Chemistry:Primaquine

From HandWiki
Short description: Pharmaceutical drug
Primaquine
Primaquine.svg
Clinical data
Other namesprimaquine phosphate
AHFS/Drugs.comMonograph
MedlinePlusa607037
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability96%[1]
MetabolismLiver
Elimination half-life6 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC15H21N3O
Molar mass259.353 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Primaquine is a medication used to treat and prevent malaria and to treat Pneumocystis pneumonia.[2] Specifically it is used for malaria due to Plasmodium vivax and Plasmodium ovale along with other medications and for prevention if other options cannot be used.[2] It is an alternative treatment for Pneumocystis pneumonia together with clindamycin.[2][3] It is taken by mouth.[2]

Common side effects include nausea, vomiting, and stomach cramps.[2][4] Primaquine should not be given to people with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of red blood cell breakdown.[4] It is often recommended that primaquine not be used during pregnancy.[5][6] It may be used while breastfeeding if the baby is known not to have G6PD deficiency.[6] The mechanisms of action is not entirely clear but is believed to involve effects on the malaria parasites' DNA.[2]

Primaquine was first made in 1946.[3] It is on the World Health Organization's List of Essential Medicines.[7][8] It is available as a generic medication.[2]

Medical uses

Malaria

Primaquine is primarily used to prevent relapse of malaria due to Plasmodium vivax and Plasmodium ovale.[9] It eliminates hypnozoites, the dormant liver form of the parasite,[10] after the organisms have been cleared from the bloodstream.[9] If primaquine is not administered to patients with proven P. vivax or P. ovale infection, a very high likelihood of relapse exists for weeks or months (sometimes years).[9] But it has been hypothesized that primaquine (and perhaps also the newer, related drug tafenoquine) might kill a proportion of non-circulating merozoites as well as hypnozoites, such as merozoites in bone marrow, thereby reducing the number of recrudescences (not only hypnozoite-mediated relapses) that take place.[11] Clarity in this regard is expected to be forthcoming soon.[12] Use of primaquine in combination with quinine or chloroquine each of which is very effective at clearing P. vivax from blood, improves outcomes; they appear to also potentiate the action of primaquine.[13]

As of 2016, the US Centers for Disease Control and Prevention recommends the use of primaquine for primary prophylaxis prior to travel to areas with a high incidence of P. vivax, and for terminal prophylaxis (anti-relapse therapy) after travel.[4]

A single dose of primaquine has rapid and potent ability to kill gametocytes (stage V) of P. falciparum and P. vivax in blood; it also kills asexual trophozoites of P. vivax in blood, but not of P. falciparum.[13] Because of its action against gametocytes, the WHO recommends it for use in reducing transmission to control P. falciparum infections.[14]

Pneumocystis pneumonia

Primaquine is also used in the treatment of Pneumocystis pneumonia (PCP), a fungal infection commonly occurring in people with AIDS and, more rarely, in those taking immunosuppressive drugs. To treat PCP effectively, it is usually combined with clindamycin.[3]

Special populations

Primaquine has not been studied extensively in people 65 and older so it is not known if dosing should be adjusted for this population.[15]

Primaquine should not be administered to anyone with G6PD deficiency because a severe reaction can occur, resulting in hemolytic anemia.[4] However, the WHO has recommended that a single dose of primaquine (0.25 mg/kg) is safe to give even in individuals with G6PD deficiency, for the purpose of preventing transmission of P. falciparum malaria.[14]

Primaquine is contraindicated in pregnancy, because the glucose-6-phosphate dehydrogenase status of the fetus would be unknown.[4]

Primaquine overdose can cause a dangerous reduction in various blood cell counts, and therefore should be avoided in people at risk for agranulocytosis, which include people with conditions such as rheumatoid arthritis and lupus erythematosus, and those taking concurrent medications that also decrease blood cell counts.[15]

Hemolytic reactions (moderate to severe) may occur in individuals with G6PD deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G6PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency of erythrocytic G6PD) while receiving primaquine and related drugs.[16][17]

Adverse reactions

Common side effects of primaquine administration include nausea, vomiting, and stomach cramps.[4][15]

In persons with cytochrome b5 reductase deficiency, primaquine causes methemoglobinemia, a condition in which the blood carries less oxygen that it does normally.[15]

Overdosing can reduce the number of function of various kinds of blood cells, including loss of red blood cells, methemoglobinemia, and loss of white blood cells.[15]

Persons with glucose-6-phosphate dehydrogenase deficiency (G6PD) may develop hemolytic anemia from primaquine.[18]

Pharmacology

Mechanism of action

Primaquine is lethal to P. vivax and P. ovale in the liver stage, and also to P. vivax in the blood stage through its ability to do oxidative damage to the cell. However, the exact mechanism of action is not fully understood.[6] Liver hypnozoites aside, primaquine can possibly eliminate P. vivax merozoites in bone marrow as a result of accumulation there of hydrogen peroxide.[19]

Pharmacokinetics

Primaquine is well-absorbed in the gut and extensively distributed in the body without accumulating in red blood cells. Administration of primaquine with food or grapefruit juice increases its oral bioavailibity.[20] In blood, about 20% of circulating primaquine is protein-bound, with preferential binding to the acute phase protein orosomucoid. With a half-life on the order of 6 hours, it is quickly metabolized by liver enzymes to carboxyprimaquine, which does not have anti-malarial activity. Renal excretion of the parent drug is less than 4%.[6][21]

Chemistry

Primaquine is an analog of pamaquine which was the first drug of the 8-aminoquinoline class; tafenoquine is another such drug.[13]

History

Primaquine was first made by Robert Elderfield of Columbia University in the 1940s as part of a coordinated effort led by the Office of Scientific Research and Development in World War II to develop anti-malarial drugs to protect and treat soldiers fighting in the Pacific theater.[13][22]

Society and culture

It is on the World Health Organization's List of Essential Medicines.[7][8]

Names

It is a generic drug and is available under many brand names worldwide, including Jasoprim, Malirid, Neo-Quipenyl, Pimaquin, Pmq, Primachina, Primacin, Primaquina, Primaquine, Primaquine diphosphate, Primaquine Phosphate, and Remaquin.[23]

Research

Primaquine has been studied in animal models of Chagas disease and was about four times as effective as the standard of care, nifurtimox.[3]

A clinical trial in 2022 demonstrated the efficacy of higher-dose primaquine in preventing relapse of P. vivax malaria.[25]

References

  1. ↑ "Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size". British Journal of Clinical Pharmacology 19 (6): 745–750. June 1985. doi:10.1111/j.1365-2125.1985.tb02709.x. PMID 4027117. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Primaquine Phosphate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/primaquine-phosphate.html. 
  3. ↑ 3.0 3.1 3.2 3.3 "Primaquine revisited six decades after its discovery". European Journal of Medicinal Chemistry 44 (3): 937–953. March 2009. doi:10.1016/j.ejmech.2008.08.011. PMID 18930565. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Malaria - Chapter 3". CDC Health Information for International Travel 2016 (Yellow Book). CDC and Oxford University Press. 2016. ISBN 978-0-19-937915-6. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria#1939. 
  5. ↑ Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 57. ISBN 9781284057560. 
  6. ↑ 6.0 6.1 6.2 6.3 "Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I". The American Journal of Tropical Medicine and Hygiene 75 (3): 402–415. September 2006. doi:10.4269/ajtmh.2006.75.402. PMID 16968913. http://www.ajtmh.org/content/75/3/402.long. 
  7. ↑ 7.0 7.1 World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ 8.0 8.1 World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  9. ↑ 9.0 9.1 9.2 "Treatment of Malaria (Guidelines For Clinicians)". CDC. July 2013. https://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. 
  10. ↑ "Malaria: origin of the term "hypnozoite"". Journal of the History of Biology 44 (4): 781–786. 2011. doi:10.1007/s10739-010-9239-3. PMID 20665090. 
  11. ↑ Markus, MB. (2021). "Safety and efficacy of tafenoquine for Plasmodium vivax malaria prophylaxis and radical cure: overview and perspectives". Therapeutics and Clinical Risk Management 17: 989–999. doi:10.2147/TCRM.S269336. PMID 34526770. 
  12. ↑ Markus, MB (2023). "Putative contribution of 8-aminoquinolines to preventing recrudescence of malaria". Tropical Medicine and Infectious Disease 8 (5): 278. doi:10.3390/tropicalmed8050278. PMID 37235326. 
  13. ↑ 13.0 13.1 13.2 13.3 "Can primaquine therapy for vivax malaria be improved?". Trends in Parasitology 19 (3): 115–120. March 2003. doi:10.1016/S1471-4922(03)00005-9. PMID 12643993. http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1094&context=usnavyresearch. 
  14. ↑ 14.0 14.1 Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva, Switzerland: World Health Organization. October 2012. https://www.who.int/malaria/publications/atoz/who_pq_policy_recommendation/en/index.html. Retrieved 2 January 2014. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "Primaquine label". FDA. November 2007. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/008316s017lbl.pdf. 
  16. ↑ "PRIMAQUINE - Food and Drug Administration". https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/008316s023lbl.pdf. 
  17. ↑ "The haemolytic effect of various regimens of primaquine with chloroquine in American Negroes with G6PD deficiency and the lack of an effect of various antimalarial suppressive agents on erythrocyte metabolism". Bulletin of the World Health Organization 36 (2): 303–308. 1967. PMID 4864652. 
  18. ↑ (in en) Travel Medicine E-Book. Elsevier Health Sciences. 2018. p. 185. ISBN 9780323547710. https://books.google.com/books?id=M4d7DwAAQBAJ&pg=PA185. 
  19. ↑ Markus, Miles B. (2019). "Killing of Plasmodium vivax by primaquine and tafenoquine". Trends in Parasitology 35 (11): 857–859. doi:10.1016/j.pt.2019.08.009. PMID 31522991. 
  20. ↑ Cuong BT, Binh VQ, Dai B, et al. Does gender, food or grapefruit juice alter the pharmacokinetics of primaquine in healthy subjects? British Journal of Clinical Pharmacology. 2006;61(6):682-689. doi:10.1111/j.1365-2125.2006.02601.x.
  21. ↑ "PRIMAQUINE | C15H21N3O". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/primaquine#section=Mechanism-of-Action. 
  22. ↑ 22.0 22.1 "Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report". Journal of the National Malaria Society 9 (4): 285–292. December 1950. PMID 14804087. 
  23. ↑ "Primaquine brand names". Drugs.com. https://www.drugs.com/international/primaquine.html. 
  24. ↑ "Potentiation of the curative action of primaquine in vivax malaria by quinine and chloroquine". The Journal of Laboratory and Clinical Medicine 46 (2): 301–306. August 1955. PMID 13242948. 
  25. ↑ "Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria". The New England Journal of Medicine 386 (13): 1244–1253. March 2022. doi:10.1056/NEJMoa2104226. PMID 35353962. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Primaquine&oldid=3422521"