Trypanosomiasis pentamidine

Pentamidine is an aromatic diamidine (Figure 52-3) formulated as an isethionate salt. Pentamidine is only administered parenterally. The drug leaves the circulation rapidly, with an initial half-life of about 6 hours, but it is bound avidly by tissues. Pentamidine thus accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. The drug can be detected in urine 6 or more weeks after treatment. Only trace amounts of pentamidine appear in the central nervous system, so it is not effective against central nervous system African trypanosomiasis. Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis. Absorption into the systemic circulation after inhalation appears to be minimal. The mechanism of action of pentamidine is unknown. 

First introduced as a therapy for trypanosomiasis in 1937, pentamidine is now used in a variety of protozoal and fungal infections and, as such, finds use in the treatment of trypanosomiasis, leishmaniasis, and pneumocystis (PCP). The drug is primarily used for treatment of PCP. When used for trypanosomiasis, pentamidine is only effective against Trypanosoma brucei rhodesiense (east African sleeping sickness) and, even then, only during the early stage of the disease, because the drug does not readily cross the blood-brain barrier. 

The answer is d. (Hardman, p 989.) Both trimethoprim-sulfamethoxazole and pentamidine are effective in pneumonia caused by E carinii. This protozoal disease usually occurs in immunodeficient patients, such as those with AIDS. Nifurtimox is effective in trypanosomiasis and metronidazole in amebiasis and leishmaniasis, as well as in anaerobic bacterial infections. Penicillins are not considered drugs of choice for this particular disease state. 

Drugs used for trypanosomiasis include nifurtimox, suramin, melarsoprol and pentamidine. The first choice agent for treating leishmaniasis is sodium stibogluconate. Alternatives are amphotericin B (see Section V.a) and pentamidine. 

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. 

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. 

It is used in the treatment of pneumocystosis (pulmonary and extrapulmonary disease caused by P. carinii), African trypanosomiasis (disease caused by Trypanosoma brucei) and leishmaniasis. Systemic pentamidine is highly toxic and can lead to severe hypotension, tachycardia, dyspnea, dizziness, hypoglycemia. Other adverse effects are skin rash, metallic taste, gastrointestinal symptoms, thrombocytopenia and cardiac arrhythmias. 

Suramin is a sulfated naphthylamine that was introduced in the 1920s. It is the first-line therapy for early hemolymphatic East African trypanosomiasis ( brucei rhodesiense infection), but because it does not enter the central nervous system, it is not effective against advanced disease. Suramin is less effective than pentamidine for early West African trypanosomiasis. The drug s mechanism of action is unknown. It is administered intravenously and displays complex pharmacokinetics with very tight protein binding. Suramin has a short initial half-life but a terminal elimination half-life of about 50 days. The drug is slowly cleared by renal excretion. 

Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with pentamidine may improve efficacy. Suramin can also be used for chemoprophylaxis against African trypanosomiasis. Adverse effects are common. Immediate reactions can include fatigue, nausea, vomiting, and, more rarely, seizures, shock, and death. Later reactions include fever, rash, headache, paresthesias, neuropathies, renal abnormalities including proteinuria, chronic diarrhea, hemolytic anemia, and agranulocytosis. 

Trypanosomiasis [Chagas disease African sleeping sickness] Heart brain many other organs Early stages pentamidine, suramin Later stages melarsoprol Nifurtimox... 

Pentamidine, an aromatic diamine, has been known since the late 1930s as a treatment for trypanosomiasis and some forms of leishmaniasis. In recent times it has been extensively used in the treatment of Pneumocystis jiroveci pneumonia. Its mechanism of action is probably related to inhibition of dihydrofolate reductase and inhibition of oxidative phosphorylation and nucleic acid synthesis, as well as an effect on aerobic glycolysis. 

Pentamidine is a diamidine compound developed more than five decades ago [128]. Initially, it was only used for its antiprotozoal properties against African trypanosomiasis [129], and visceral leishmaniasis [130]. Subsequently, its use was extended to the treatment and prophylaxis of PCP in immunosuppressed patients [131-133]. The use of pentamidine, which was rare in countries without tropical diseases, increased notably because of the high incidence of PCP observed in patients with AIDS [72, 97, 134-136]. Until 1984, pentamidine distribution in the USA was restricted indeed it was only available through the Center for Disease Control. Although TMP-SMZ is regarded as the preferred treatment for PCP [102, 103], pentamidine or less frequently used combinations (trime-trexate/leucovorin, clindamycin/ primaquine [137]) are reasonable alternatives when TMP-SMZ is not tolerated or is without effect [138]. 

Pentamidine has been used for the prophylaxis and treatment of African trypanosomiasis. It also has some value for treating visceral leishmaniasis. Pentamidine rapidly disappears from the pla.sma after intravenous injection and is distributed to the tissues, where it is stored for a long period. This property probably contributes to the usefulness of the drug as a prophylactic agent. 

Pentamidine is an aromatic diamidine that was initially synthesized in the 1930s in a search for hypoglycemic agents. Because of its antiprotozoal activity, pentamidine has been used extensively for treatment and chemoprophylaxis of African trypanosomiasis. The exact mechanism of action of pentamidine is not known in vitro, it has been found to interfere with folate metabolism, anaerobic glycolysis, oxidative phosphorylation, and nucleic acid replication [1], Pentamidine usually is given parenterally in a dose of 4mg/kg/day as the isethionate salt, the only preparation available in the United States [1], Administration must be parenteral because gastrointestinal absorption is poor. Adverse reactions to pentamidine appear to be dose dependent, in that a 3-g total dose, which usually is reached in the second week of parenteral therapy, frequently causes toxicity [2]. 

Table 7-2 lists the various drugs that have been useful for a variety of protozoal diseases. It will be noted that several are indicated for more than one condition (e.g., pentamidine against leishmaniasis, trypanosomiasis, and pneumocystosis). Several of these not yet discussed will now be considered. 

Pentamidine (4 mg/kg once a day for 14 days) is indicated in the treatment of Pneumocystis carinii pneumonia (PCP), prevention of PCP in high-risk, HIV-infected patients, and in the treatment of trypanosomiasis and visceral leishmaniasis. 

Drugs for the treatment of human African trypanosomiasis are also inadequate. The diamidine pentamidine and the sulphonated naphthylamine suramin have been used for over 50 years, require parenteral administration and are only effective against the early haemolymphatic stage of the disease. The only drug currently available for the treatment of the late stage CNS infection is the... 

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