Primaquine

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Primaquine
Primaquine.svg
Clinical data
Other namesprimaquine phosphate
AHFS/Drugs.com Monograph
MedlinePlus a607037
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 96% [1]
Metabolism Liver
Elimination half-life 6 hours
Identifiers
  • (RS)-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
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ECHA InfoCard 100.001.807 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H21N3O
Molar mass 259.353 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O(c1cc(NC(C)CCCN)c2ncccc2c1)C
  • InChI=1S/C15H21N3O/c1-11(5-3-7-16)18-14-10-13(19-2)9-12-6-4-8-17-15(12)14/h4,6,8-11,18H,3,5,7,16H2,1-2H3 Yes check.svgY
  • Key:INDBQLZJXZLFIT-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<i>Plasmodium</i> Genus of parasitic protists that can cause malaria

Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.

<span class="mw-page-title-main">Glucose-6-phosphate dehydrogenase deficiency</span> Medical condition

Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.

<span class="mw-page-title-main">Gametocyte</span> Eukaryotic germ stem cell

A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called spermatocytes, and female gametocytes are called oocytes.

<span class="mw-page-title-main">Artemether</span> Chemical compound

Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine.

<span class="mw-page-title-main">Chloroquine</span> Medication used to treat malaria

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.

Recrudescence is the recurrence of an undesirable condition. In medicine, it is usually defined as the recurrence of symptoms after a period of remission or quiescence, in which sense it can sometimes be synonymous with relapse. In a narrower sense, it can also be such a recurrence with higher severity than before the remission. "Relapse" conventionally has a specific meaning when used in relation to malaria.

<i>Plasmodium vivax</i> Species of single-celled organism

Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than Plasmodium falciparum, the deadliest of the five human malaria parasites, P. vivax malaria infections can lead to severe disease and death, often due to splenomegaly. P. vivax is carried by the female Anopheles mosquito; the males do not bite.

<i>Plasmodium ovale</i> Species of single-celled organism

Plasmodium ovale is a species of parasitic protozoon that causes tertian malaria in humans. It is one of several species of Plasmodium parasites that infect humans, including Plasmodium falciparum and Plasmodium vivax which are responsible for most cases of malaria in the world. P. ovale is rare compared to these two parasites, and substantially less dangerous than P. falciparum.

<i>Plasmodium malariae</i> Species of single-celled organism

Plasmodium malariae is a parasitic protozoan that causes malaria in humans. It is one of several species of Plasmodium parasites that infect other organisms as pathogens, also including Plasmodium falciparum and Plasmodium vivax, responsible for most malarial infection. Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by P. falciparum or P. vivax. The signs include fevers that recur at approximately three-day intervals – a quartan fever or quartan malaria – longer than the two-day (tertian) intervals of the other malarial parasite.

<i>Plasmodium knowlesi</i> Species of single-celled organism

Plasmodium knowlesi is a parasite that causes malaria in humans and other primates. It is found throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Like other Plasmodium species, P. knowlesi has a life cycle that requires infection of both a mosquito and a warm-blooded host. While the natural warm-blooded hosts of P. knowlesi are likely various Old World monkeys, humans can be infected by P. knowlesi if they are fed upon by infected mosquitoes. P. knowlesi is a eukaryote in the phylum Apicomplexa, genus Plasmodium, and subgenus Plasmodium. It is most closely related to the human parasite Plasmodium vivax as well as other Plasmodium species that infect non-human primates.

<span class="mw-page-title-main">8-Aminoquinoline</span> Chemical compound

8-Aminoquinoline is the 8-amino derivative of quinoline. Often abbreviated AQ, it is a pale yellow solid. It is structurally analogous to 8-hydroxyquinoline.

<span class="mw-page-title-main">Pamaquine</span> A drug (of the 8-aminoquinoline class) formerly used to treat malaria

Pamaquine is an 8-aminoquinoline drug formerly used for the treatment of malaria. It is closely related to primaquine.

<span class="mw-page-title-main">Tafenoquine</span> Antimalarial drug

Tafenoquine, sold under the brand name Krintafel among others, is a medication used to prevent and to treat malaria. With respect to acute malaria, it is used together with other medications to prevent relapse by Plasmodium vivax. It may be used to prevent all types of malaria. It is taken by mouth.

<span class="mw-page-title-main">History of malaria</span> History of malaria infections

The history of malaria extends from its prehistoric origin as a zoonotic disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak malaria infested every continent except Antarctica. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the Plasmodium parasites which cause it, research attention has focused on their biology as well as that of the mosquitoes which transmit the parasites.

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.

<span class="mw-page-title-main">Apicomplexan life cycle</span> Apicomplexa life cycle

Apicomplexans, a group of intracellular parasites, have life cycle stages that allow them to survive the wide variety of environments they are exposed to during their complex life cycle. Each stage in the life cycle of an apicomplexan organism is typified by a cellular variety with a distinct morphology and biochemistry.

Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models.

Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine and pyrimethamine. For the treatment of malaria it is typically used along with other antimalarial medication such as artesunate. In areas of Africa with moderate to high rates of malaria, three doses are recommended during the second and third trimester of pregnancy.

References

  1. ↑ Mihaly GW, Ward SA, Edwards G, Nicholl DD, Orme ML, Breckenridge AM (June 1985). "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. doi:10.1111/j.1365-2125.1985.tb02709.x. PMC   1463857 . PMID   4027117.
  2. 1 2 3 4 5 6 7 "Primaquine Phosphate". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 2 December 2016.
  3. 1 2 3 4 Vale N, Moreira R, Gomes P (March 2009). "Primaquine revisited six decades after its discovery". European Journal of Medicinal Chemistry. 44 (3): 937–953. doi:10.1016/j.ejmech.2008.08.011. hdl: 10216/82052 . PMID   18930565.
  4. 1 2 3 4 5 6 Arguin PM, Tan KR (2016). "Malaria - Chapter 3". In Brunette GW (ed.). CDC Health Information for International Travel 2016 (Yellow Book). CDC and Oxford University Press. ISBN   978-0-19-937915-6. Archived from the original on 2016-01-14.
  5. ↑ Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 57. ISBN   9781284057560.
  6. 1 2 3 4 Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ (September 2006). "Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I". The American Journal of Tropical Medicine and Hygiene. 75 (3): 402–415. doi: 10.4269/ajtmh.2006.75.402 . PMID   16968913. Archived from the original on 2014-01-23.
  7. 1 2 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. 1 2 World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  9. 1 2 3 "Treatment of Malaria (Guidelines For Clinicians)" (PDF). CDC. July 2013. Archived (PDF) from the original on 2017-08-29.
  10. ↑ Markus MB (2011). "Malaria: origin of the term "hypnozoite"". Journal of the History of Biology. 44 (4): 781–786. doi:10.1007/s10739-010-9239-3. PMID   20665090. S2CID   1727294.
  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 . PMC   8435617 . 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 . PMC   10223033 . PMID   37235326.
  13. 1 2 3 4 Baird JK, Rieckmann KH (March 2003). "Can primaquine therapy for vivax malaria be improved?". Trends in Parasitology. 19 (3): 115–120. doi:10.1016/S1471-4922(03)00005-9. PMID   12643993.
  14. 1 2 Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva, Switzerland: World Health Organization. October 2012. Archived from the original on 2 January 2014. Retrieved 2 January 2014.
  15. 1 2 3 4 5 "Primaquine label" (PDF). FDA. November 2007. Archived (PDF) from the original on 10 November 2016. Retrieved 10 November 2016.
  16. ↑ "PRIMAQUINE - Food and Drug Administration" (PDF).
  17. ↑ Brewer GJ, Zarafonetis CJ (1967). "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. PMC   2476383 . PMID   4864652.
  18. ↑ Keystone JS, Kozarsky PE, Connor BA, Nothdurft HD, Mendelson M, Leder K (2018). Travel Medicine E-Book. Elsevier Health Sciences. p. 185. ISBN   9780323547710.
  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. S2CID   202582476.
  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. Archived from the original on 2016-11-10. Retrieved 2016-11-09.
  22. 1 2 Edgcomb JH, Arnold J, Yount EH, Alving AS, Eichelberger L, Jeffery GM, et al. (December 1950). "Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report". Journal of the National Malaria Society. 9 (4): 285–292. PMID   14804087.
  23. ↑ "Primaquine brand names". Drugs.com. Archived from the original on 11 November 2016. Retrieved 10 November 2016.
  24. ↑ Alving AS, Arnold J, Hockwald RS, Clayman CB, Dern RJ, Beutler E, Flanagan CL (August 1955). "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. PMID   13242948.
  25. ↑ Chamma-Siqueira NN, Negreiros SC, Ballard SB, Farias S, Silva SP, Chenet SM, et al. (March 2022). "Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria". The New England Journal of Medicine. 386 (13): 1244–1253. doi:10.1056/NEJMoa2104226. PMC   9132489 . PMID   35353962. S2CID   247840931.
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