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Questions And Answer

• Pharmacology and mechanism of action

  Melarsoprol (Mel B) is a trivalent arsenical compound which was introduced into clinical medicine in 1949 by Friedman ^[1]. It is active against all stages of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense infections. However, because of toxicity, it is only used in late-stage trypanosomiasis. The mechanism of action of melarsoprol is not well characterized. However, there is evidence showing that melarsoprol forms a complex with parasite trypanothione which protects the parasite from oxidant damage and lysis ^[2]. The formation of trypanothione depends on polyamine biosynthesis which is blocked by another trypanosomicide, eflornithine. A possible synergistic effect of eflornithine and melarsoprol has been reported by Jennings ^[3]. ;

• Indications

  Melarsoprol is only indicated for the treatment of late stage (CNS involvement) of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. It is a clinical experience that patients with Trypanosoma brucei rhodesiense who relapse usually respond to a second course of melarsoprol, while those with Trypanosoma brucei gambiense who relapse rarely do so ^[4]. Thus, patients with Trypanosoma brucei gambiense who do not respond to the first treatment course of melarsoprol should be switched to eflornithine. ;

• Side effects

  The most serious side effect with the use of melarsoprol is encephalopathy which is usually seen between 5 and 12 days after the first dose. It occurs in about 2–10% of the patients of which 50–75% of them may die ^[5]. Melarsoprol encephalopathy has been classified as two different entities: reactive and haemorrhagic encephalopathies. Reactive encephalopathy is relatively more common and is characterized by mental and motor excitation, drowsiness which progresses into coma and convulsions. It is often reversible. The haemorrhagic type has been described as a rare entity, which is nearly always fatal. While reactive encephalopathy is attributed to drug-related immunological response, the haemorrhagic encephalopathy is thought to be due to melarsoprol toxicity^[5]. Other authors have disputed this distinction and have described the two types of encephalopathy merely as various stages of severity of the same condition ^[4]. Although the exact mechanism of melarsoprol encephalopathy is as yet unknown and remains controversial, recent reports say that it is likely to be due to an immunological reaction triggered by high initial doses of melarsoprol ^{[6, 7]}. Management of these reactions includes corticosteroids and hyper-osmotic solutions to reduce cerebral oedema, anticonvulsants and subcutaneous injections of adrenaline. The administration of corticosteroids during melarsoprol treatment may reduce the risk of encephalopathy. In a recent randomized comparative study in Trypanosoma brucei gambiense, the incidence of encephalopathy was only 12% in patients treated with prednisolone (1 mg/ kg daily to a maximum of 40 mg) together with melarsoprol as compared to those treated with melarsoprol alone who had an incidence of 35% ^[8]. Other reactions such as albuminuria and abdominal colic are common (10–15% incidence). After the first administration of melarsoprol, as with other antitrypanosomal drugs, a fever of up to 40 °C is seen in about 60% of the patients ^[9]. Nausea, vomiting and diarrhoea may be seen. Skin reactions, arthralgia, agranulocytosis, aplastic anaemia, thrombocytopenia, renal and hepatic failure and Guillain-Barré-like syndrome have been reported occasionally ^[8-10]. ;

• Contraindications and precautions

  Patients should be hospitalized and well supervised during melarsoprol treatment. Patients in poor general condition may not tolerate the drug. The drug can evoke severe haemolytic reactions in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. The administration of melarsoprol to leprous patients may induce erythema nodosum. The drug may aggravate the condition of the patient during viral infections such as influenza. In such situations treatment may be postponed. The solution used for i.v. administration contains propylene glycol which is highly irritant to the tissues. Extravascular leakage will cause severe tissue destruction and thrombophlebitis. Therefore, the solution must be carefully and slowly injected with a fine needle. Melarsoprol should not be given to patients with the early stage of the disease, since the drug can cause encephalopathy even in such patients . ;

• Preparations

  • Arsobal® (Specia). 5 ml ampoules of 36 mg/ml in propylene glycol solution. ;

• References

  1. Friedman EAH (1949). Mel B in the treatment of human trypanosomiasis. Amer J Trop Med Hyg, 29, 173–180.
  2. Fairlamb AH, Henderson GB, Cerami A (1989). Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proc Natl Acad Sci USA, 86, 2607–2611.
  3. Jennings FW (1988). Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment. Trans R Soc Trop Med Hyg, 82, 572– 573.
  4. Pepin J, Milord F (1994). The treatment of human African trypanosomiasis. Adv Parasitol, 33, 1– 47.
  5. Robertsson DHH (1963). The treatment of sleeping sickness (mainly due to Trypanosoma rhodesiense) with melarsoprol. I. Reactions observed during treatment. Trans R Soc Trop Med Hyg, 57, 1246–1250.
  6. Haller L, Adams H, Merouze F, Dago A (1986). Clinical and pathological aspects of human African trypanosomiasis (T.b. gambiense) with particular reference to reactive encephalopathy. Am J Trop Med Hyg, 35, 94–99.
  7. Pepin J, Milord F (1991). African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis. Trans R Soc Trop Med Hyg, 85, 222–224.
  8. Robertsson DHH (1963). The treatment of sleeping sickness (mainly due to Trypanosoma rhodesiense) with melarsoprol. II. An assessment of its curative value. Trans R Soc Trop Med Hyg, 57, 176–183.
  9. Ferreira FSC, Costa FMC (1963). Restates do tratamento da tripanosomiose humana africana com o arsobal. Gaz Med Portoguesa, 166, 11–618.
  10. Gherardi RK, Chariot P, Vanderstigel M, Malapert D, Verroust J, Astier A, Brun-Buisson C, Schaeffer A (1990). Organic arsenic-induced Guillain-Barré-like syndrome due to melarsoprol: a clinical, electrophysiological, and pathological study. Muscle & Nerve, 13, 637–645. ;

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