxicity was greater for the combination than AraG alone, although median time to neutrophil and platelet recovery was consistent with other salvage therapies. All patients had some response to the combined therapy and five of the seven went into complete remission after one or two courses of AraG/VP/CPM. Our experience supports the safety of giving AraG as salvage therapy in synchrony with etoposide and cyclophosphamide, although neurological toxicity must be closely monitored.

Output: Chemical/Disease Entities: nelarabine (Chemical), etoposide (Chemical), cyclophosphamide (Chemical), nelarabine (Chemical), AraG (Chemical), etoposide (Chemical), VP (Chemical), cyclophosphamide (Chemical), CPM (Chemical), AraG (Chemical), neuropathy (Disease), musculoskeletal pain (Disease), Haematological toxicity (Disease), AraG (Chemical), AraG (Chemical), VP (Chemical), CPM (Chemical), AraG (Chemical), etoposide (Chemical), cyclophosphamide (Chemical), neurological toxicity (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: The 3-week sulphasalazine syndrome strikes again. A 34-year-old lady developed a constellation of dermatitis, fever, lymphadenopathy and hepatitis, beginning on the 17th day of a course of oral sulphasalazine for sero-negative rheumatoid arthritis. Cervical and inguinal lymph node biopsies showed the features of severe necrotising lymphadenitis, associated with erythrophagocytosis and prominent eosinophilic infiltrates, without viral inclusion bodies, suggestive of an adverse drug reaction.A week later, fulminant drug-induced hepatitis, associated with the presence of anti-nuclear autoantibodies (but not with other markers of autoimmunity), and accompanied by multi-organ failure and sepsis, supervened. She subsequently died some 5 weeks after the commencement of her drug therapy.Post-mortem examination showed evidence of massive hepatocellular necrosis, acute hypersensitivity myocarditis, focal acute tubulo-interstitial nephritis and extensive bone marrow necrosis, with no evidence of malignancy. It is thought that the clinico-pathological features and chronology of this case bore the hallmarks of the so-called "3-week sulphasalazine syndrome", a rare, but often fatal, immunoallergic reaction to sulphasalazine.

Output: Chemical/Disease Entities: sulphasalazine (Chemical), dermatitis (Disease), fever (Disease), lymphadenopathy (Disease), hepatitis (Disease), sulphasalazine (Chemical), rheumatoid arthritis (Disease), lymphadenitis (Disease), adverse drug reaction (Disease), drug-induced hepatitis (Disease), autoimmunity (Disease), multi-organ failure (Disease), sepsis (Disease), massive hepatocellular necrosis (Disease), myocarditis (Disease), nephritis (Disease), bone marrow necrosis (Disease), malignancy (Disease), sulphasalazine (Chemical), sulphasalazine (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Bupropion (Zyban) toxicity. Bupropion is a monocyclic antidepressant structurally related to amphetamine. Zyban, a sustained-release formulation of bupropion hydrochloride, was recently released in Ireland, as a smoking cessation aid. In the initial 6 months since it's introduction, 12 overdose cases have been reported to The National Poisons Information Centre. 8 patients developed symptoms of toxicity. Common features included tachycardia, drowsiness, hallucinations and convulsions. Two patients developed severe cardiac arrhythmias, including one patient who was resuscitated following a cardiac arrest. All patients recovered without sequelae. We report a case of a 31 year old female who required admission to the Intensive Care Unit for ventilation and full supportive therapy, following ingestion of 13.5g bupropion. Recurrent seizures were treated with diazepam and broad complex tachycardia was successfully treated with adenosine. Zyban caused significant neurological and cardiovascular toxicity in overdose. The potential toxic effects should be considered when prescribing it as a smoking cessation aid.

Output: Chemical/Disease Entities: Bupropion (Chemical), Zyban (Chemical), toxicity (Disease), Bupropion (Chemical), antidepressant (Chemical), amphetamine (Chemical), Zyban (Chemical), bupropion hydrochloride (Chemical), overdose (Disease), toxicity (Disease), tachycardia (Disease), hallucinations (Disease), convulsions (Disease), cardiac arrhythmias (Disease), cardiac arrest (Disease), bupropion (Chemical), seizures (Disease), diazepam (Chemical), tachycardia (Disease), adenosine (Chemical), Zyban (Chemical), overdose (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Survey of complications of indocyanine green angiography in Japan. PURPOSE: We evaluated the safety of indocyanine green for use in fundus angiography. METHODS: We sent a questionnaire concerning complications of indocyanine green to 32 institutions in Japan, which were selected on the basis of the client list from the Topcon Company, which manufactures the indocyanine green fundus camera. RESULTS: Ophthalmologists at 15 institutions responded, reporting a total of 3,774 indocyanine green angiograms performed on 2,820 patients between June 1984 and September 1992. Before angiography, intradermal or intravenous indocyanine green testing, or both was performed at 13 of 15 institutions. For three patients, the decision was made not to proceed with angiography after positive preangiographic testing. The dosage of indocyanine green used for angiography varied from 25 to 75 mg, depending upon the institution. There were 13 cases of adverse reactions (0.34%), ten of which were mild reactions such as nausea, exanthema, urtication, itchiness, and urgency to defecate, and did not require treatment. Also recorded were one case of pain of the vein, which required treatment, and two cases of hypotension. The two hypotensive patients required treatment for shock. CONCLUSIONS: A comparison of frequency of adverse reactions to indocyanine green with the previously reported frequency of such reactions to fluorescein sodium indicated that indocyanine green is a safe as fluorescein for use in angiography.

Output: Chemical/Disease Entities: indocyanine green (Chemical), indocyanine green (Chemical), indocyanine green (Chemical), indocyanine green (Chemical), indocyanine green (Chemical), indocyanine green (Chemical), indocyanine green (Chemical), nausea (Disease), exanthema (Disease), urtication (Disease), itchiness (Disease), pain (Disease), hypotension (Disease), hypotensive (Disease), shock (Disease), indocyanine green (Chemical), fluorescein sodium (Chemical), indocyanine green (Chemical), fluorescein (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Bradykinin receptors antagonists and nitric oxide synthase inhibitors in vincristine and streptozotocin induced hyperalgesia in chemotherapy and diabetic neuropathy rat model. PURPOSE: The influence of an irreversible inhibitor of constitutive NO synthase (L-NOArg; 1.0 mg/kg ip), a relatively selective inhibitor of inducible NO synthase (L-NIL; 1.0 mg/kg ip) and a relatively specific inhibitor of neuronal NO synthase (7-NI; 0.1 mg/kg ip), on antihyperalgesic action of selective antagonists of B2 and B1 receptors: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin (HOE 140; 70 nmol/kg ip) or des Arg10 HOE 140 (70 nmol/kg ip) respectively, in model of diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy was investigated. METHODS: The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal test described by Randall-Selitto. RESULTS: The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia. Pretreatment with L-NOArg and L-NIL but not 7-NI, significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140. It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine. Moreover, L-NOArg and 7-NI but not L-NIL intensify antihyperalgesic activity of HOE 140 or des-Arg10HOE 140 in toxic neuropathy. CONCLUSIONS: Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy. In streptozotocin-induced hyperalgesia, inducible NO synthase participates in pronociceptive activity of bradykinin, whereas in vincristine-induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway. Therefore, concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain, even in hospital care.

Output: Chemical/Disease Entities: Bradykinin (Chemical), nitric oxide (Chemical), vincristine (Chemical), streptozotocin (Chemical), hyperalgesia (Disease), diabetic neuropathy (Disease), NO (Chemical), NO (Chemical), NO (Chemical), bradykinin (Chemical), HOE 140 (Chemical), des Arg10 HOE 140 (Chemical), pain (Disease), bradykinin (Chemical), NO (Chemical), NO (Chemical), diabetic hyperalgesia (Disease), HOE 140 (Chemical), des Arg10 HOE 140 (Chemical), NO (Chemical), NO (Chemical), bradykinin (Chemical), hyperalgesia (Disease), vincristine (Chemical), HOE 140 (Chemical), des-Arg10HOE 140 (Chemical), toxic neuropathy (Disease), streptozotocin (Chemical), hyperalgesia (Disease), NO (Chemical), bradykinin (Chemical), vincristine (Chemical), hyperalgesia (Disease), bradykinin (Chemical), NO (Chemical), bradykinin (Chemical), NO (Chemical), neuropathic pain (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer. INTRODUCTION: Cyclophosphamide is an alkylating agent given frequently as a component of many conditioning regimens. In high doses, its nonhematological dose-limiting toxicity is cardiomyopathy. STUDY DESIGN: We combined paclitaxel, melphalan and high-dose cyclophosphamide, thiotepa, and carboplatin in a triple sequential high-dose regimen for patients with metastatic breast cancer. Analysis was performed on 61 women with chemotherapy-responsive metastatic breast cancer receiving 96-h infusional cyclophosphamide as part of a triple sequential high-dose regimen to assess association between presence of peritransplant congestive heart failure (CHF) and the following pretreatment characteristics: presence of electrocardiogram (EKG) abnormalities, age, hypertension, prior cardiac history, smoking, diabetes mellitus, prior use of anthracyclines, and left-sided chest irradiation. RESULTS: Six of 61 women (10%) developed clinically reversible grade 3 CHF following infusional cyclophosphamide with a median percent decline in ejection fraction of 31%. Incidence of transient cyclophosphamide-related cardiac toxicity (10%) is comparable to previous recorded literature. Older age was significantly correlated with the CHF development; with median ages for the entire group and for patients developing CHF of 45 and 59, respectively. No association was found with other pretreatment characteristics. CONCLUSIONS: As a result of these findings, oncologists should carefully monitor fluid balance in older patients. Routine EKG monitoring during infusional cyclophosphamide did not predict CHF development.

Output: Chemical/Disease Entities: Cardiac toxicity (Disease), cyclophosphamide (Chemical), breast cancer (Disease), Cyclophosphamide (Chemical), toxicity (Disease), cardiomyopathy (Disease), paclitaxel (Chemical), melphalan (Chemical), cyclophosphamide (Chemical), thiotepa (Chemical), carboplatin (Chemical), breast cancer (Disease), breast cancer (Disease), cyclophosphamide (Chemical), congestive heart failure (Disease), CHF (Disease), hypertension (Disease), diabetes mellitus (Disease), anthracyclines (Chemical), CHF (Disease), cyclophosphamide (Chemical), cyclophosphamide (Chemical), cardiac toxicity (Disease), CHF (Disease), CHF (Disease), cyclophosphamide (Chemical), CHF (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.

Output: Chemical/Disease Entities: carbamazepine (Chemical), vigabatrin (Chemical), absence seizures (Disease), Carbamazepine (Chemical), vigabatrin (Chemical), absence seizures (Disease), carbamazepine (Chemical), Vigabatrin (Chemical), carbamazepine (Chemical), myoclonic jerks (Disease), carbamazepine (Chemical), vigabatrin (Chemical), sodium valproate (Chemical), lamotrigine (Chemical), ethosuximide (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Hemolytic anemia associated with the use of omeprazole. Omeprazole is the first drug designed to block the final step in the acid secretory process within the parietal cell. It has been shown to be extremely effective in the treatment of peptic ulcer disease, reflux esophagitis, and the Zollinger-Ellison syndrome. Although clinical experience with omeprazole is still limited, many controlled studies have established the short-term safety of this drug. We report the first case of a serious short-term adverse reaction with the use of omeprazole: hemolytic anemia. The patient developed weakness, lethargy, and shortness of breath 2 days after starting therapy with omeprazole. Two weeks after the initiation of therapy, her hematocrit had decreased from 44.1% to 20.4%, and she had a positive direct Coombs antiglobulin test and an elevated indirect bilirubin. After she discontinued the omeprazole, her hemoglobin and hematocrit gradually returned to normal. The mechanism by which omeprazole caused the patient's hemolytic anemia is uncertain, but physicians should be alerted to this possible adverse effect.

Output: Chemical/Disease Entities: Hemolytic anemia (Disease), omeprazole (Chemical), Omeprazole (Chemical), peptic ulcer disease (Disease), reflux esophagitis (Disease), Zollinger-Ellison syndrome (Disease), omeprazole (Chemical), omeprazole (Chemical), hemolytic anemia (Disease), lethargy (Disease), shortness of breath (Disease), omeprazole (Chemical), bilirubin (Chemical), omeprazole (Chemical), omeprazole (Chemical), hemolytic anemia (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: The use and toxicity of didanosine (ddI) in HIV antibody-positive individuals intolerant to zidovudine (AZT) One hundred and fifty-one patients intolerant to zidovudine (AZT) received didanosine (ddI) to a maximum dose of 12.5 mg/kg/day. Patient response was assessed using changes in CD4+ lymphocyte subset count, HIV p24 antigen, weight, and quality of life. Seventy patients developed major opportunistic infections whilst on therapy; this was the first AIDS diagnosis in 17. Only minor changes in CD4+ lymphocyte subset count were observed in AIDS patients, although a more significant rise occurred in those with earlier stages of disease. Of those positive for p24 antigen at the commencement of the study 67% showed a positive response, and this was most likely in those with CD4+ lymphocyte subset counts above 100 mm3. A positive weight response was seen in 16% of patients. Most patients showed improvement in individual parameters and global score of quality of life. Adverse reactions possibly attributable to didanosine were common. The most common side-effect was diarrhoea, which resulted in cessation of therapy in 19 individuals. Peripheral neuropathy occurred in 12 patients and pancreatitis in six. Thirteen patients developed a raised serum amylase without abdominal pain. Seven patients developed glucose tolerance curves characteristic of diabetes but these were mild, did not require treatment and returned to normal on ceasing didanosine.

Output: Chemical/Disease Entities: toxicity (Disease), didanosine (Chemical), ddI (Chemical), HIV antibody-positive (Disease), zidovudine (Chemical), AZT (Chemical), zidovudine (Chemical), AZT (Chemical), didanosine (Chemical), ddI (Chemical), opportunistic infections (Disease), AIDS (Disease), AIDS (Disease), didanosine (Chemical), diarrhoea (Disease), Peripheral neuropathy (Disease), pancreatitis (Disease), abdominal pain (Disease), glucose tolerance curves (Disease), diabetes (Disease), didanosine (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Can angiogenesis be a target of treatment for ribavirin associated hemolytic anemia? BACKGROUND/AIMS: Recently ribavirin has been found to inhibit angiogenesis and a number of angiogenesis inhibitors such as sunitinib and sorafenib have been found to cause acute hemolysis. We aimed to investigate whether there is a relation between hemoglobin, haptoglobin and angiogenesis soluble markers which are modifiable and can help in developing strategies against anemia. METHODS: Fourteen patients chronically infected with hepatitis C virus were treated by pegylated interferon alpha 2a and ribavirin. Serum hemoglobin, haptoglobin and angiogenesis markers of vascular endothelial growth factor and angiopoetin-2 were investigated before and after therapy. RESULTS: We observed a significant decrease in haptoglobin levels at the end of the treatment period. Hemoglobin levels also decreased but insignificantly by treatment. In contrast with the literature, serum levels of angiogenesis factors did not change significantly by pegylated interferon and ribavirin therapy. We found no correlation of angiogenesis soluble markers with either hemoglobin or haptoglobin. CONCLUSION: This is the first study in the literature investigating a link between angiogenesis soluble markers and ribavirin induced anemia in patients with hepatitis C and we could not find any relation. Future research with larger number of patients is needed to find out modifiable factors that will improve the safety of ribavirin therapy.

Output: Chemical/Disease Entities: ribavirin (Chemical), hemolytic anemia (Disease), ribavirin (Chemical), sunitinib (Chemical), sorafenib (Chemical), hemolysis (Disease), anemia (Disease), chronically infected with hepatitis C virus (Disease), pegylated interferon alpha 2a (Chemical), ribavirin (Chemical), pegylated interferon (Chemical), ribavirin (Chemical), ribavirin (Chemical), anemia (Disease), hepatitis C (Disease), ribavirin (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.

Output: Chemical/Disease Entities: Cocaine (Chemical), topiramate (Chemical), cocaine (Chemical), toxicity (Disease), cocaine (Chemical), toxicity (Disease), nitric oxide (Chemical), topiramate (Chemical), cocaine addiction (Disease), cocaine (Chemical), cocaine (Chemical), GSH (Chemical), glutathione (Chemical), cocaine (Chemical), glutathione (Chemical), cocaine (Chemical), Topiramate (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Antinociceptive and antiamnesic properties of the presynaptic cholinergic amplifier PG-9. The antinociceptive effect of 3 alpha-tropyl 2-(p-bromophenyl)propionate [(+/-)-PG-9] (10-40 mg kg-1 s.c.; 30-60 mg kg-1 p.o.; 10-30 mg kg-1 i.v.; 10-30 micrograms/mouse i.c.v.) was examined in mice, rats and guinea pigs by use of the hot-plate, abdominal-constriction, tail-flick and paw-pressure tests. (+/-)-PG-9 antinociception peaked 15 min after injection and then slowly diminished. The antinociception produced by (+/-)-PG-9 was prevented by the unselective muscarinic antagonist atropine, the M1-selective antagonists pirenzepine and dicyclomine and the acetylcholine depletor hemicholinium-3, but not by the opioid antagonist naloxone, the gamma-aminobutyric acidB antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid, the H3 agonist R-(alpha)-methylhistamine, the D2 antagonist quinpirole, the 5-hydroxytryptamine4 antagonist 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, the 5-hydroxytryptamin1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide and the polyamines depletor reserpine. Based on these data, it can be postulated that (+/-)-PG-9 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. (+/-)-PG-9 (10-40 mg kg-1 i.p.) was able to prevent amnesia induced by scopolamine (1 mg kg-1 i.p.) and dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Affinity profiles of (+/-)-PG-9 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4), have shown an M4/M1 selectivity ratio of 10.2 that might be responsible for the antinociception and the anti-amnesic effect induced by (+/-)-PG-9 through an increase in acetylcholine extracellular levels. In the antinociceptive and antiamnesic dose range, (+/-)-PG-9 did not impair mouse performance evaluated by the rota-rod test and Animex apparatus.

Output: Chemical/Disease Entities: PG-9 (Chemical), 3 alpha-tropyl 2-(p-bromophenyl)propionate (Chemical), PG-9 (Chemical), PG-9 (Chemical), PG-9 (Chemical), atropine (Chemical), pirenzepine (Chemical), dicyclomine (Chemical), acetylcholine (Chemical), hemicholinium-3 (Chemical), naloxone (Chemical), gamma-aminobutyric acidB (Chemical), 3-aminopropyl-diethoxy-methyl-phosphinic acid (Chemical), R-(alpha)-methylhistamine (Chemical), quinpirole (Chemical), 5-hydroxytryptamine4 (Chemical), 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester (Chemical), 5-hydroxytryptamin1A (Chemical), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (Chemical), reserpine (Chemical), PG-9 (Chemical), PG-9 (Chemical), amnesia (Disease), scopolamine (Chemical), dicyclomine (Chemical), PG-9 (Chemical), amnesic (Disease), PG-9 (Chemical), acetylcholine (Chemical), PG-9 (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Hyperbaric oxygen therapy for control of intractable cyclophosphamide-induced hemorrhagic cystitis. We report a case of intractable hemorrhagic cystitis due to cyclophosphamide therapy for Wegener's granulomatosis. Conservative treatment, including bladder irrigation with physiological saline and instillation of prostaglandin F2 alpha, failed to totally control hemorrhage. We then used hyperbaric oxygen at an absolute pressure of 2 atm, 5 days a week for 8 consecutive weeks. The bleeding ceased completely by the end of treatment and the patient remained free of hematuria thereafter. No side effect was noted during the course of therapy. In future, this form of therapy can offer a safe alternative in the treatment of cyclophosphamide-induced hemorrhagic cystitis.

Output: Chemical/Disease Entities: oxygen (Chemical), cyclophosphamide (Chemical), cyclophosphamide (Chemical), Wegener's granulomatosis (Disease), prostaglandin F2 alpha (Chemical), hemorrhage (Disease), oxygen (Chemical), bleeding (Disease), hematuria (Disease), cyclophosphamide (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Further studies on effects of irrigation solutions on rat bladders. Further studies on the effects of certain irrigating fluids on the rat bladder for 18 hours are reported. The results have shown that the degradation product p-choloroaniline is not a significant factor in chlorhexidine-digluconate associated erosive cystitis. A high percentage of kanamycin-colistin and povidone-iodine irrigations were associated with erosive cystitis and suggested a possible complication with human usage. Picloxydine irrigations appeared to have a lower incidence of erosive cystitis but further studies would have to be performed before it could be recommended for use in urological procedures.

Output: Chemical/Disease Entities: p-choloroaniline (Chemical), chlorhexidine-digluconate (Chemical), cystitis (Disease), kanamycin (Chemical), colistin (Chemical), povidone-iodine (Chemical), cystitis (Disease), Picloxydine (Chemical), cystitis (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Clinical experiences in an open and a double-blind trial. A total of sixty patients were trated with bromperidol first in open conditions (20 patients), then on a double blind basis (40 patients) with haloperidol as the reference substance. The open study lasted for four weeks; the drug was administrated in the form of 1 mg tablets. The daily dose (initial dose: 1 mg; mean dose at the end of the trial: 4.47 mg) was always administered in one single dose. Nineteen patients finished the trial, and in 18 cases the therapeutic result was considered very good to good. These results were confirmed by statistical analysis. Nine patients exhibited mild to moderate extrapyramidal concomitant symptoms; no other side effects were observed. The results of detailed laboratory tests and evaluations of various quantitative and qualitative tolerability parameters were not indicative of toxic effects. In the double blind study with haloperidol, both substances were found to be highly effective in the treatment of psychotic syndromes belonging predominantly to the schizophrenia group. Certain clues, including the onset of action, seem to be indicative of the superiority of bromperidol. No differences were observed with respect to side effects and general tolerability.

Output: Chemical/Disease Entities: bromperidol (Chemical), haloperidol (Chemical), extrapyramidal concomitant symptoms (Disease), haloperidol (Chemical), psychotic syndromes belonging predominantly to the schizophrenia group (Disease), bromperidol (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats. The antiepileptic drugs, phenobarbitone and carbamazepine are well known to cause cognitive impairment on chronic use. The increase in free radical generation has been implicated as one of the important mechanisms of cognitive impairment by antiepileptic drugs. Curcumin has shown antioxidant, anti-inflammatory and neuro-protective properties. Therefore, the present study was carried out to investigate the effect of chronic curcumin administration on phenobarbitone- and carbamazepine-induced cognitive impairment and oxidative stress in rats. Pharmacokinetic interactions of curcumin with phenobarbitone and carbamazepine were also studied. Vehicle/drugs were administered daily for 21days to male Wistar rats. Passive avoidance paradigm and elevated plus maze test were used to assess cognitive function. At the end of study period, serum phenobarbitone and carbamazepine, whole brain malondialdehyde and reduced glutathione levels were estimated. The administration of phenobarbitone and carbamazepine for 21days caused a significant impairment of learning and memory as well as an increased oxidative stress. Concomitant curcumin administration prevented the cognitive impairment and decreased the increased oxidative stress induced by these antiepileptic drugs. Curcumin co-administration did not cause any significant alteration in the serum concentrations of both phenobarbitone as well as carbamazepine. These results show that curcumin has beneficial effect in mitigating the deterioration of cognitive functions and oxidative damage in rats treated with phenobarbitone and carbamazepine without significantly altering their serum concentrations. The findings suggest that curcumin can be considered as a potential safe and effective adjuvant to phenobarbitone and carbamazepine therapy in preventing cognitive impairment associated with these drugs.

Output: Chemical/Disease Entities: Curcumin (Chemical), cognitive dysfunction (Disease), phenobarbitone (Chemical), carbamazepine (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), cognitive impairment (Disease), cognitive impairment (Disease), Curcumin (Chemical), curcumin (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), cognitive impairment (Disease), curcumin (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), malondialdehyde (Chemical), glutathione (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), impairment of learning and memory (Disease), curcumin (Chemical), cognitive impairment (Disease), Curcumin (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), curcumin (Chemical), deterioration of cognitive functions (Disease), phenobarbitone (Chemical), carbamazepine (Chemical), curcumin (Chemical), phenobarbitone (Chemical), carbamazepine (Chemical), cognitive impairment (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Pyrrolidine dithiocarbamate protects the piriform cortex in the pilocarpine status epilepticus model. Pyrrolidine dithiocarbamate (PDTC) has a dual mechanism of action as an antioxidant and an inhibitor of the transcription factor kappa-beta. Both, production of reactive oxygen species as well as activation of NF-kappaB have been implicated in severe neuronal damage in different sub-regions of the hippocampus as well as in the surrounding cortices. The effect of PDTC on status epilepticus-associated cell loss in the hippocampus and piriform cortex was evaluated in the rat fractionated pilocarpine model. Treatment with 150 mg/kg PDTC before and following status epilepticus significantly increased the mortality rate to 100%. Administration of 50 mg/kg PDTC (low-dose) did not exert major effects on the development of a status epilepticus or the mortality rate. In vehicle-treated rats, status epilepticus caused pronounced neuronal damage in the piriform cortex comprising both pyramidal cells and interneurons. Low-dose PDTC treatment almost completely protected from lesions in the piriform cortex. A significant decrease in neuronal density of the hippocampal hilar formation was identified in vehicle- and PDTC-treated rats following status epilepticus. In conclusion, the NF-kappaB inhibitor and antioxidant PDTC protected the piriform cortex, whereas it did not affect hilar neuronal loss. These data might indicate that the generation of reactive oxygen species and activation of NF-kappaB plays a more central role in seizure-associated neuronal damage in the temporal cortex as compared to the hippocampal hilus. However, future investigations are necessary to exactly analyze the biochemical mechanisms by which PDTC exerted its beneficial effects in the piriform cortex.

Output: Chemical/Disease Entities: Pyrrolidine dithiocarbamate (Chemical), pilocarpine (Chemical), status epilepticus (Disease), Pyrrolidine dithiocarbamate (Chemical), PDTC (Chemical), oxygen (Chemical), neuronal damage (Disease), PDTC (Chemical), status epilepticus (Disease), pilocarpine (Chemical), PDTC (Chemical), status epilepticus (Disease), PDTC (Chemical), status epilepticus (Disease), status epilepticus (Disease), neuronal damage (Disease), PDTC (Chemical), PDTC (Chemical), status epilepticus (Disease), PDTC (Chemical), neuronal loss (Disease), oxygen (Chemical), seizure (Disease), neuronal damage (Disease), PDTC (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Safety profile of a nicotine lozenge compared with that of nicotine gum in adult smokers with underlying medical conditions: a 12-week, randomized, open-label study. BACKGROUND: Nicotine polacrilex lozenges deliver 25% to 27% more nicotine compared with equivalent doses of nicotine polacrilex gum. The increased nicotine exposure from the lozenge has raised questions about the relative safety of the lozenge and gum. OBJECTIVE: The objective of this study was to compare the safety profiles of the 4-mg nicotine lozenge and 4-mg nicotine gum in smokers with selected label-restricted diseases. METHODS: This was a multicenter, randomized, open-label study in adult smokers with heart disease, hypertension not controlled by medication, and/or diabetes mellitus. Patients were randomized in a 1:1 ratio to receive the 4-mg nicotine lozenge or 4-mg nicotine gum. Safety assessments were made at baseline and at 2, 4, 6, and 12 weeks after the start of product use. RESULTS: Nine hundred one patients were randomized to treatment, 447 who received the lozenge and 454 who received the gum (safety population). The majority were women (52.7%). Patients' mean age was 53.9 years, their mean weight was 193.9 pounds, and they smoked a mean of 25.2 cigarettes per day at baseline. Five hundred fifty-three patients, 264 taking the lozenge and 289 taking the gum, used the study product for > or =4 days per week during the first 2 weeks (evaluable population). The nicotine lozenge and nicotine gum were equally well tolerated, despite increased nicotine exposure from the lozenge. The incidence of adverse events in the 2 groups was similar during the first 2 weeks of product use (evaluation population: 55.3% lozenge, 54.7% gum), as well as during the entire study (safety population: 63.8% and 58.6%, respectively). Stratification of patients by sex, age, extent of concurrent smoking, extent of product use, and severity of adverse events revealed no clinically significant differences between the lozenge and gum. The most common adverse events were nausea (17.2% and 16.1%; 95% CI, -3.7 to 6.0), hiccups (10.7% and 6.6%; 95% CI, 0.5 to 7.8), and headache (8.7% and 9.9%; 95% Cl, -5.0 to 2.6). Serious adverse events were reported in 11 and 13 patients in the respective groups. Fewer than 6% of patients in either group were considered by the investigator to have a worsening of their overall disease condition during the study. The majority of patients (>60%) experienced no change in their disease status from baseline. CONCLUSION: The 4-mg nicotine lozenge and 4-mg nicotine gum had comparable safety profiles in these patients with label-restricted medical conditions.

Output: Chemical/Disease Entities: nicotine (Chemical), nicotine (Chemical), Nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), heart disease (Disease), hypertension (Disease), diabetes mellitus (Disease), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nicotine (Chemical), nausea (Disease), hiccups (Disease), headache (Disease), nicotine (Chemical), nicotine (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Development of levodopa-induced dyskinesias in parkinsonian monkeys may depend upon rate of symptom onset and/or duration of symptoms. Levodopa-induced dyskinesias (LIDs) present a major problem for the long-term management of Parkinson's disease (PD) patients. Due to the interdependence of risk factors in clinical populations, it is difficult to independently examine factors that may influence the development of LIDs. Using macaque monkeys with different types of MPTP-induced parkinsonism, the current study evaluated the degree to which rate of symptom progression, symptom severity, and response to and duration of levodopa therapy may be involved in the development of LIDs. Monkeys with acute (short-term) MPTP exposure, rapid symptom onset and short symptom duration prior to initiation of levodopa therapy developed dyskinesia between 11 and 24 days of daily levodopa administration. In contrast, monkeys with long-term MPTP exposure, slow symptom progression and/or long symptom duration prior to initiation of levodopa therapy were more resistant to developing LIDs (e.g., dyskinesia developed no sooner than 146 days of chronic levodopa administration). All animals were similarly symptomatic at the start of levodopa treatment and had similar therapeutic responses to the drug. These data suggest distinct differences in the propensity to develop LIDs in monkeys with different rates of symptom progression or symptom durations prior to levodopa and demonstrate the value of these models for further studying the pathophysiology of LIDs.

Output: Chemical/Disease Entities: levodopa (Chemical), dyskinesias (Disease), parkinsonian (Disease), Levodopa (Chemical), dyskinesias (Disease), LIDs (Disease), Parkinson's disease (Disease), PD (Disease), LIDs (Disease), MPTP (Chemical), parkinsonism (Disease), levodopa (Chemical), LIDs (Disease), MPTP (Chemical), levodopa (Chemical), dyskinesia (Disease), levodopa (Chemical), MPTP (Chemical), levodopa (Chemical), LIDs (Disease), dyskinesia (Disease), levodopa (Chemical), levodopa (Chemical), LIDs (Disease), levodopa (Chemical), LIDs (Disease)


Instruction: Extract chemical and disease entities from the following text.

Input: Propylthiouracil-induced perinuclear-staining antineutrophil cytoplasmic autoantibody-positive vasculitis in conjunction with pericarditis. OBJECTIVE: To describe a case of propylthiouracil-induced vasculitis manifesting with pericarditis. METHODS: We present the first case report of a woman with hyperthyroidism treated with propylthiouracil in whom a syndrome of pericarditis, fever, and glomerulonephritis developed. Serologic testing and immunologic studies were done, and a pericardial biopsy was performed. RESULTS: A 25-year-old woman with Graves' disease had a febrile illness and evidence of pericarditis, which was confirmed by biopsy. Serologic evaluation revealed the presence of perinuclear-staining antineutrophil cytoplasmic autoantibodies (pANCA) against myeloperoxidase (MPO). Propylthiouracil therapy was withdrawn, and she was treated with a 1-month course of prednisone, which alleviated her symptoms. A literature review revealed no prior reports of pericarditis in anti-MPO pANCA-positive vasculitis associated with propylthio- uracil therapy. CONCLUSION: Pericarditis may be the initial manifestation of drug-induced vasculitis attributable to propylthio- uracil therapy.

Output: Chemical/Disease Entities: Propylthiouracil (Chemical), vasculitis (Disease), pericarditis (Disease), propylthiouracil (Chemical), vasculitis (Disease), pericarditis (Disease), hyperthyroidism (Disease), propylthiouracil (Chemical), pericarditis (Disease), fever (Disease), glomerulonephritis (Disease), Graves' disease (Disease), febrile illness (Disease), pericarditis (Disease), Propylthiouracil (Chemical), prednisone (Chemical), pericarditis (Disease), vasculitis (Disease), propylthio- uracil (Chemical), Pericarditis (Disease), vasculitis (Disease), propylthio- uracil (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Two mouse lines selected for differential sensitivities to beta-carboline-induced seizures are also differentially sensitive to various pharmacological effects of other GABA(A) receptor ligands. Two mouse lines were selectively bred according to their sensitivity (BS line) or resistance (BR line) to seizures induced by a single i.p. injection of methyl beta-carboline-3-carboxylate (beta-CCM), an inverse agonist of the GABA(A) receptor benzodiazepine site. Our aim was to characterize both lines' sensitivities to various physiological effects of other ligands of the GABA(A) receptor. We measured diazepam-induced anxiolysis with the elevated plus-maze test, diazepam-induced sedation by recording the vigilance states, and picrotoxin- and pentylenetetrazol-induced seizures after i.p. injections. Results presented here show that the differential sensitivities of BS and BR lines to beta-CCM can be extended to diazepam, picrotoxin, and pentylenetetrazol, suggesting a genetic selection of a general sensitivity and resistance to several ligands of the GABA(A) receptor.

Output: Chemical/Disease Entities: beta-carboline (Chemical), seizures (Disease), GABA (Chemical), seizures (Disease), methyl beta-carboline-3-carboxylate (Chemical), beta-CCM (Chemical), GABA (Chemical), benzodiazepine (Chemical), GABA (Chemical), diazepam (Chemical), diazepam (Chemical), picrotoxin (Chemical), pentylenetetrazol (Chemical), seizures (Disease), beta-CCM (Chemical), diazepam (Chemical), picrotoxin (Chemical), pentylenetetrazol (Chemical), GABA (Chemical)


Instruction: Extract chemical and disease entities from the following text.

Input: Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. 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.

Output: Chemical/Disease Entities: ketamine (Chemical), cancer (Disease), morphine (Chemical), Pain (Disease), morphine (Chemical), N-methyl-D-aspartate (Chemical), NMDA (Chemical), ketamine (Chemical), pain (Disease), neuropathic pain (Disease), ketamine (Chemical), cancer (Disease), pain (Disease), morphine (Chemical), Pain (Disease), nausea (Disease), vomiting (Disease), confusion (Disease), dry mouth (Disease), Ketamine (Chemical), pain (Disease), Hallucinations (Disease), diazepam (Chemical), ketamine (Chemical), ketamine (Chemical), ketamine (Chemical), Ketamine (Chemical), morphine (Chemical), pain (Disease), neuropathic pain (Disease), ketamine (Chemical)