Platelets  is a  peer-reviewed   medical journal  covering all aspects of  platelet -related research. The  editors-in-chief  are Steve Watson and Paul Harrison ( University of Birmingham ). It was established in 1990 and is published by  Taylor & Francis .


Official website


Seminars in Thrombosis and Hemostasis  is a  peer-reviewed   medical   review journal  covering  hematology , with a specific focus on disorders related to  thrombosis  and  hemostasis . It was established in 1974 and is published eight times per year by  Thieme Medical Publishers . The  editor-in-chief  is Emmanuel J. Favaloro. According to the  Journal Citation Reports , the journal has a 2018  impact factor  of 3.401. [ 1 ]


Thrombosis and Haemostasis  is a  peer-review   scientific journal  of  medicine . It is published by  Thieme Medical Publishers . It is the official journal of several groups and societies:  European Society of Cardiology  (Thrombosis working group, Atherosclerosis and Vascular Biology working group),  Sociedad Española de Trombosis y Hemostasia ,  Australian Vascular Biology Society , and  Gesellschaft für Thrombose- und Hämostaseforschung e.V .  A related publication is  TH Open . The journal was established in 1957 and is published monthly. The current  editors-in-chief  are Christian Weber and Gregory Y. H. Lip.


The journal is  abstracted and indexing  in the following bibliographic databases: [ 1 ]


According to the  Journal Citation Reports , the journal has a 2017  impact factor  of 4.952. [ 2 ]


Transfusion  is a monthly  peer-reviewed   medical journal  covering  transfusion medicine  that is published by  Wiley  on behalf of the  Association for the Advancement of Blood and Biotherapies . According to the  Journal Citation Reports , it had a 2021  impact factor  of 3.337. [ 1 ]  The journal was established in 1960 with  Tibor J. Greenwalt  as its founding  editor-in-chief . [ 2 ] [ 3 ]  As of 2021, the editor-in-chief is Richard Kaufman. [ 4 ]


The journal is abstracted and indexed in  Scopus , [ 5 ]   Index Medicus / MEDLINE / PubMed , [ 6 ]   EMBASE ,  CINAHL ,  BIOSIS Previews ,  CAB Abstracts , [ 7 ]   Current Contents /Clinical Medicine and Life Sciences,  Biological Abstracts , and the  Science Citation Index Expanded . [ 8 ]


Vox Sanguinis , formerly known as the  Bulletin of the Central Laboratory of the Blood Transfusion Service of the Dutch Red Cross , is a  peer-reviewed   medical journal  covering  hematology . It was established in 1953 and published 8 times per year by  Wiley-Blackwell  on behalf of the International Society of Blood Transfusion. The  editor-in-chief  is Miquel Lozano ( Clinic Barcelona  Sección de Hemotherapia). According to the  Journal Citation Reports , the journal has a 2019 impact factor of 2.347, ranking it 46th out of 76 journals in the category "Hematology". [ 1 ]


An  anti-CD22 immunotoxin  is a  monoclonal antibody  targeting  CD22  linked to a  cytotoxic agent . As of August 2009, it was studied in the treatment of some types of  B-cell  cancer.
It binds to CD22, a receptor  protein  on the surface of normal B cells and B-cell  tumors , and, upon internalization, kills the cells, acting as  immunotoxin .


As of August 2009, several anti-CD22 immunotoxins are undergoing clinical trials.


CAT-3888 or BL22 is an anti-CD22  immunotoxin  and in 2015 completed a  Phase I  clinical (human) trial for the treatment of  hairy cell leukemia [ 1 ]  at the  NIH  in the U.S.


Technically, CAT-3888 is an anti-CD22 immunotoxin fusion protein between a murine anti-CD22 disulfide-linked Fv (dsFv)  antibody fragment  and an edited copy of bacterial Pseudomonas exotoxin PE38.  The toxin is activated intracellularly, by the low  pH  of the  lysosome  into which the entire protein was internalized via the CD22 receptor.  The toxin kills the targeted cell through  ribosome  inactivation. [ 2 ]


CAT-3888 was initially designed and produced at the U.S.  National Cancer Institute , one of the agencies which make up the  NIH .  As of 2005, early development of BL22 was funded by California biotech  Genencor . [ 3 ]


In 2001, results  of remissions in a phase I trial for  leukemia  were reported. [ 4 ]


CAT-3888 was succeeded by  moxetumomab pasudotox  (CAT-8015, HA22), an anti-CD22 immunotoxin comprising a modified  Pseudomonas exotoxin  and an anti- CD22  antibody fragment. [ 5 ]


Like CAT-3888, CAT-8015 changes three amino acids in the antibody fragment to increase the binding affinity for the target molecule.  Both of these proteins are designed to bind to the same part of the CD22 receptor on the surface of B cells. [ citation needed ]


Research is being carried on directly by Dr. Robert J. Kreitman at the National Cancer Institute. [ 6 ]  The patent holder is MedImmune, a subsidiary of AstraZeneca. [ 7 ]  MedImmune discontinued development of CAT-3888 in 2008 and continues to develop CAT-8015. [ 8 ]


Early Phase I results find that CAT-8015 exhibits a greater affinity for CD22 than  CAT-3888. [ 9 ]  It may be useful against any B cell  leukemia  or  lymphoma , and indeed is currently in a Phase I clinical trial, also at NIH, in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). [ 10 ] [ 11 ] [ 12 ]


Cambridge Antibody Technology  acquired CAT-3888 and CAT-8015 in 2005 from  Genencor , a subsidiary of  Danisco [ 3 ]  (where they were known as GCR-3888 and GCR-8015). [ 13 ]  CAT was then purchased in 2007 by British pharmaceutical company  AstraZeneca  for $15.2 billion. [ 14 ] [ 15 ]  AstraZeneca consolidated its biologics portfolio in MedImmune and Cambridge Antibody Technology which was rebranded to create a dedicated biologics division known as 'MedImmune'. [ 16 ]


CAT-5001  (formerly SS1P) is a  Pseudomonas exotoxin   immunotoxin  that targets  mesothelin , which is a cell surface  glycoprotein  present on normal mesothelial cells that is overexpressed in numerous cancers including  pleural  and  peritoneal mesothelioma ,  ovarian cancer  and  pancreatic cancer . [ 5 ]   Cambridge Antibody Technology  acquired CAT-5001 from Enzon Pharmaceuticals in May 2006. [ 17 ]


Avatrombopag , sold under the brand name  Doptelet ,  is a  medication  that used for certain conditions that lead to  thrombocytopenia  (low  platelets ) such as thrombocytopenia associated with  chronic liver disease  in adults who are to undergo a planned medical or dental procedure. [ 8 ] [ 9 ]  It was approved for medical use in the United States in May 2018, [ 10 ] [ 11 ]  the European Union in June 2019, [ 7 ]  and Australia in January 2023. [ 1 ]


It acts as a  thrombopoietin receptor  agonist. [ 12 ]


Benzestrol  ( INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name ) (brand names  Chemestrogen ,  Ocestrol ,  Octestrol ,  Octoestrol ,  Octofollin ) is a  synthetic   nonsteroidal estrogen  of the  stilbestrol  group which was formerly used medically but has since been discontinued. [ 1 ] [ 2 ] [ 3 ]  The stilbestrol estrogens, the best-known of which is  diethylstilbestrol  (DES) were used extensively in the mid-1900s and were finally banned by the FDA due to them causing tumors in the children of women who used them. [ 4 ]


Benzestrol and other stilbestrol were used as synthetic estrogens in order to prevent premature births. [ 4 ]  Based on the idea that premature births happened because the mother did not produce enough estrogen on her own, doctors prescribed benzestrol to mothers in order to increase their estrogen levels.


Studies have been done in the past on normal, mature and castrate female rats. Benzestrol produced the same type of estrus in the castrate rat when injected at 0.8 to 1.0 micrograms as when the rat was injected with 2.0 to 2.5 micrograms of estrone. [ 5 ]  This is significant because less benzestrol could be used to produce the same effect as estrone in increasing estrogen production. It has been used in the past as a nonsteroidal estrogen antagonist.


Benzestrol is described as a very potent estrogen. [ 6 ]  It is reported to have about 130% of the  relative binding affinity  of  estradiol  for the  estrogen receptors . [ 7 ]


Benzestrol is usually grouped with the stilbestrol estrogens. However, benzestrol is technically not a stilbestrol derivative because its central chain is elongated by one carbon. In any case, it is a very close analogue of the stilbestrol estrogens. [ 8 ]


Benzestrol is a drug in the stilbestrol family of estrogens. These drugs were first produced in the late 1930s. Benzestrol itself was reported in 1946. [ 1 ]  In 1953, experiments began on benzestrol and other stilbestrols to see if they actually helped stop premature births. This study in 1953 found that benzestrol did not in fact help stop premature births. [ 4 ]  A study in 1971 found that benzestrol was the cause of a rare vaginal cancer in girls and women whose mothers had been on benzestrol while pregnant. [ 4 ]


Centhaquine  (brand name  Lyfaquin ) is a cardiovascular drug. [ 1 ]   In India, it is approved for the treatment of  hypovolemic shock . [ 2 ]


Centhaquine is a  vasopressor  that activates  α 2A -  and  α 2B -adrenoreceptors . [ 3 ]  It increases  venous return  and improves  tissue perfusion .


Efbemalenograstim alfa , sold under the brand name  Ryzneuta , is a  medication  used to decrease the incidence of infection in  chemotherapy -induced  neutropenia . [ 1 ]  It is a leukocyte growth factor. [ 1 ]  It is given by  subcutaneous  injection. [ 1 ]


The most common side effects of efbemalenograstim alfa are nausea, anemia, and thrombocytopenia. [ 5 ]


Efbemalenograstim alfa is an immunostimulant/colony stimulating factor that belongs to the class of  hematopoietic  growth factors (granulocyte colony stimulating factor; G CSF) which increase the production and differentiation of mature and functionally active neutrophils from bone marrow precursor cells. [ 2 ]  It was approved for medical use in China in May 2023, [ 4 ]  in the United States in November 2023, [ 5 ] [ 6 ]  and in the European Union in March 2024. [ 2 ] [ 3 ]


In the US, efbemalenograstim alfa is  indicated  to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. [ 1 ] [ 5 ]


In the EU, efbemalenograstim alfa is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). [ 2 ]


Efbemalenograstim alfa can cause fatal splenic rupture, acute respiratory distress syndrome, serious allergic reactions including anaphylaxis, sickle cell crises in patients with sickle cell disorders, glomerulonephritis, thrombocytopenia, capillary leak syndrome, and myelodysplastic syndrome and acute myeloid leukemia in people with breast and lung cancer. [ 5 ]


The US  Food and Drug Administration  approved efbemalenograstim alfa based on evidence from two main clinical trials, GC-627-04 and GC-627-05, in 515 participants with breast cancer receiving chemotherapy. [ 5 ]  There was one participant included in the trial from the United States, and 514 participants were included from sites outside of the United States. [ 5 ]  The trials were conducted at 52 sites in five countries including Hungary, Russia, Ukraine, Bulgaria, and the United States. [ 5 ]  The same trials (GC-627-04 and GC-627-05) were used to assess efficacy and safety. [ 5 ]


Efbemalenograstim alfa was evaluated in two main clinical trials that were randomized and controlled. [ 5 ]  A total of 515 participants were randomized to receive efbemalenograstim alfa or placebo, or Neulasta, after receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia to treat metastatic breast cancer. [ 5 ]  Both trials evaluated the benefit and side effects of efbemalenograstim alfa in participants. [ 5 ]  The benefit of efbemalenograstim alfa was based on the mean duration of severe neutropenia seen in participants after receiving either efbemalenograstim alfa or control (placebo or Neulasta). [ 5 ]


It was approved for medical use in China in May 2023, [ 4 ]  in the United States in November 2023, [ 1 ] [ 5 ]  and in the European Union in March 2024. [ 3 ]


In January 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ryzneuta, intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy. [ 2 ]  The applicant for this medicinal product is Evive Biotechnology Ireland Limited. [ 2 ]  Efbemalenograstim alfa was approved for medical use in the European Union in March 2024. [ 2 ] [ 3 ]


Eltrombopag , sold under the brand name  Promacta  among others, is a medication used to treat  thrombocytopenia  (abnormally low  platelet  counts) and severe aplastic anemia. [ 3 ] [ 4 ]  Eltrombopag is sold under the brand name  Revolade  outside the US and is marketed by  Novartis . [ 6 ]  It is a thrombopoietin receptor agonist. [ 3 ]  It is taken  by mouth . [ 3 ] [ 4 ]


Eltrombopag was discovered as a result of research collaboration between  GlaxoSmithKline  and  Ligand Pharmaceuticals  and is transferred to Novartis Pharmaceuticals. [ 6 ] [ 7 ] [ 8 ]


Eltrombopag was approved by the US  Food and Drug Administration  (FDA) in November 2008, for the treatment of thrombocytopenia in people with chronic  immune (idiopathic) thrombocytopenic purpura  who have had an insufficient response to  corticosteroids ,  immunoglobulin therapy , or  splenectomy . [ 9 ] [ 10 ] [ 11 ]


In August 2015, the FDA approved eltrombopag (Promacta for oral suspension) for the treatment of thrombocytopenia in children one year of age and older with idiopathic thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. [ 12 ]


In  preclinical studies , the compound was shown to interact selectively with the thrombopoietin receptor, leading to activation of the  JAK-STAT signaling pathway  and increased proliferation and differentiation of  megakaryocytes . Animal studies confirmed that it increased platelet counts. In 73 healthy volunteers, higher doses of eltrombopag caused larger increases in the number of circulating platelets without tolerability problems. [ 13 ]


Eltrombopag has been shown to be effective in two major clinical syndromes:  idiopathic thrombocytopenic purpura  (ITP) [ 14 ]  and  cirrhosis  due to  hepatitis C  (in which low platelet counts may be a contraindication for  interferon  treatment). [ 15 ]


After six weeks of therapy in a  phase III trial , eltrombopag 50 mg/day was associated with a significantly higher response rate than placebo in adult patients with chronic  idiopathic thrombocytopenic purpura  (ITP). [ 16 ]


Eltrombopag received  breakthrough therapy  designation from the US  Food and Drug Administration  (FDA) in February 2014, for people with  aplastic anemia  for which immunosuppression has not been successful. [ 17 ]   In 2017, the NIH made Eltrombopag a standard of care in aplastic anemia. [ 18 ]


In October 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Eltrombopag Viatris, intended for the treatment of people with primary immune thrombocytopenia (ITP) and thrombocytopenia associated with chronic hepatitis C. [ 19 ]  The applicant for this medicinal product is Viatris Limited. [ 19 ]  Eltrombopag Viatris was authorized in December 2024. [ 20 ]


It has been shown to produce a trilineage hematopoiesis in some people with aplastic anemia, resulting in increased platelet counts, along with red and white blood cell counts. [ 21 ]


Enarodustat  (development code  JTZ-951 ; brand name  Enaroy ) is a drug used for the treatment of  anemia , especially when associated with  chronic kidney disease  (CKD).  Enarodustat functions as a  inhibitor of hypoxia inducible factor-proly hydroxylase  (HIF-PH). [ 1 ]


The drug was approved in September 2020 in Japan for anemia associated with CKD [ 2 ]  and is currently in  clinical development  in the United States and South Korea. [ 3 ]   The drug is being developed by  Japan Tobacco  and JW Pharmaceutical. [ 4 ]


Exagamglogene autotemcel , sold under the brand name  Casgevy , is a  gene therapy  used for the treatment of  sickle cell disease [ 3 ] [ 5 ]  and transfusion-dependent  beta thalassemia . [ 3 ]  It was developed by  Vertex Pharmaceuticals  and  CRISPR Therapeutics . [ 9 ]


The treatment was approved in the United Kingdom for the treatment of sickle cell disease and transfusion-dependent beta thalassemia in November 2023. [ 10 ] [ 11 ] [ 12 ]  It was approved in the United States for the treatment of sickle cell disease in December 2023 and for the treatment of transfusion-dependent beta thalassemia in January 2024. [ 13 ] [ 14 ] [ 15 ]


Exagamglogene autotemcel is the first cell-based gene therapy treatment utilizing  CRISPR/Cas9 gene editing  technology to be approved by the US  Food and Drug Administration  (FDA). [ 13 ]  The most common side effects include low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache, and itching. [ 13 ]


In the UK, exagamglogene autotemcel is  indicated  for the treatment of transfusion-dependent beta thalassemia and sickle cell disease in patients aged 12 years and older who should be treated with  hematopoietic stem cell transplantation  but for whom a suitable stem cell donor is not available. [ 3 ]


In the US, exagamglogene autotemcel is indicated for the treatment of sickle cell disease in people aged 12 years and older with recurrent  vaso-occlusive crises , [ 6 ]  and for the treatment of people with transfusion-dependent beta-thalassemia. [ 6 ] [ 16 ]


The gene therapy is made from the recipient's own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. [ 13 ]  Prior to treatment, the recipient's own stem cells are collected, and then the recipient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in exagamglogene autotemcel. [ 13 ]  The modified blood stem cells are transplanted back into the recipient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. [ 13 ]


The most common side effects observed in clinical studies included low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache and itching. [ 13 ]


The safety and effectiveness of exagamglogene autotemcel were evaluated in an ongoing single-arm, multi-center trial in adult and adolescent participants with sickle cell disease. [ 13 ]  Participants had a history of at least two protocol-defined severe vaso-occlusive crises during each of the two years prior to screening. [ 13 ]  The primary efficacy outcome was freedom from severe vaso-occlusive crisis episodes for at least twelve consecutive months during the 24-month follow-up period. [ 13 ]  A total of 44 participants were treated with exagamglogene autotemcel. [ 13 ]  Of the 31 participants with sufficient follow-up time to be evaluable, 29 (93.5%) achieved this outcome. [ 13 ]  All treated participants achieved successful engraftment with no participants experiencing graft failure or  graft rejection . [ 13 ]


The US  Food and Drug Administration  (FDA) granted the application for exagamglogene autotemcel  priority review ,  orphan drug ,  fast track , and regenerative medicine advanced therapy designations. [ 13 ]  The FDA granted approval of Casgevy to Vertex Pharmaceuticals. [ 13 ]


In December 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Casgevy, intended for the treatment of transfusion‑dependent β‑thalassemia and sickle cell disease. [ 7 ] [ 17 ]  As Casgevy is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. [ 7 ]  The applicant for this medicinal product is Vertex Pharmaceuticals (Ireland) Limited. [ 7 ]  Exagamglogene autotemcel was approved for medical use in the European Union in February 2024. [ 7 ] [ 8 ]


The therapy has a US list price of  US$2.2 million . [ 18 ]  The cost effectiveness threshold of the therapy in the US is estimated to be between $1.35 million and $2.05 million [ 19 ]  depending on perspective (healthcare vs limited societal) and assuming the  willingness to pay  for 1  quality-adjusted life year  (QALY) at $100,000–$150,000. [ 20 ]


The UK price is estimated to be  £1 million . [ 21 ] [ 22 ]


Ferric derisomaltose , sold under the brand name  Monoferric  among others, is a  medication  for the treatment of  iron deficiency anemia  in adults who have intolerance to  oral iron  or have had unsatisfactory response to oral iron or who have non-hemodialysis dependent  chronic kidney disease  ( NDD-CKD ). [ 4 ]  It was approved for use in the United States in January 2020. [ 4 ] [ 5 ] [ 6 ]  It is given intravenously. [ 4 ]


Filgrastim , sold under the brand name  Neupogen  among others, is a  medication  used to treat  low neutrophil count . [ 19 ]  Low neutrophil counts may occur with  HIV/AIDS , following  chemotherapy  or  radiation poisoning , or be of an unknown cause. [ 19 ]  It may also be used to increase white blood cells for gathering during  leukapheresis . [ 19 ]  It is given either by  injection into a vein  or  under the skin . [ 19 ]  Filgrastim is a leukocyte growth factor. [ 18 ]


Common side effects include fever, cough, chest pain, joint pain, vomiting, and hair loss. [ 19 ]  Severe side effects include  splenic rupture  and  allergic reactions . [ 19 ]  It is unclear if use in  pregnancy  is safe for the baby. [ 19 ]  Filgrastim is a recombinant form of the naturally occurring  granulocyte colony-stimulating factor  (G-CSF). [ 19 ]  It works by stimulating the body to increase  neutrophil  production. [ 19 ]


Filgrastim was approved for medical use in the United States in 1991. [ 19 ]  It is on the  World Health Organization's List of Essential Medicines . [ 20 ] [ 21 ]  Filgrastim  biosimilar  medications are available. [ 19 ]


Filgrastim is used to treat neutropenia; [ 18 ]  acute myeloid leukemia; [ 18 ]  nonmyeloid malignancies; [ 18 ]  leukapheresis; [ 18 ]  congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia; [ 18 ]  and myelosuppressive doses of radiation. [ 18 ] [ 22 ]


Tbo-filgrastim (Granix) is  indicated  for reduction in the duration of severe neutropenia in people with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. [ 23 ]


The most commonly observed adverse effect is mild bone pain after repeated administration, [ 24 ]  and local skin reactions at the site of injection. [ 18 ]  Other observed adverse effects include serious allergic reactions (including a rash over the whole body, [ 25 ]  shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating),  ruptured spleen  (sometimes resulting in death), [ 26 ]   alveolar   hemorrhage ,  acute respiratory distress syndrome , and  hemoptysis . [ 18 ]  Severe  sickle cell crises , in some cases resulting in death, have been associated with the use of filgrastim in people with sickle cell disorders. [ 18 ]


Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results. [ 18 ]


G-CSF is a colony stimulating factor which has been shown to have minimal direct in vivo or in vitro effects on the production of other haematopoietic cell types. Neupogen (filgrastim) is the name for recombinant methionyl human granulocyte colony stimulating factor (r-metHuG-CSF). [ 18 ]


In 2015, Sandoz's filgrastim-sndz (Zarxio), obtained the approval of the US  Food and Drug Administration  (FDA) as a biosimilar. [ 11 ] [ 27 ] [ 28 ]  This was the first product to be passed under the  Biologics Price Competition and Innovation Act of 2009  (BPCI Act), as part of the  Affordable Care Act . [ 11 ]  Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen. [ 28 ]


In 2018, filgrastim-aafi (Nivestym) was approved for use in the United States. [ 1 ]


In September 2008, Ratiograstim, Tevagrastim, Biograstim, and Filgrastim ratiopharm were approved for use in the European Union. [ 10 ] [ 29 ] [ 5 ] [ 30 ]  Filgrastim ratiopharm was withdrawn in July 2011 and Biograstim was withdrawn in December 2016.


In February 2009, Filgrastim Hexal and Zarzio were approved for use in the European Union. [ 31 ] [ 12 ]


In June 2010, Nivestim was approved for use in the European Union. [ 7 ]


In October 2013, Grastofil was approved for use in the European Union. [ 6 ]


In September 2014, Accofil was approved for use in the European Union. [ 4 ]


In 2016, Fraven was approved for use by Republic of Turkey ministry of health. [ 32 ] [ 33 ]


Nivestym was approved for medical use in Canada in April 2020. [ 8 ]


In October 2021, Nypozi was approved for medical use in Canada. [ 9 ]


In February 2022, filgrastim-ayow (Releuko) was approved for medical use in the United States. [ 2 ] [ 34 ]


In June 2024, filgrastim-txid (Nypozi) was approved for medical use in the United States. [ 3 ]


In December 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zefylti, intended for the treatment of neutropenia and the mobilization of peripheral blood progenitor cells. [ 35 ]  The applicant for this medicinal product is CuraTeQ Biologics s.r.o. [ 35 ]  Zefylti is a biosimilar medicinal product. [ 35 ]  It is highly similar to the reference product Neupogen (filgrastim), which has been authorized in various EU countries. [ 35 ]


Shortly after it was introduced, analyses of whether filgrastim is a cost-effective way of preventing  febrile neutropenia  depended upon the clinical situation and the financial model used to pay for treatment. [ 36 ]  The longer-acting  pegfilgrastim  may in some cases be more cost-effective. [ 37 ]


2D9Q ,  1CD9 ,  1GNC ,  1PGR ,  1RHG


NM_000759 NM_001178147 NM_172219 NM_172220


NP_000750 NP_001171618 NP_757373 NP_757374


Granulocyte colony-stimulating factor  ( G-CSF  or  GCSF ), also known as  colony-stimulating factor 3  ( CSF 3 ), is a  glycoprotein  that stimulates the  bone marrow  to produce  granulocytes  and  stem cells  and release them into the  bloodstream . [ 5 ] [ 6 ]


Functionally, it is a  cytokine  and  hormone , a type of  colony-stimulating factor , and is produced by a number of different  tissues . The  pharmaceutical  analogs of naturally occurring G-CSF are called  filgrastim  and  lenograstim .


G-CSF also stimulates the survival, proliferation, differentiation, and function of  neutrophil precursors  and mature  neutrophils .


G-CSF is produced by  endothelium ,  macrophages , and a number of other  immune  cells. The natural human glycoprotein exists in two forms, a 174- and 177- amino-acid -long  protein  of molecular weight 19,600 grams per  mole . The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products by  recombinant DNA  (rDNA) technology. [ 7 ]


The gene for G-CSF is located on  chromosome 17 , locus q11.2-q12. Nagata et al. found that the GCSF gene has four  introns , and that two different  polypeptides  are synthesized from the same gene by differential splicing of mRNA. [ 12 ]


The two polypeptides differ by the presence or absence of three amino acids. Expression studies indicate that both have authentic GCSF activity. [ citation needed ]


It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the  G-CSF factor stem-loop destabilising element . [ citation needed ]


Chemotherapy can cause  myelosuppression  and unacceptably low levels of  white blood cells  ( leukopenia ), making patients susceptible to  infections  and  sepsis . G-CSF stimulates the production of  granulocytes , a type of white blood cell. In  oncology  and  hematology , a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery and reduce mortality from  neutropenia  after  chemotherapy , allowing higher-intensity treatment regimens. [ 13 ]  It is administered to oncology patients via subcutaneous or intravenous routes. [ 14 ]  A QSP model of neutrophil production and a PK/PD model of a cytotoxic chemotherapeutic drug (Zalypsis) have been developed to optimize the use of G-CSF in chemotherapy regimens with the aim to prevent mild-neutropenia. [ 15 ]


G-CSF was first trialled as a therapy for neutropenia induced by chemotherapy in 1988. The treatment was well tolerated and a dose-dependent rise in circulating neutrophils was noted. [ 16 ]


A study in mice has shown that G-CSF may decrease  bone mineral density . [ 17 ]


G-CSF administration has been shown to attenuate the  telomere  loss associated with chemotherapy. [ 18 ]


Neutropenia  can be a severe side effect of  clozapine , an  antipsychotic  medication in the treatment of  schizophrenia . G-CSF can restore neutrophil count. Following a return to baseline after stopping the drug, it may sometimes be safely  rechallenged  with the added use of G-CSF. [ 19 ] [ 20 ]


G-CSF is also used to increase the number of  hematopoietic stem cells  in the blood of the donor before collection by  leukapheresis  for use in  hematopoietic stem cell transplantation . For this purpose, G-CSF appears to be safe in  pregnancy  during  implantation  as well as during the  second and third trimesters . [ 21 ]   Breastfeeding  should be withheld for three days after CSF administration to allow for  clearance  of it from the milk. [ 21 ]  People who have been administered colony-stimulating factors do not have a higher risk of  leukemia  than people who have not. [ 21 ]


G-CSF may also be given to the receiver in  hematopoietic stem cell transplantation , to compensate for  conditioning regimens . [ 18 ]


The skin disease  Sweet's syndrome  is a known side effect of using this drug. [ 22 ]


Two research teams independently identified mouse granulocyte-colony stimulating factor (G-CSF) in the 1960s: Ray Bradley at  Universtiy of Melbourne  and  Donald Metcalf  at  Walter and Eliza Hall Institute , from  Australia , and Yasuo Ichikawa, Dov Pluznik and  Leo Sachs  at the  Weizmann Institute of Science ,  Israel . [ 23 ] [ 24 ] [ 7 ]


In 1983, Donald Metcalf's research team, led by  Nicos Nicola , isolated the murine cytokine from medium conditioned with lung tissue obtained from endotoxin-treated mice. [ 25 ] [ 26 ] [ 7 ]


In 1985,  Karl Welte ,  Erich Platzer ,  Janice Gabrilove ,  Roland Mertelsmann  and  Malcolm Moore  at the  Memorial Sloan Kettering Cancer Center  (MSK) purified human G-CSF produced by bladder cancer cell line 5637 from conditioned medium. [ 27 ] [ 7 ]


In 1986, Karl Welte's team at MSK patented the method of producing and using human G-CSF under the name "human hematopoietic pluripotent colony stimulating factor" or "human pluripotent colony stimulating factor" (P-CSF). [ 28 ]  Also in 1986, two independent research groups working with pharmaceutical companies cloned the G-CSF gene that made possible large-scale production and its clinical use:  Shigekazu Nagata 's team in collaboration with  Chugai Pharmaceutical Co . from  Japan , and  Lawrence Souza 's team at  Amgen  in collaboration with Karl Welte's research team members from  Germany  and the  USA . [ 12 ] [ 29 ] [ 7 ]


The  recombinant  human G-CSF (rhG-CSF) synthesised in an  E. coli  expression system is called  filgrastim . The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. [ citation needed ]


The  Food and Drugs Administration  (FDA) first approved filgrastim on February 20, 1991 marketed by  Amgen  with the brand name  Neupogen . [ 30 ]  It was innitially approved to reduce the risk of infection in patients with non-myeloid malignancies who are taking myelosuppressive anti-cancer drugs associated with  febrile neutropenia  with fever. [ 30 ]


Several bio-generic versions are now also available in markets such as Europe and Australia. Filgrastim (Neupogen) and  PEG-filgrastim  (Neulasta), or  pegylated  form of filgratim, are two commercially available forms of rhG-CSF. The pegylated form of filgratim form has a much longer  half-life , reducing the necessity of daily injections.


The FDA approved the first  biosimilar  of Neulasta in June 2018. It is made by  Mylan  and sold as Fulphila. [ 31 ]


Another form of rhG-CSF called  lenograstim  is synthesised in  Chinese hamster ovary cells  (CHO cells). As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174-amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies.


In 2015, filgrastim was included on the  WHO Model List of Essential Medicines , a list containing the medications considered to be most effective and safe to meet the most important needs in a  health system . [ 32 ] [ 33 ]


G-CSF when given early after exposure to radiation may improve white blood cell counts, and is stockpiled for use in radiation incidents. [ 34 ] [ 35 ]


Mesoblast  planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plus  SDF  (stromal cell-derived factor) directly to the heart. [ 36 ]


G-CSF has been shown to reduce  inflammation , reduce  amyloid beta  burden, and reverse cognitive impairment in a mouse model of  Alzheimer's disease . [ 37 ]


Due to its neuroprotective properties, G-CSF is currently under investigation for  cerebral ischemia  in a clinical phase IIb  [ 38 ]  and several clinical pilot studies are published for other neurological disease such as  amyotrophic lateral sclerosis [ 39 ]  A combination of human G-CSF and  cord blood  cells has been shown to reduce impairment from chronic traumatic brain injury in rats. [ 40 ]


1CSG ,  2GMF ,  4NKQ ,  5C7X ,  5D70 ,  5D71 ,  5D72 ,  4RS1


Granulocyte-macrophage colony-stimulating factor  ( GM-CSF ), also known as  colony-stimulating factor 2 (CSF2) , is a  monomeric   glycoprotein  secreted by  macrophages ,  T cells ,  mast cells ,  natural killer cells ,  endothelial cells  and  fibroblasts  that functions as a  cytokine . The  pharmaceutical  analogs of naturally occurring GM-CSF are called  sargramostim  and  molgramostim .


Unlike  granulocyte colony-stimulating factor , which specifically promotes  neutrophil  proliferation and maturation, GM-CSF affects more cell types, especially macrophages and  eosinophils . [ 5 ]


GM-CSF is a  monomeric   glycoprotein  that functions as a  cytokine —it is a  white blood cell   growth factor . [ 6 ]  GM-CSF stimulates  stem cells  to produce  granulocytes  ( neutrophils ,  eosinophils , and  basophils ) and  monocytes . Monocytes exit the circulation and migrate into tissue, whereupon they mature into  macrophages  and  dendritic cells . Thus, it is part of the  immune / inflammatory   cascade , by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting  infection . [ citation needed ]


GM-CSF also has some effects on mature cells of the immune system. These include, for example, enhancing neutrophil migration and causing an alteration of the receptors expressed on the cells surface. [ 7 ]


GM-CSF signals via signal transducer and activator of transcription,  STAT5 . [ 8 ]  In macrophages, it has also been shown to signal via  STAT3 . The cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production of  reactive oxygen species  that culminate in fungal zinc starvation and toxicity. [ 9 ]  Thus, GM-CSF facilitates development of the immune system and promotes defense against infections. [ citation needed ]


GM-CSF also plays a role in embryonic development by functioning as an  embryokine  produced by reproductive tract. [ 10 ]


The human gene has been localized in close proximity to the  interleukin 3  gene within a  T helper  type 2-associated cytokine gene cluster at chromosome region 5q31, which is known to be associated with interstitial deletions in the  5q- syndrome  and  acute myelogenous leukemia . GM-CSF and IL-3 are separated by an insulator element and thus independently regulated. [ 11 ]  Other genes in the cluster include those encoding  interleukins 4 ,  5 , and  13 . [ 12 ]


Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form. [ citation needed ]


GM-CSF was first cloned in 1985, and soon afterwards three potential drug products were being made using  recombinant DNA  technology:  molgramostim  was made in  Escherichia coli  and is not glycosylated,  sargramostim  was made in yeast, has a leucine instead of proline at position 23 and is somewhat glycosylated, and  regramostim  was made in Chinese hamster ovary cells (CHO) and has more glycosylation than sargramostim.  The amount of glycosylation affects how the body interacts with the drug and how the drug interacts with the body. [ 13 ]


At that time,  Genetics Institute, Inc.  was working on molgramostim, [ 14 ]   Immunex  was working on  sargramostim  (Leukine), [ 15 ]  and  Sandoz  was working on regramostim. [ 16 ]


Molgramostim was eventually co-developed and co-marketed by Novartis and Schering-Plough under the trade name Leucomax for use in helping white blood cell levels recover following chemotherapy, and in 2002 Novartis sold its rights to Schering-Plough. [ 17 ] [ 18 ]


Sargramostim was approved by the US FDA in 1991 to accelerate white blood cell recovery following autologous  bone marrow transplantation  under the trade name Leukine, and passed through several hands, ending up with  Genzyme , [ 19 ]  which was subsequently acquired by  Sanofi . Leukine is now owned by Partner Therapeutics (PTx).


Imlygic was approved by the US FDA in October 2015, [ 20 ]  and in December 2015 by the EMA, as an oncolytic virotherapy, commercialized by Amgen Inc. This  oncolytic herpes virus , named  Talimogene laherparepvec , has been genetically engineered to express human GM-CSF using the tumor cells machinery. [ 21 ]


GM-CSF is found in high levels in joints with  rheumatoid arthritis  and blocking GM-CSF as a  biological target  may reduce the inflammation or damage. Some drugs (e.g.  otilimab ) are being developed to  block  GM-CSF. [ 22 ]  In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, and has shown promise restoring  monocyte [ 23 ]  and  neutrophil [ 24 ]  function, although the impact on patient outcomes is currently unclear and awaits larger studies.


GM-CSF stimulates  monocytes  and  macrophages  to produce pro-inflammatory cytokines, including  CCL17 . [ 25 ]  Elevated GM-CSF has been shown to contribute to inflammation in  inflammatory arthritis ,  osteoarthritis ,  colitis   asthma ,  obesity , and  COVID-19 . [ 25 ] [ 26 ] [ 27 ]


Monoclonal antibodies  against GM-CSF are being used as treatment in clinical trials against  rheumatoid arthritis ,  ankylosing spondylitis , and COVID-19. [ 25 ]


A  hematinic  is a  nutrient  required for the formation of  blood cells  in the process of  hematopoiesis . [ 1 ]  The main hematinics are  iron ,  Vitamin B 12 , and  folate . [ 2 ]  Deficiency in hematinics can lead to  anaemia . In cases of hematinic deficiency, hematinics can be administered as medicines, in order to increase the  hemoglobin  content of the  blood .


Erythropoietin  (EPO) is a  hormone  that stimulates  erythropoiesis , which can also be given as a medicine to increase the hemoglobin content of the blood, but EPO is not classified as a hematinic as it is not considered a nutrient, but a hormone.


Iron(III)-hydroxide polymaltose complex   is a medication used to treat iron deficiency / iron deficiency anemia and belongs to the group of oral  iron preparations . The preparation is a macromolecular complex, consisting of  iron(III) hydroxide  (trivalent iron, Fe 3+ , Fe(OH) 3 ·H 2 O) and the carrier polymaltose and is available in solid form as a film-coated or chewable tablet and in liquid form as a syrup, drinkable solution, or drops.  It is used for treating  iron deficiency  without anemia (latent iron deficiency) or with  anemia  (apparent iron deficiency). Prior to administration, the iron deficiency should be diagnostically established and verified via laboratory tests (e.g., low  ferritin  concentration, low  transferrin saturation ).


The drug has been on the market since 1978 and is approved in over 85 countries. In many countries it is known with brand name Maltofer.


The drug is absorbed in the small intestine, primarily in the  duodenum  and  jejunum . Absorption occurs via a controlled, active mechanism. No passive diffusion takes place, which ensures that practically no unbound (to  transferrin ) iron reaches the blood. [ 1 ]  The absorbed iron is primarily stored in the  liver  as ferritin (protein used for iron storage) and subsequently made available to the body for various functions, primarily for incorporation into the red blood cells'  hemoglobin , thereby transporting oxygen in the blood.


The utilization and absorption by the erythrocytes of the iron administered orally in the form of iron polymaltose complex is correlated with the absorption in the intestines, whereby the relative absorption decreases with increased dosage and the more severe the iron deficiency, the greater the Absorption. [ 2 ]  As with ascorbate and sulfate oral iron preparations, only about 10-15% of the iron is absorbed. [ 3 ]  A dose of 100 mg of iron is thus necessary in order for 10 mg to be absorbed.


After administration, the maximum absorption capacity is reached already after 30 minutes and continuously increasing absorption can be observed over 24 hours. [ 2 ]  The non-absorbed iron is excreted via the stool.


The effectiveness and safety have been investigated and documented in numerous clinical studies and in various patient populations. [ 4 ]  This has included children, young people, adults, and the elderly, in addition to pregnant women and breastfeeding mothers.


Randomized , open, multicenter, controlled study in pregnant women affected by iron deficiency anemia. INTERVENTION: Iron polymaltose 100 mg 2x a day in comparison to iron sulfate 100 mg 2x a day.  STUDY DURATION: 90 days. RESULTS: hemoglobin improvement after 90 days by 2.16g/dL (iron polymaltose) and 1.93g/dL (iron sulfate). Ferritin levels after 90 days: 17.9 ng/mL (iron polymaltose), 15.7 ng/mL (iron sulfate). Side-effects observed in 29.3% of patients receiving iron polymaltose and 56.4% of those receiving iron sulfate. [ 5 ]


Randomized, open study in children affected by iron deficiency anemia. INTERVENTION: Iron polymaltose 5 mg/kg body weight in one administration a day, compared to iron sulfate 5 mg/kg body weight, divided up over 2 administrations a day. STUDY DURATION: 4 months. RESULTS: hemoglobin improvement after 4 months by 2.3g/dL (iron polymaltose) and 3g/dL (iron sulfate). Fewer gastrointestinal side-effects with iron polymaltose. The mean acceptance value after 4 months was higher with iron polymaltose than with iron sulfate. [ 6 ]


Randomized, multicenter, double-blind study in adults affected by iron deficiency anemia. INTERVENTION: Iron polymaltose 100 mg 2x a day in comparison to iron sulfate 60 mg 3x a day.  STUDY DURATION: 9 weeks. RESULTS: hemoglobin improvement in both groups after 3, 6, and 9 weeks, whereby after 3 and 6 weeks, a significant improvement was observed in the iron sulfate group. After 9 weeks, comparable improvement in both groups. Side-effects occurred in 22% of patients receiving iron polymaltose and 25% of those receiving iron sulfate. [ 7 ]


Iron polymaltose must not be used in the event of known  hypersensitivity  or intolerance to the active ingredient or one of the excipients. Iron preparations are not administered to treat anemia that is not associated with iron deficiency. Furthermore, iron preparations must not be used in the event of known iron overload or iron utilization disorders.


Iron polymaltose must not be administered at the same time as parenteral iron preparations. No interactions with other medications or foods are known.


Commonly observed side-effects, occurring in 1 to 10% of cases, include stool discoloration,  diarrhea ,  nausea , and  dyspepsia . Uncommon side-effects, occurring in 0.1 to 1% of cases, include  constipation ,  vomiting ,  stomachache ,  tooth discoloration ,  itchiness , and  headache . As very rare side-effects, occurring in 0.1 to 0.01% of cases,  allergic  reactions have been observed.


The preparation is available in various galenic formulations: syrup, drops, drinkable solution, film-coated tablets, and chewable tables. The syrup, drops, or drinkable solution are preferable for children. The preparation is dosed according to age. The following general dosage guidelines apply (for iron deficiency with anemia):


The quantity of active ingredient per unit is 100 mg of iron per chewable or film-coated tablet, 50 mg of iron per 1mL of drops, 10 mg of iron per 1mL of syrup, 100 mg of iron per 1 drinkable solution (5mL).


Iron polymaltose should be taken with food, as this improves absorption. [ 8 ]


The preparation contains different excipients depending upon the galenic formulation.


The preparation should be stored in its original packaging at room temperature (15-25 °C) and consumed by the date printed on the packaging.


Iron supplements , also known as  iron salts  and  iron pills , are a number of  iron  formulations used to treat and prevent  iron deficiency  including  iron deficiency anemia . [ 11 ] [ 12 ]  For prevention they are only recommended in those with  poor absorption ,  heavy menstrual periods ,  pregnancy ,  hemodialysis , or a diet low in iron. [ 12 ] [ 13 ]  Prevention may also be used in  low birth weight  babies. [ 12 ]  They are taken by mouth,  injection into a vein , or  injection into a muscle . [ 12 ]  While benefits may be seen in days, up to two months may be required until iron levels return to normal. [ 14 ]


Common side effects include  constipation , abdominal pain, dark stools, and  diarrhea . [ 14 ]  Other side effects, which may occur with excessive use, include  iron overload  and  iron toxicity . [ 11 ] [ 13 ]  Ferrous salts used as supplements by mouth include  ferrous fumarate ,  ferrous gluconate ,  ferrous succinate , and  ferrous sulfate . [ 13 ]  Injectable forms include  iron dextran  and  iron sucrose . [ 13 ]  They work by providing the iron needed for  making red blood cells . [ 14 ]


Iron pills have been used medically since at least 1681, with an easy-to-use formulation being created in 1832 using Chicken  Liver  extracts and majority from plants. [ 15 ]  Ferrous salt is on the  World Health Organization's List of Essential Medicines . [ 16 ]  Ferrous salts are available as a  generic medication  and  over the counter . [ 11 ]   Slow release  formulations, while available, are not recommended. [ 12 ]  In 2021, ferrous sulfate was the 105th most commonly prescribed medication in the United States, with more than 6   million prescriptions. [ 17 ] [ 18 ]


Iron supplements are used to treat or prevent  iron deficiency  and  iron-deficiency anemia ; [ 8 ]  parenteral irons can also be used to treat functional iron deficiency, where requirements for iron are greater than the body's ability to supply iron such as in inflammatory states. The main criterion is that other causes of anemia have also been investigated, such as  vitamin B 12  or  folate deficiency , drug induced or due to other poisons such as lead, as often the anemia has more than one underlying cause. [ 19 ]


Iron deficiency anemia is classically a microcytic, hypochromic anemia. Generally, in the UK oral preparations are trialled before using parenteral delivery, [ 20 ]  unless there is the requirement for a rapid response, previous intolerance to oral iron or likely failure to respond. Intravenous iron may decrease the need for  blood transfusions  however it increases the risk of infections when compared to oral iron. [ 21 ]  Daily oral supplementation of iron during pregnancy reduces the risk of maternal anemia and that effects on infant and on other maternal outcomes are not clear. [ 22 ]  Another review found tentative evidence that intermittent iron supplements by mouth for mothers and babies is similar to daily supplementation with fewer side effects. [ 23 ]  Supplements by mouth should be taken on an empty stomach, optionally with a small amount of food to reduce discomfort. [ 24 ]


Athletes may be at elevated risk of iron deficiency and so benefit from supplementation, but the circumstances vary between individuals and dosage should be based on tested  ferritin  levels, since in some cases supplementation may be harmful. [ 25 ]


Frequent blood donors may be advised to take iron supplements.  Canadian Blood Services  recommends discussing "taking iron supplements with your doctor or pharmacist" as "the amount of iron in most multivitamins may not meet your needs and iron supplements may be necessary". [ 26 ]  The  American Red Cross  recommends "taking a multivitamin with 18 mg of iron or an iron supplement with 18-38 mg of elemental iron for 60 days after each blood donation, for 120 days after each power red donation or after frequent platelet donations". [ 27 ]  A 2014  Cochrane Review  found that blood donors were less likely to be deferred for low hemoglobin levels if they were taking oral iron supplements, although 29% of those who took them experienced side effects in contrast to the 17% that took a placebo. It is unknown what the long-term effects of iron supplementation for blood donors may be. [ 28 ]


Side effects of therapy with oral iron are most often  diarrhea  or  constipation  and  epigastric  abdominal discomfort. Taken after a meal, side effects decrease, but there is an increased risk of interaction with other substances. Side effects are  dose-dependent , and the dose may be adjusted.


The patient may notice that their stools become black. This is completely harmless, but patients must be warned about this to avoid unnecessary concern. When iron supplements are given in a liquid form, teeth may reversibly discolor (this can be avoided through the use of a straw). Intramuscular injection can be painful, and brown discoloration may be noticed.


Treatments with  iron(II) sulfate  have higher incidence of adverse events than  iron(III)-hydroxide polymaltose complex  (IPC) [ 29 ] [ 30 ] [ 31 ]  or iron bis-glycinate chelate. [ 32 ] [ 33 ]


Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than six years. [ 34 ]


Iron poisoning may result in mortality or short-term and long-term morbidity. [ 35 ]


Because one of the functions of elevated  ferritin  (an acute phase reaction protein) in acute infections is thought to be to sequester iron from bacteria, it is generally thought that iron supplementation (which circumvents this mechanism) should be avoided in patients who have active bacterial infections. Replacement of iron stores is seldom such an emergency situation that it cannot wait for any such acute infection to be treated.


Some studies have found that iron supplementation can lead to an increase in  infectious disease  morbidity in areas where bacterial infections are common. For example, children receiving iron-enriched foods have demonstrated an increased rate in  diarrhea  overall and enteropathogen shedding. Iron deficiency protects against infection by creating an unfavorable environment for bacterial growth. Nevertheless, while iron deficiency might lessen infections by certain pathogenic diseases, it also leads to a reduction in resistance to other strains of viral or bacterial infections, such as  Salmonella typhimurium  or  Entamoeba histolytica . Overall, it is sometimes difficult to decide whether iron supplementation will be beneficial or harmful to an individual in an environment that is prone to many infectious diseases; however this is a different question than the question of supplementation in individuals who are already ill with a bacterial infection. [ 36 ]


Children living in areas prone for malarial infections are also at risk of developing anemia. It was thought that iron supplementation given to such children could increase the risk of malarial infection in them. A Cochrane systematic review published in 2016 found high quality evidence that iron supplementation does not increase the risk of clinical malaria in children. [ 37 ]


Contraindications often depend on the substance in question. Documented  hypersensitivity  to any ingredients and anemias without proper work-up (i.e., documentation of iron deficiency) is true of all preparations. Some can be used in iron deficiency, others require iron deficiency anaemia to be present. Some are also contraindicated in  rheumatoid arthritis . [ 7 ]


Individuals may be genetically predisposed to excessive iron absorption, as is the case with those with  HFE hereditary hemochromatosis . Within the general population, 1 out of 400 people has the homozygous form of this genetic trait, and 1 out of every 10 people has its heterozygous form. [ 38 ]  Neither individuals with the homozygous or heterozygous form should take iron supplements. [ 38 ]


Non- heme  iron forms an insoluble complex with several other drugs, resulting in decreased absorption of both iron and the other drug. Examples include  tetracycline ,  penicillamine ,  methyldopa ,  levodopa ,  bisphosphonates  and  quinolones . The same can occur with elements in food, such as  calcium , which impacts both heme and non-heme iron absorption. [ 39 ]  Absorption of iron is better at a low pH (i.e. an acidic environment), and absorption is decreased if there is a simultaneous intake of antacids.


Many other substances decrease the rate of non-heme iron absorption. One example is  tannins  from foods such as  tea [ 40 ]  and  phytic acid . [ 41 ]  Because iron from plant sources is less easily absorbed than the heme-bound iron of animal sources,  vegetarians  and  vegans  should have a somewhat higher total daily iron intake than those who eat meat, fish or poultry. [ 42 ] [ 43 ]


Taken after a meal, there are fewer side effects but there is also less absorption because of interaction and pH alteration. Generally, an interval of 2–3 hours between the iron intake and that of other drugs seems advisable, but is less convenient for patients and can impact on compliance.


The first pills were commonly known as Blaud's pills, [ 44 ]  which were named after  P. Blaud of Beaucaire , the French physician who introduced and started the use of these medications as a treatment for patients with  anemia . [ 45 ]


Iron can be supplemented  by mouth  using various forms, such as  iron(II) sulfate . This is the most common and well studied soluble iron  salt  sold under brand names such as Feratab, Fer-Iron, and Slow-FE. It is in complex with  gluconate ,  dextran ,  carbonyl iron , and other salts.  Ascorbic acid , vitamin C, increases the absorption of non-heme sources of iron. [ 46 ]


Heme iron polypeptide (HIP) (e.g. Proferrin ES and Proferrin Forte) can be used when regular iron supplements such as ferrous sulfate or ferrous fumarate are not tolerated or absorbed. A clinical study demonstrated that HIP increased serum iron levels 23 times greater than ferrous fumarate on a milligram-per-milligram basis. [ 47 ]


Another alternative is ferrous  glycine   sulfate  or ferroglycine sulfate, has less gastrointestinal side-effects than standard preparations such as iron fumarate. [ 48 ]   [ better source needed ]  It is unusual among oral preparations of iron supplements in that the iron in this preparation has very high oral bioavailability, especially in the liquid formulation. This option should be evaluated before resorting to parenteral therapy. It is especially useful in iron deficiency anemia associated with  autoimmune gastritis  and  Helicobacter pylori  gastritis, where it generally has satisfactory effect. [ 49 ]


Since iron stores in the body are generally depleted, and there is a limit to what the body can process (about 2–6 mg/kg of body mass per day; i.e. for a 100 kg/220 lb man this is equal to a maximum dose of 200–600 mg/per day) without  iron poisoning , this is a chronic therapy which may take 3–6 months. [ 50 ]


Due to the frequent intolerance of oral iron and the slow improvement, parenteral iron is recommended in many indications. [ 51 ] [ 52 ]


Iron therapy (intravenously or intramuscular) is given when therapy by mouth has failed (not tolerated), oral absorption is seriously compromised (by illnesses, or when the person cannot swallow), benefit from oral therapy cannot be expected, or fast improvement is required (for example, prior to elective surgery). [ 53 ]   Parenteral therapy  is more expensive than oral iron preparations and is not suitable during the first trimester of  pregnancy . [ 8 ]


There are cases where parenteral iron is preferable over oral iron. These are cases where oral iron is not tolerated, where the  haemoglobin  needs to be increased quickly (e.g. post partum, post operatively, post transfusion), where there is an underlying inflammatory condition (e.g. inflammatory bowel disease) or renal patients, the benefits of parenteral iron far outweigh the risks.


Low-certainty evidence suggests that IBD-related anemia treatment with  Intravenous (IV) iron infusion  may be more effective than  oral iron therapy , with fewer people needing to stop treatment early due to adverse effects. [ 54 ]  The type of iron preparation may be an important determinant of clinical benefit. Moderate-certainty evidence suggests response to treatment may be higher when IV  ferric carboxymaltose , rather than IV  iron sucrose  preparation is used, despite very-low certainty evidence of increased adverse effects, including bleeding, in those receiving ferric carboxymaltose treatment. [ 54 ]


In many cases, use of intravenous iron such as ferric carboxymaltose has lower risks of adverse events than a blood transfusion and as long as the person is stable is a better alternative. [ 55 ]  Ultimately this always remains a clinical decision based on local guidelines, although National Guidelines are increasingly stipulating IV iron in certain groups of patients. [ 56 ] [ 57 ]


A Cochrane review of controlled trials comparing  intravenous (IV) iron therapy  with oral iron supplements in people with  chronic kidney disease , found low-certainty evidence that people receiving IV-iron treatment were 1.71 times as likely to reach their target  hemoglobin  levels. [ 58 ]  Overall, hemoglobin was 0.71g/dl higher than those treated with oral iron supplements. Iron stores in the liver, estimated by serum  ferritin , were also 224.84 μg/L higher in those receiving IV-iron. [ 58 ]  However, there was also low-certainty evidence that allergic reactions were more likely following IV-iron therapy. It was unclear whether type of iron therapy administration affects the risk of death from any cause, including cardiovascular, nor whether it may alter the number of people who may require a blood transfusion or dialysis. [ 58 ]


Soluble iron salts have a significant risk of adverse effects and can cause toxicity due to damage to cellular macromolecules. Delivering iron parenterally has utilised various different molecules to limit this. This has included  dextrans ,  sucrose , carboxymaltose, and Isomaltoside 1000. [ citation needed ]


One formulation of parenteral iron is iron dextran which covers the old high molecular weight (brand name Dexferrum) and the much safer low molecular iron dextrans (brand names including Cosmofer and Infed). [ 59 ]


Iron  sucrose  has an occurrence of allergic reactions of less than 1 in 1000. [ 60 ]  A common side effect is taste changes, especially a  metallic taste , occurring in between 1 in 10 and 1 in 100 treated patients. [ 60 ]  It has a maximum dose of 200 mg on each occasion according to the SPC, but it has been given in doses of 500 mg. Doses can be given up to 3 times a week. [ 61 ]


Iron carboxymaltose is marketed as Ferinject, [ 8 ]  Injectafer, [ 9 ] [ 62 ]  and Iroprem in various countries. [ 63 ]  The most common side effects are  headaches  which occur in 3.3%, and hypophosphatemia, which occurs in more than 35%. [ 8 ] [ 9 ]


Iron isomaltoside 1000 (brand name Monofer) is a formulation of parenteral iron that has a matrix structure that results in very low levels of free iron and labile iron. It can be given at high doses – 20 mg/kg in a single visit – no upper dose limit. This formulation has the benefit of giving a full iron correction in a single visit. [ 64 ] [ 63 ]


Ferric maltol , marketed as Accrufer [ 10 ]  and Ferracru, is available in oral and intravenous preparations. When used as a treatment for IBD-related anemia, very low certainty evidence suggests a marked benefit with oral ferric maltol compared with placebo. However it was unclear whether the IV preparation was more effective than oral ferric maltol. [ 54 ]


Lipegfilgrastim , sold under the  brand name   Lonquex , is a medication used to reduce the duration of  neutropenia  and the incidence of  febrile neutropenia  in adults. [ 1 ]  It is given by  injection  under the skin in the abdomen, upper arm or thigh. [ 1 ]


The most common side effects include  nausea  as well as  bone  and  muscle pain . [ 1 ]


Lipegfilgrastim is similar to  granulocyte colony stimulating factor  ( G‑CSF ), a naturally occurring  protein  in the body that stimulates the production of  white blood cells  including  neutrophils  in the  bone marrow . [ 1 ]  Lipegfilgrastim acts in the same way as G‑CSF, increasing the production of neutrophils and thereby helping to reduce the duration of neutropenia and the occurrence of  febrile neutropenia  (a sign of infection) in people receiving  chemotherapy . [ 1 ]


Lipegfilgrastim is a  filgrastim  biosimilar. [ 1 ]  In lipegfilgrastim, the filgrastim has been ' pegylated ' (attached to  polyethylene glycol ). [ 1 ]  This slows down the medicine's removal from the body and allows the medicine to be given less often. [ 1 ]


Lipegfilgrastim was authorized for medical use in the  European Union  in July 2013. [ 1 ]


Lipegfilgrastim is indicated for the reduction in the duration of  neutropenia  and the incidence of  febrile neutropenia  in adults treated with  cytotoxic  chemotherapy for  malignancy  (with the exception of  chronic myeloid leukaemia  and  myelodysplastic syndromes ). [ 1 ]


Lovotibeglogene autotemcel , sold under the brand name  Lyfgenia , is a  lentiviral   gene therapy  used for the treatment of  sickle cell disease . [ 1 ] [ 3 ] [ 4 ] [ 5 ]


The most common side effects include stomatitis (mouth sores of the lips, mouth, and throat), low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia (fever and low white blood cell count), consistent with chemotherapy and underlying disease. [ 3 ]


The US  Food and Drug Administration  (FDA) approved lovotibeglogene autotemcel in December 2023. [ 3 ] [ 6 ]


Lovotibeglogene autotemcel is  indicated  for the treatment of people aged twelve years of age and older with sickle cell disease and a history of  vaso-occlusive events . [ 1 ] [ 3 ]


The recipient's blood stem cells are genetically modified to produce HbA (T87Q), a gene-therapy derived  hemoglobin A , which is similar to the normal adult  hemoglobin  produced in persons not affected by sickle cell disease. [ 3 ]  Red blood cells containing HbA (T87Q) have a lower risk of sickling and occluding blood flow. [ 3 ]  These modified stem cells are then delivered to the recipient. [ 3 ]


The gene therapy is made from the recipient's own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. [ 3 ]  Prior to treatment, the recipient's own stem cells are collected, and then the recipient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in lovotibeglogene autotemcel. [ 3 ]


The US FDA label contains a black box warning about hematologic malignancy (blood cancer). [ 1 ] [ 3 ]


The safety and effectiveness of lovotibeglogene autotemcel is based on the analysis of data from a single-arm, 24-month multicenter study in participants with sickle cell disease and history of Vaso-occlusive episodes (VOEs) between the ages of twelve and fifty years. [ 3 ]  Effectiveness was evaluated based on complete resolution of VOEs (VOE-CR) between six and eighteen months after infusion with lovotibeglogene autotemcel. [ 3 ]  Twenty-eight (88%) of 32 participants achieved VOE-CR during this time period. [ 3 ]


The FDA granted the application for lovotibeglogene autotemcel  priority review ,  orphan drug ,  fast track , and regenerative medicine advanced therapy designations. [ 3 ]  The FDA granted approval of Lyfgenia to Bluebird Bio Inc. [ 3 ]


The cost effectiveness threshold of the therapy is estimated to be between  US$1.35 million  to $2.05 million. [ 7 ]


Lovotibeglogene autotemcel is the  international nonproprietary name . [ 8 ]


Lovotibeglogene autotemcel is sold under the brand name Lyfgenia. [ 1 ]


Lusutrombopag , sold under the brand name  Mulpleta  among others, is a  medication  that has been developed for certain conditions that lead to  thrombocytopenia  (abnormally low  platelet  counts) such as thrombocytopenia associated with  chronic liver disease  in patients prior to elective invasive procedures. [ 1 ]  It is being manufactured and marketed in Japan by  Shionogi . [ 2 ] [ 3 ] [ 4 ]  It was approved by the U.S.  Food and Drug Administration  (FDA) in July 2018, and NICE in January 2020. [ 5 ] [ 6 ]


It was approved for medical use in the European Union in February 2019. [ 7 ]


Miltefosine , sold under the trade name  Impavido  among others, is a medication mainly used to treat  leishmaniasis  and free-living  amoeba infections  such as  Naegleria fowleri  and  Balamuthia mandrillaris . [ 4 ]  This includes the three forms of leishmaniasis:  cutaneous ,  visceral  and mucosal. [ 5 ]  It may be used with  liposomal amphotericin B  or  paromomycin . [ 6 ]  It is taken by mouth. [ 5 ]


Common side effects include  vomiting , abdominal pain,  fever ,  headaches , and decreased kidney function. [ 4 ]  More severe side effects may include  Stevens–Johnson syndrome  or  low blood platelets . [ 4 ]  Use during  pregnancy  appears to cause harm to the baby and use during  breastfeeding  is not recommended. [ 4 ]  How it works is not entirely clear. [ 4 ]


Miltefosine was first made in the early 1980s and studied as a treatment for  cancer . [ 7 ]  A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India. [ 8 ]  It is on the  World Health Organization's List of Essential Medicines . [ 9 ] [ 10 ]


Miltefosine is primarily used for the treatment of  visceral  and  New World cutaneous leishmaniasis , and is undergoing  clinical trials  for this use in several countries. [ 11 ] [ 12 ]  This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines. [ 13 ]  Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however, a 2005 survey concluded that miltefosine is the only effective oral treatment for both forms of leishmaniasis. [ 14 ]


Miltefosine has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba,  Naegleria fowleri , acquired through water entering the nose during a plunge in contaminated water. [ 15 ]  It has orphan drug status in the United States for  acanthamoeba keratitis  and  primary amebic meningoencephalitis  (PAM). [ 16 ] [ 17 ]


Miltefosine is listed as pregnancy category D by the FDA. This means there is evidence-based adverse reaction data from investigational or marketing experience or studies in humans of harm to the human fetus. [ 18 ]   Despite this evidence, the potential benefits of miltefosine may warrant use of the drug in pregnant women despite potential risks.  A pregnancy test should be done prior to starting treatment. Effective  birth control  should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe. [ 3 ]


Miltefosine is contraindicated in individuals who have a  hypersensitivity  to this medication, pregnant women, and people who have the  Sjögren-Larsson syndrome . [ 19 ]  It is embryotoxic and fetotoxic in rats and rabbits, and  teratogenic  in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and  contraception  is required beyond the end of treatment in women of child-bearing age. [ 20 ]


Common  side effects  from miltefosine treatment are  nausea  and  vomiting , which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness. [ 21 ]


Serious side effects include rash, diarrhea, and arthritis. [ 21 ]  The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed. [ 22 ]


Miltefosine primarily acts on  Leishmania  by affecting the species's promastigote and amastigote stages. [ 23 ]  Miltefosine exerts its activity by interacting with lipids, inhibiting  cytochrome c oxidase  and causing apoptosis-like cell death. [ 24 ]  This may affect membrane integrity and mitochondrial function of the parasite. [ citation needed ]


While initially studied as a cancer medication, due to side effects it was never used for this purpose. [ 25 ]


Phospholipid  group  alkylphosphocholine  were known since the early 1980s, particularly in terms of their binding affinity with  cobra  venom. [ 26 ]  In 1987 the phospholipids were found to be potent toxins on  leukemic cell culture . [ 27 ]  Initial  in vivo  investigation on the  antineoplastic  activity showed positive result, but then only at high dosage and at high toxicity. [ 28 ]  At the same time in Germany, Hansjörg Eibl, at the  Max Planck Institute for Biophysical Chemistry , and Clemens Unger, at the  University of Göttingen , demonstrated that the  antineoplastic activity  of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against  methylnitrosourea -induced  mammary carcinoma , but less so on  transplantable   mammary carcinomas  and  autochthonous   benzo(a)pyrene -induced  sarcomas , and relatively inactive on Walker 256  carcinosarcoma  and autochthonous acetoxymethylmethylnitrosamine-induced  colonic tumors  of rats. [ 29 ] [ 30 ]  It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the  glycerol  group, is highly selective on cell types and acts through different mechanism. [ 31 ] [ 32 ]


In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the  London School of Hygiene and Tropical Medicine  as having antileishmanial effect as well. The compound was effective against  Leishmania donovani   amastigotes  in cultured mouse peritoneal  macrophages  at a dose of 12.8 mg/kg/day in a five-day course. [ 33 ]  However, priority was given to the development of the compound for cutaneous  metastases  of  breast cancer . In 1992 a new research was reported in which the compound was highly effective in mouse against different  life cycle stages  of different  Leishmania  species, and in fact, more potent than the conventional  sodium stibogluconate  therapy by a factor of more than 600. [ 34 ]  Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety. [ 35 ]  This promising development promulgated a unique public–private partnership collaboration between  ASTA Medica  (later Zentaris GmbH), the  World Health Organization  (WHO) Special Programme for Research and Training in Tropical Diseases, and the  Government of India . Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis. [ 3 ]


In 2013, the US  Centers for Disease Control and Prevention  recommended miltefosine for the treatment of free-living amoeba infections such as  granulomatous amoebic encephalitis  and  primary amoebic meningoencephalitis , two fatal protozoal diseases. [ 36 ]  Historically, only four survivors have been recorded out of 138 confirmed infections in North America. One American survived the infection in 1978 and one individual from Mexico in 2003. In 2013, two children survived and recovered from primary amoebic meningoencephalitis after treatment with miltefosine. [ 37 ] [ 38 ]  In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive  Naegleria fowleri  infection. [ 39 ]


Since 2017 Miltefosine is commercially available in the United States through Profounda. [ 40 ]  Previously one could only get it from the  CDC  for emergency use under an expanded access  IND  protocol for treatment of free-living amoeba (FLA) infections:  primary amoebic meningoencephalitis  caused by  Naegleria fowleri  and granulomatous amoebic encephalitis caused by  Balamuthia mandrillaris  and  Acanthamoeba  species. [ 37 ]  Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company. [ 41 ]


In the  developing world  a course of treatment costs US$65 to $150. [ 6 ]  In the  developed world  treatment may be 10 to 50 times greater. [ 6 ]


It is active against some  bacteria  and  fungi , [ 3 ] [ 42 ]  as well as human  trematode   Schistosoma mansoni  and the snail that spreads it  Biomphalaria alexandrina . [ 43 ]


Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs.  Animal and  in vitro  studies suggest it may have broad anti-protozoal and anti-fungal properties:


Miltefosine targets HIV infected  macrophages , which play a role  in vivo  as long-lived HIV-1 reservoirs. The HIV protein  Tat  activates pro-survival  PI3K / Akt  pathway in primary human macrophages.  Miltefosine acts by inhibiting the  PI3K/Akt pathway , thus removing the infected macrophages from circulation, without affecting healthy cells. [ 56 ] [ 57 ]  It significantly reduces replication of HIV-1 in cocultures of human  dendritic cells  (DCs) and  CD4 +  T cells , which is due to a rapid secretion of soluble factors and is associated with induction of type-I  interferon  (IFN) in the human cells. [ 58 ]


Pentavalent antimonials  ( Meglumine antimoniate # ,  Sodium stibogluconate )


Piperaquine/dihydroartemisinin  ( DHA/PPQ ), sold under the brand name  Eurartesim  among others, is a  fixed dose combination  medication used in the treatment of  malaria . [ 2 ]  It is a combination of  piperaquine  and  dihydroartemisinin . [ 2 ]  Specifically it is used for malaria of the  P. falciparum  and  P. vivax  types. [ 3 ] [ 4 ]  It is taken by mouth. [ 3 ]


Side effects are uncommon. [ 4 ]  Concerns include the possibility of  QT prolongation . [ 4 ]  Versions are available for use in children. [ 3 ]  Use in early  pregnancy  is not recommended. [ 4 ]  The two medications work by different mechanisms. [ 4 ]


Piperaquine/dihydroartemisinin was approved for medical use in Europe in 2011. [ 3 ]  The combination is on the  World Health Organization's List of Essential Medicines . [ 2 ] [ 5 ]  It is commercially available in Africa and Asia. [ 3 ]  It has been used to treat more than 4.5   million people as of 2017. [ 3 ]


Dihydroartemisinin  (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs.


Piperaquine  is an antimalarial drug, a bisquinoline first made in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based antimalarials became available. The combination dihydroartemisinin-piperaquine is an effective antimalarial that is used widely around the world. In South-East Asia, where resistance has emerged towards both artemisinin and piperaquine, the combination is being trialed with a third drug, namely  mefloquine . [ 6 ]


Piperaquine is characterized by slow absorption and a long biological half-life, making it a good partner drug with artemisinin derivatives which are fast acting but have a short biological half-life.


This product is available in the market of several countries:


Rh o (D) immune globulin  ( RhIG ) is a medication used to prevent  RhD isoimmunization  in mothers who are  RhD negative  and to treat  idiopathic thrombocytopenic purpura  (ITP) in people who are  Rh positive . [ 2 ]  It is often given both during and following  pregnancy . [ 2 ]  It may also be used when RhD-negative people are given RhD-positive blood. [ 2 ]  It is given by  injection into muscle  or a  vein . [ 2 ]  A single dose lasts 12 weeks. [ 2 ]  It is made from  human blood plasma . [ 3 ]


Common side effects include  fever , headache, pain at the site of injection, and  red blood cell breakdown . [ 2 ]  Other side effects include  allergic reactions ,  kidney problems , and a very small risk of viral infections. [ 2 ]  In those with ITP, the amount of red blood cell breakdown may be significant. [ 2 ]  Use is safe with  breastfeeding . [ 2 ]  Rho(D) immune globulin is made up of  antibodies  to the  antigen  Rh o (D) present on some  red blood cells . [ 2 ]  It is believed to work by blocking a person's immune system from recognizing this antigen. [ 2 ]


Rh o (D) immune globulin came into medical use in the 1960s, [ 4 ]  following the pioneering work of  John G. Gorman . In 1980, Gorman shared the  Lasker-DeBakey Clinical Medical Research Award  for pioneering work on the  rhesus blood group system . [ 5 ]


RhIG is on the  World Health Organization's List of Essential Medicines . [ 6 ] [ 7 ]


Even in normal pregnancies, a small number of fetal blood cells enters the maternal bloodstream (fetomaternal hemorrhage). If a mother is RhD negative, but the fetus is RhD positive, the mother's immune system may develop an immune response (develops  antibodies ) to the unfamiliar RhD antigens from the fetus. This process is called  RhD alloimmunization . Alloimmunization usually has minimal effect on the first such pregnancy; but, in a second such pregnancy, pre-existing maternal RhD IgG antibodies can cross the placenta in enough amounts to damage fetal red blood cells. This condition is called  erythroblastosis fetalis  and can be fatal to the fetus. [ 8 ]


The RhD status of the fetus is determined by genetic inheritance. In a pregnancy where the mother is RhD negative and the father is RhD positive, the probability of the fetus having RhD positive blood is dependent on whether the father is  homozygous  for RhD (i.e., both RhD alleles are present) or  heterozygous  (i.e., only one RhD allele is present). If the father is homozygous, the fetus will necessarily be RhD positive, as the father will necessarily pass on a RhD positive allele. If the father is heterozygous, there is a 50% chance that the fetus will be RhD positive, as he will randomly pass on either the RhD positive allele or not. [ 9 ] : 130  . Not all Rh-negative patients are capable of being immunized to the RhD antigen, and mothers may only become immunized after many repeated pregnancies. The risk of  hemolytic disease  (including due to RhD) significantly increases if the mother has had a past transfusion of Rh-positive blood.  [ 10 ]


Exposure to fetal blood cells that can cause RhD alloimmunization can happen during normal pregnancy and delivery, miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, or trauma. [ 3 ] [ 8 ]  92% of women who develop an anti-D during pregnancy do so at or after 28 weeks gestation. [ 11 ] [ 9 ] [ 12 ]


In an RhD negative mother, RhIG can temporarily prevent sensitization of the maternal immune system to RhD  antigens , with each 100 μg of anti-D being able to neutralize about 4 mL of fetal blood. [ 13 ]  With the widespread use of RhIG,  Rh disease  of the  fetus  and  newborn  has almost disappeared in the developed world. The risk that an RhD negative mother can be  alloimmunized  by a RhD positive fetus can be reduced from approximately 16% to less than 0.1% by the appropriate administration of RhIG. [ 11 ] [ 9 ] [ 14 ]  In data collected from communities in Canada, without treatment as many as 14% of affected fetuses are stillborn, 30% of affected live births almost certainly fatal without treatment, and 30% with severe  jaundice  that untreated risks brain damage from  kernicterus . [ 8 ]
 [ 15 ] . Prior to effective transfusion therapy, the mortality rate of hemolytic disease was 70-80%, dropping to 30-50% with small transfusions and 13-33% for more aggressive transfusions before RhIg treatments were introduced.  [ 10 ]


The  American College of Obstetricians and Gynecologists  (ACOG) recommends that all RhD negative mothers, regardless of fetal blood type, receive RhIG at about 28 weeks gestation, and again shortly after delivery in the case of an RhD positive or RhD unknown baby. [ 16 ]  It should be given within 3 days of a potential exposure to Rh positive blood from the baby such as may occur during second and third trimester miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma, or delivery (amounts detailed in the next section). [ 8 ]  It is given by intramuscular injection as part of modern routine  antenatal  care. Despite excellent results, the medication retains an FDA  Pregnancy Category  C. [ citation needed ]


RhIG is recommended in the UK after antenatal pathological events that are likely to cause a feto–maternal hemorrhage. Applicable 'pathologic events' include accidents that may induce fetomaternal hemorrhage (motor vehicle accidents, falls, abdominal trauma), following obstetric/gynecologic procedures during pregnancy, and at the time of threatened- or spontaneous-/elective  abortions , regardless of gestational age. RhIG is also recommended after normal delivery, with amounts detailed in the next section. [ 13 ]


There is insufficient evidence that the use of Rho(D) immune globulin after a spontaneous miscarriage is needed and a  Cochrane review  recommends that local practices be followed. [ 17 ]


Rh immune globulin is composed of IgG antibodies and therefore is able to cross the placenta. In rare cases this can cause a baby to have a weakly positive  direct antiglobulin test  (DAT) due to sensitization of fetal cells from mothers who have received multiple doses of RhIG. However, no treatment is necessary as the clinical course is benign. [ 18 ]


Widespread use of RhIG started with postpartum administration, as delivery is the main source of significant fetomaternal hemorrhage.
A D-negative mother who is not alloimmunized to D should also receive an appropriate dose of RhIG after delivery of a D-positive infant. (In older recommendations, the Rh status of the infant is only known at delivery from testing of  cord blood .) [ 9 ]  If the infant is D-positive, the mother should have a postpartum blood sample screened for fetomaternal hemorrhage in order to determine the appropriate dosage of RhIG to be administered.  (The presence of residual anti-D from antepartum RhIG administration does not indicate ongoing protection from alloimmunization – repeat administration of RhIG is necessary.) [ 13 ]


The  rosette test  is a sensitive method to detect fetomaternal hemorrhage of 10 cc or more.  This qualitative (not quantitative) test will be positive if fetal D-positive cells are present in the maternal sample, indicating a significantly large fetomaternal hemorrhage has occurred.  A rosette test may be falsely positive if the mother is positive for the  weak D  phenotype and falsely negative if the neonate is weak D.  If the mother is positive for the weak D phenotype, the rosette test should not be used; instead, a quantitative test such as the  Kleihauer–Betke test  or flow cytometry should be utilized. If the rosette test is negative, then a dose of 300 micrograms of RhIG is given (sufficient to prevent alloimmunization after delivery in 99% of cases). [ 11 ] [ 19 ]   The RhIG dose suppresses the immune response to up to 30 cc of whole fetal blood (15 cc of red blood cells). If a fetomaternal hemorrhage in excess of 30 cc has occurred, additional testing is mandatory in order to determine the appropriate dosage of RhIG to prevent alloimmunization.  A positive rosette test should be followed by a quantitative test such as the Kleihauer–Betke test or an alternative approach such as  flow cytometry .  See the article on Kleihauer–Betke test for details on how the volume of fetomaternal hemorrhage is calculated. The dosage of RhIG is calculated from the volume of fetal hemorrhage (in mL).  Ex: 50 mL fetal hemorrhage / 30 mL = 1.667 (round up to 2) then add 1 = 3 vials of RhIG. [ citation needed ]


Postpartum RhIG should be administered within 72 hours of delivery.  If prophylaxis is delayed, the likelihood that alloimmunization will be prevented is decreased.  However, ACOG still recommends that RhIG be administered because partial protection still occurs. [ 11 ] [ 12 ]   If the D-type of a newborn or stillborn is unknown or cannot be determined, RhIG should be administered.


Primary  immune thrombocytopenia  (ITP) is an acquired immune-mediated disorder characterized by isolated  thrombocytopenia , defined as a peripheral blood platelet count less than 100 x 10 9 /L, and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia.  Symptoms of ITP include abnormal bleeding and bruising due to the reduction in  platelet count . [ 20 ]   Rh o (D) Immune Globulin Intravenous [Human; Anti-D] is indicated for use in non-splenectomized, Rh o (D)-positive children with chronic or acute ITP, adults with chronic ITP, and children and adults with ITP secondary to HIV infection. Anti-D must be administered via the intravenous route when used in clinical situations requiring an increase in platelet count. The mechanism of action of anti-D is not fully understood; however, after administration the anti-D coated red blood cell complexes saturate  Fcγ receptors  sites on  macrophages , resulting in preferential destruction of  red blood cells  (RBCs), therefore sparing antibody-coated  platelets . [ 21 ]  Anti-D is recommended as a first-line therapy for ITP, along with corticosteroids and intravenous immune globulin (IVIG). [ 20 ] [ 22 ]   [WinRho SDF is an anti-D manufactured, distributed and marketed by  Cangene  in the US. There is a black box warning on WinRho SDF due to the risk of potentially fatal intravascular hemolysis when used in the treatment of ITP. [ 21 ]  Life-threatening  anemia ,  kidney  failure, and  disseminated intravascular coagulation  (DIC) have occurred in people treated with WinRho SDF for ITP. [ citation needed ]


The following females are not candidates for RhIG:


The first Rho(D) immune globulin treatment "skymed" was introduced by  Ortho Clinical Diagnostics , a subsidiary holding of  Jskymed , and was first administered on May 29, 1968, to Marianne Cummins in  Teaneck ,  New Jersey . [ 24 ]


In 1996, ZLB Bioplasma (part of  CSL Behring ) was given approval to sell Rhophylac in Europe. Effectiveness was demonstrated in a clinical trial in 2003 and in 2004 Rhophylac was approved in the United States. [ 25 ]


Conventional Rho(D) immune globulin is extracted from human  blood plasma . Excluding  autoimmunity , only people who are themselves Rho(D) negative can make the anti-D antibody. As a result, there is a limited pool of people from which to draw plasma that can contain the desired IgG. Special anti-D donation programs are set up to account for this rarity. [ 26 ]  Volunteers are given an injection containing the D antigen in order to make their immune system start producing the antibody (alloimmunization) or to boost the amounts. Only those who have no ability to become pregnant may apply. [ 27 ]


The most common way anti-D products are manufactured is by a form of the  Cohn cold ethanol fractionation process  developed in the 1950s.  Variations of the Cohn method developed in the 1950s may not completely clear aggregates of immunoglobulins, which can cause problems for patients if administered intravenously, and is a primary reason why most anti-Ds are for intramuscular use only.  A non-Cohn manufacturing variation is ChromaPlus process approved by the  U.S. Food and Drug Administration  (FDA) that is used to make Rhophylac. [ 28 ]   Rho(D) immune globulin may trigger an allergic reaction. Steps are taken in the plasma-donor screening process and the manufacturing process to eliminate bacterial and viral contamination, although a small, residual risk may remain for contamination with small viruses. There is also a theoretical possibility of transmission of the  prion  responsible for  Creutzfeldt–Jakob disease , or of other, unknown infectious agents. [ 29 ]


There has been continual attempts to produce a  monoclonal  anti-D IgG formulation suitable for replacing the current polyclonal formulation. [ 30 ]  A monoclonal antibody can be produced without requiring human donors (and associated supply and disease risks) and would be more consistent from batch to batch. [ 8 ]


India has approved a monoclonal formulation called  Rhoclone  (Bharat Serums and Vaccines Ltd.), [ 31 ]  made from  hybridoma cultures . The country has also tested and recently marketed a  recombinant  version of Rhoclone expressed in  CHO cells . [ 32 ]  This recombinant formulation, Trinbelimab, marketed as AntiD, is also being evaluated in a large Real-world Prospective Study that aims to enroll 20,000 Rh-negative mothers. [ 33 ]


Roledumab  and  Rozrolimupab  are two other formulations that have undergone some clinical trials. The former is a monoclonal IgG. The latter is a recombinant mixture of 25 IgGs. [ 8 ]


RhIG can be administered by either intramuscular (IM) or intravenous (IV) injection, depending on the preparation. [ 34 ]   The IM-only preparation should never be administered IV due to the risk of complement system activation.  Multiple IM doses should be given at different sites or at different times within the 72-hour window.  Or, multiple IV doses can be administered according to the instructions in the package insert. [ citation needed ]


Rh o (D) immune globulin is also spelled Rh 0 (D) immune globulin (letter  o  and digit  zero  are both widely attested; more at  Rh blood group system - Rh nomenclature ).


AntiD (Recombinant) and Rhoclone are the only Rh0(D) immune globulin marketed in the world. both manufactured by BSV Ltd. Rhophylac is manufactured by CSL Limited. RhoGAM and MICRhoGam are brand names of Kedrion Biopharma. Other brand names are BayRHo-D, Gamulin Rh, HypRho-D Mini-Dose, Mini-Gamulin Rh, Partobulin SDF ( Baxter ), Rhesonativ (Octapharma), and RhesuGam (NBI).  KamRho-D I.M. is a brand name of Kamada Ltd.


The United States  distribution  rights for WinRho SDF (another brand name) were transferred from Baxter to the manufacturer,  Cangene , in 2010; they had been held by Baxter since 2005. [ 35 ]   Sales of WinRho fell every year under the agreement with Baxter, the supposition being that Baxter was favoring the sale of its own product over WinRho; according to one analyst, "WinRho was always an afterthought for a big company like Baxter." [ 36 ]


Taurolidine  is an  antimicrobial  that is used to prevent infections in  catheters . [ 1 ]  Side effects and the induction of  bacterial resistance  is uncommon. [ 1 ]  It is also being studied as a treatment for  cancer . [ 2 ]


It is derived from the endogenous  amino acid  derivative  taurine . The putative method of action involves the metabolism of taurolidine to taurinamide and ultimately taurine and water, liberating formaldehyde that chemically reacts with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This reaction denatures the endotoxins and complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and inactivates susceptible exotoxins. [ 3 ]


Taurolidine is an antimicrobial agent used as part of a  catheter lock solution  in an effort to prevent catheter infections. [ 4 ]


No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 grams daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, carbon dioxide and water. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness,  erythema , facial flushing, headache,  epistaxis , and nausea have been reported. [ 12 ]


Taurolidine has a relatively low acute and subacute toxicity. [ 1 ]  Intravenous injection of 5 grams taurolidine into humans over 0.5–2 hours produce only burning sensation while instilling, numbness, and erythema at the injection sites. [ 12 ]  For treatment of  peritonitis , taurolidine was administered by  peritoneal lavage , intraperitoneal instillation or intravenous infusion, or by a combination thereof. The total daily dose ranged widely from 0.5 to 50 g. The total cumulative dose ranged from 0.5 to 721 g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40 g/day. Total daily doses of up to 40 g and total cumulative doses exceeding 300 g were safe and well tolerated. [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]


Following administration of taurolidine, the antimicrobial and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via methylol taurultam to methylol taurinamide and taurine. These labile N-methylol derivatives of taurultam and taurinamide react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when taurolidine is pre-warmed to 37 °C (99 °F). Microbes are killed and the resulting toxins are inactivated; the destruction time  in vitro  is 30 minutes. [ 19 ]


The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency  in vivo  than indicated by  in vitro   minimum inhibitory concentration  (MIC) values, and also appears to preclude susceptibility to resistance mechanisms. [ 14 ]


Taurolidine binding to  lipopolysaccharides  (LPS) prevents microbial adherence to host epithelial cells, thereby prevents microbial invasion of uninfected host cells. Although the mechanism underlying its antineoplastic activity has not been fully elucidated, it may be related to this agent's anti-adherence property. [ 6 ] [ 7 ]  Taurolidine has been shown to block  interleukin 1  (IL-1) and  tumour necrosis factor  (TNF) in human peripheral blood  mononuclear cells  (PBMC). [ 20 ]  In addition, taurolidine also promotes  apoptosis  by inducing various apoptotic factors and suppresses the production of  vascular endothelial growth factor  (VEGF), a protein that plays an important role in  angiogenesis . [ 21 ]


Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic and anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus). [ 15 ] [ 16 ] [ 22 ]


The chemical name for taurolidine is 4,4'-Methylene-bis(1,2,4-thiadiazinane)-1,1,1’,1'-tetraoxide.


It is a white to off white odourless crystalline powder. It is practically insoluble in chloroform, slightly soluble in boiling acetone, ethanol, methanol, and ethyl acetate, sparingly soluble in water 8 at 20° and ethyl alcohol, soluble in dilute  hydrochloric acid , and dilute sodium hydroxide, and freely soluble in N,N-dimethylformamide (at 60 °C).


Taurolidine was first synthesized in the laboratories of Geistlich Pharma AG, Switzerland in 1972. Clinical trials begun in 1975 in patients with severe peritonitis.