Примахин

Использование

Primaquine is the most effective and most toxic drug from the whole series of known 8-aminoquinolines. It is generally used for treating exoerythrocyte forms of malaria caused by P. vivax and P. ovale. It also acts on the sexual forms of the plasmodia, which die in the human body upon using this drug.
Primaquine is used for treating and preventing late relapses of 3- and 4-day malaria as well as tropic malaria. Synonyms of this drug are avlon and others.

Показания

Primaquine is the least toxic and most effective of the 8- aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline–quinone metabolite that inhibits the coenzyme Q–mediated respiratory chain of the exoerythrocytic parasite.

Определение

ChEBI: A N-substituted diamine that is pentane-1,4-diamine substituted by a 6-methoxyquinolin-8-yl group at N4 position. It is a drug used in the treatment of malaria and Pneumocystis pneumonia.

Антимикробная активность

Primaquine is highly active against the hepatic stages of the malaria life cycle, including the latent hypnozoite stage of P. vivax. It has poor activity against erythrocytic stages of malaria parasites, other than gametocytes. The isomers have similar antiplasmodial activity but differ in toxicity. It exhibits activity against Pneumocystis jirovecii and, in experimental models, against Babesia spp. and the intracellular stages of Leishmania spp. and Trypanosoma cruzi.

Приобретенная устойчивость

Failure rates of up to 35% have been reported in South East Asia in patients treated with a standard course for P. vivax infections.

Фармацевтические приложения

A synthetic 8-aminoquinoline, formulated as the diphosphate for oral administration.

Механизм действия

Moving the side chain from the fourth position of the quinoline ring to the eighth position completely changes the compound’s spectrum of activity. Unlike the 4-substituted aminoquinolines, primaquine has practically no effect on erythrocyte forms of the malaria parasite. Its activity is limited to tissue forms of the parasite in mammals and in the mosquitoes themselves. This makes primaquine an especially valuable drug, allowing radical recovery and simultaneous prevention, which is usually not achieved by using erythrocyte drugs. The place of action of primaquine is the mitochondria of the malarial parasite. It seems likely that primaquine interferes in the process of electron transfer, causing damage to mitochondrial enzymatic systems. This is expressed in the swelling and vacuolization of the parasite’s mitochondria. Host mitochondria are not affected.

Фармакокине?тика

Oral absorption: >75%
C_max 45 mg oral: 0.2 mg/L after 2–3 h
Plasma half-life: 4–10 h
Volume of distribution: 2 L/kg
Plasma protein binding: Extensive
Bioavailability is variable after oral administration. There is extensive tissue distribution. About 60% of the dose is metabolized to carboxyprimaquine, which can reach levels 50 times that of the parent drug; this metabolite has a half-life of 16 h, a low tissue distribution and is detectable at 120 h. Methoxy and hydroxy metabolites are also detectable. Less than 4% of the original dose is excreted unchanged in urine.

Клиническое использование

Radical cure of malaria caused by P. vivax or P. ovale
Mild or moderately severe infections with Pn. jirovecii (in combination with clindamycin).
Because of its gametocytocidal properties, primaquine has been used rarely in a single dose to prevent the spread of chloroquine- resistant P. falciparum.

Побочные эффекты

At standard doses side effects are mild: abdominal cramps, anemia, leukocytosis and methemoglobinemia. However, primaquine is often associated with serious adverse effects due to the toxic metabolites 5-hydroxyprimaquine or 6-methoxy- 8-aminoquinoline which are considered to be directly responsible for complications such as hemolytic anemia. Toxicity is worse in people deficient of glucose-6-phosphate dehydrogenase (G6PD) or glutathione synthetase. Adverse effects can be further increased by the repeated administration of high doses, due to its limited oral bioavailability.