Пентамидин

Описание

Pentamidine is an aromatic diamine that is effective against protozoal diseases, such as amoebic dysentery, malaria, trypanosomiasis, and leishmaniasis. In clinical studies, it has also been shown to be an effective prophylaxis against pneumocystis pneumonia.

Химические свойства

Crystalline Solid

Показания

Pentamidine (Pentam 300) binds to DNA and may inhibit kinetoplast DNA replication and function. It also may act by inhibiting dihydrofolate reductase and interfering with polyamine metabolism. An effect on organism respiration, especially at high doses, also may play a role.

Антимикробная активность

Pentamidine has broad activity in experimental models against P. falciparum, Toxoplasma gondii, Leishmania spp., Trypanosoma spp. and Babesia spp. It also has activity against Pn. jirovecii.

Приобретенная устойчивость

Relapse rates of 7–16% have been reported in the treatment of human African trypanosomiasis in West Africa. Patients usually respond to a subsequent course of treatment with melarsoprol. A membrane transporter is involved in crossresistance of arsenic-resistant T. brucei to diamidines, affecting diminazene and stilbamidine more than pentamidine.

Фармацевтические приложения

A synthetic diamidine, available as the isethionate (2-hydroxymethane sulfonate) salt for parenteral use. It is also administered by instillation of a nebulized solution directly into the lungs.

Механизм действия

Pentamidine is not well absorbed from the intestinal tract after oral administration and generally is given by intramuscular injection. The drug binds to tissues, particularly the kidney, and is slowly excreted, mostly as the unmodified drug. It does not enter the central nervous system (CNS). Its sequestration in tissues accounts for its prophylactic use in trypanosomiasis.

Фармакокине?тика

Oral absorption: Negligible
C_max 4 mg/kg intramuscular: c. 0.5 mg/L after 1 h
Plasma half-life: c. 6.5 h
Volume of distribution: 3 L/kg
Plasma protein binding: c. 70%
Pentamidine is rapidly and extensively metabolized by rat liver, and high concentrations are retained in renal and hepatic tissue for up to 6 months after administration. In humans distribution is mainly in the liver, kidney, adrenal glands and spleen, with lower accumulation in the lung. This tissue retention is the basis for its prophylactic use. Although transport across the blood–brain barrier has been demonstrated in experimental models, it is probably unable to cross the blood–brain barrier in sufficient quantity to be trypanocidal: <1% of the plasma concentration has been measured in the CSF of sleeping sickness patients. About 15–20% of the dose is excreted in the urine but because of retention in tissues there is an extremely long terminal half-life (>12 days).

Клиническое использование

Pentamidine is active against Pneumocystis carinii, trypanosomes, and leishmaniasis unresponsive to pentavalent antimonials. It is an alternative agent for the treatment of P. carinii pneumonia. Although it is more toxic than trimethoprim–sulfamethoxazole, it has been widely used in patients with acquired immunodeficiency syndrome (AIDS), in whom P. carinii infection is common.
Pentamidine is an alternative drug for visceral leishmaniasis, especially when sodium stibogluconate has failed or is contraindicated. Pentamidine is also a reserve agent for the treatment of trypanosomiasis before the CNS is invaded. This characteristic largely restricts its use to Gambian trypanosomiasis.

Побочные эффекты

Side effects range from local irritation and sterile abscess at the site of injection to transient effects (vomiting, abdominal discomfort) and serious systemic effects (hypotension, effects on the heart, hypoglycemia and hyperglycemia, leukopenia, thrombocytopenia). In a study of the treatment of South American cutaneous leishmaniasis, 17% of patients prematurely terminated treatment due to toxicity and another 30% reported side effects.