Melarsoprol

(BAN, rINN)
Melarsoprol Chemical formula
Synonyms: Mel B; Melarsen Oxide-BAL; Mélarsoprol; Melarsoprolum; RP3854. 2-[4-(4,6-Diamino-1,3,5-triazin-2-ylamino)phenyl]-1,3,2dithiarsolan-4-ylmethanol.
Cyrillic synonym: Меларсопрол.

💊 Chemical information

Chemical formula: C12H15AsN6OS2 = 398.3.
CAS — 494-79-1.
ATC — P01CD01.
ATC Vet — QP51AD04.

💊 Adverse Effects and Treatment

Adverse effects are common and may be severe during the treatment of African trypanosomiasis with melarsoprol. It may be difficult to distinguish between effects of the disease, Jarisch-Herxheimer reactions resulting from the release of antigens from trypanosomes killed by melarsoprol, and adverse effects due to the drug’s arsenic content or to hypersensitivity. For the adverse effects of arsenic and their treatment, see Arsenic Trioxide. A severe febrile reaction may occur after the first injection of melarsoprol, especially in patients with large numbers of trypanosomes in their blood. It is therefore common practice to give 2 or 3 injections of suramin or pentamidine before starting melarsoprol therapy. The greatest risk is from reactive encephalopathy which occurs in about 10% of patients treated with melarsoprol and is usually seen between the end of the first 3- or 4-day course of injections and the start of the second course. Encephalopathy may be sudden in onset or develop slowly. Symptoms include fever, headache, tremor, slurring of speech, convulsions, and coma; death has occurred in up to 5% of patients treated with melarsoprol. Less commonly, haemorrhagic encephalopathy may occur. The prophylactic use of corticosteroids has been suggested during treatment courses of melarsoprol (see African Trypanosomiasis, below). Treatment of reactive encephalopathy has included the use of corticosteroids, hypertonic solutions to combat cerebral oedema, anticonvulsants such as diazepam, and subcutaneous adrenaline; dimercaprol has been given on the assumption that encephalopathy resulted from arsenic poisoning, but has not generally been of benefit. Hypersensitivity reactions to melarsoprol may occur during the second and subsequent courses of treatment. Desensitisation with gradually increasing doses of melarsoprol has been attempted; corticosteroids may help to control symptoms during this procedure. Some authorities consider that the use of small doses of melarsoprol may increase the risk of resistance. Melarsoprol injection is very irritant and extravasation during intravenous use should be avoided. Vomiting and abdominal colic may occur if it is injected too rapidly. Other adverse effects reported include agranulocytosis, hypertension, peripheral neuropathy, proteinuria, severe diarrhoea, myocardial damage, exfoliative dermatitis, and hepatic disturbances.
1. Pepin J, et al. Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1989; i: 1246–50
2. Pepin J, Milord F. African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis. Trans R Soc Trop Med Hyg 1991; 85: 222–4
3. Pepin J, et al. Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg 1995; 89: 92–7.

💊 Precautions

Use of melarsoprol in febrile patients has been associated with an increased incidence of reactive encephalopathy, and therefore it should not be given during epidemics of influenza. Intercurrent infections such as malaria and pneumonia should be treated before melarsoprol is used. Severe haemolytic reactions have been reported in patients with G6PD deficiency. It may precipitate erythema nodosum when given to patients with leprosy. Patients should be in hospital when they are treated with melarsoprol and dosage decided after taking into account their general condition. Treatment of pregnant women with trypanosomiasis should be deferred until after delivery. Pregnant women with meningoencephalitis may be treated with pen-
tamidine (Trypanosoma brucei gambiense) or suramin (T. b. rhodesiense).

💊 Pharmacokinetics

Melarsoprol is reported to be unreliably absorbed if given orally and is usually given by intravenous injection. A small amount penetrates into the CSF where it has a local trypanocidal action. It is rapidly metabolised and excreted in the faeces and urine so any prophylactic effect is short-lived.

💊 Uses and Administration

Melarsoprol, a trivalent arsenical derivative, is a trypanocide which appears to act by inhibiting trypanosomal pyruvate kinase. It is effective in the treatment of all stages of African trypanosomiasis due to Trypanosoma brucei gambiense or T. brucei rhodesiense, but because of its toxicity its use is usually reserved for stages of the disease involving the CNS. Resistance has been reported to develop. Patients undergoing therapy with melarsoprol should be treated in hospital. Melarsoprol is given by intravenous injection as a 3.6% solution in propylene glycol. The injection should be given slowly, care being taken to prevent leakage into the surrounding tissues, and the patient should remain supine and fasting for several hours after the injection. Treatment protocols vary, but in general melarsoprol is given in low doses initially, especially in children and debilitated patients, increased gradually to the maximum daily dose of 3.6 mg/kg. Doses are given daily for 3 or 4 days and the course repeated 2 or 3 times with an interval of 7 to 10 days between courses. Since massive destruction of parasites resulting in a JarischHerxheimer reaction is particularly dangerous during treatment with melarsoprol, several doses of suramin or pentamidine may be given to induce the reaction before melarsoprol is started. Melarsonyl potassium is a water-soluble derivative of melarsoprol which was formerly used as an alternative to melarsoprol but was probably more toxic and less effective.

African trypanosomiasis.

Melarsoprol, which is effective against both Trypanosoma brucei gambiense and T. b. rhodesiense, is usually only given to treat the meningoencephalitic stage of African trypanosomiasis because it may produce potentially fatal encephalopathy. However, protection against this toxicity may be provided by prophylaxis with prednisolone.1,2 Therapy with melarsoprol and eflornithine was reported to be effective in a patient who had not responded to either drug alone.3 A comparative study4 in 500 patients with second-stage infection with T. b. gambiense found that a more concise dosage regimen of melarsoprol 2.2 mg/kg daily, as a single course over 10 days, was similar in efficacy to standard regimens of 1.2 to 3.6 mg/kg daily for 3 or 4 days repeated twice over a 26-day period with 7-day intervals between series, although there was no difference between the regimens in the incidence of associated encephalopathy.
1. Pepin J, et al. Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1989; i: 1246–50
2. Pepin J, et al. Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg 1995; 89: 92–7
3. Simarro PP, Asumu PN. Gambian trypanosomiasis and synergism between melarsoprol and eflornithine: first case report. Trans R Soc Trop Med Hyg 1996; 90: 315
4. Burri C, et al. Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Lancet 2000; 355: 1419–25.
Published November 30, 2018.