melarsoprol

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.

Description

Knowingly or unknowingly, arsenic-containing drugs have been used for treatment of parasitic conditions for thousands of years. In the late 1800s and early 1900s, Paul Ehrlich introduced the use of trivalent arsenicals. Melarsoprol, an organoarsenical, came into use in the late 1940s, and it remains the first-choice drug in the treatment of trypanosomiasis. Until 1990, it also was the only treatment for late-stage sleeping sickness.

Uses

Melarsoprol is a drug used for the treatment of African trypanosomes, a sleeping sickness in humans, a disease that is typically fatal without chemotherapy.

Definition

ChEBI: Melarsoprol is a member of triazines.

Antimicrobial activity

It is highly and rapidly active against Trypanosoma brucei gambiense and T. brucei rhodesiense in vitro at submicromolar concentrations. It is much less active against the trypanosomes that infect domestic animals, T. congolense and T. vivax. Co-administration with eflornithine is effective against central nervous system (CNS) infection with T. brucei in rodent models, but clinical studies have found the combination less effective than nifurtimox–eflornithine.

Acquired resistance

Up to 25% of cases of T. brucei gambiense in Central Africa relapse. Patients infected with T. brucei rhodesiense normally respond to a second course of the drug, but those with T. brucei gambiense do not. In laboratory-generated resistant strains, decreased sensitivity results from reduced uptake of the drug by bloodstream trypomastigotes that either lack an adenine/adenosine transporter (TbAT1) or contain a transporter gene with point mutations. There is conflicting evidence about the role of this mechanism of resistance in isolates from patients unresponsive to treatment.

Health Hazard

Melarsoprol (4, Mel B, Arsobal C12H15AsN6OS2) is applied for T. b. gambiense or T. b. rhodesiense. The drug, administered intravenously, is a solution containing a combination of BAL (2,3-dimercaptopropanol) and the trivalent arsenic compound, melarsen oxide. Not only can the drug cause serious side effects such as intense dermal irritation, myocarditis, and renal and hepatic damage, but it is also responsible for death in 5% of patients.

Pharmaceutical Applications

Mel B. A derivative of trivalent melarsen oxide and dimercaprol (BAL), possessing a melaminyl moiety. Formulated in 3.6% propylene glycol for intravenous administration. It is almost insoluble in water.

Mechanism of action

It generally is accepted that the enzyme with which melarsoprol reacts is an enzyme involved in glycolysis, and as a result, inhibition of pyruvate kinase occurs. It is argued, however, that the inhibition may not occur at pyruvate kinase but, rather, at a step before the pyruvate kinase. Blockage of glycolysis would be expected to lead to loss of motility and cell lysis. More recently, Fairlamb et al. have proposed a mechanism of action that results in the inhibition of trypanothione reductase through the formation of a stable complex between melaroprol and trypanothione. Melarsoprol reacts with the cysteine sulfhydryl of trypanothione to form the stable adduct shown in Figure 39.10. Supportive of this mechanism is the synergistic action of melarsoprol with eflornithine (DMFO). Two drugs that produce sequential blockage of the synthesis of trypanothione.

Pharmacokinetics

Serum levels of 2–4 mg/L were achieved 24 h after administration of 3.6 mg/kg, falling to 0.1 mg/L at 120 h after the fourth daily injection. Elimination was biphasic with a half-life of 35 h. The volume of distribution was 100 L. It is rapidly metabolized by microsomal enzymes to melarsen oxide, reaching maximum plasma concentration by 15 min and eliminated with a half-life of 3.9 h. This metabolite can cross the blood–brain barrier and effect a CNS cure in mice. Levels of melarsoprol in the cerebrospinal fluid (CSF) reached around 300 μg/L, about 50 times lower than serum levels.

Clinical Use

2-p-(4,6-Diamino-s-triazin-2-yl-amino)phenyl-4-hydroxymethyl-1,3,2-dithiarsoline (Mel B, Arsobal) is prepared byreduction of a corresponding pentavalent arsanilate to thetrivalent arsenoxide followed by reaction of the latter with2,3-dimercapto-1-propanol (British anti-Lewisite [BAL]). Ithas become the drug of choice for the treatment of thelater stages of both forms of African trypanosomiasis.Melarsoprol has the advantage of excellent penetration intothe CNS and, therefore, is effective against meningoencephaliticforms of T. gambiense and T. rhodesiense.Trivalent arsenicals tend to be more toxic to the host (as wellas the parasites) than the corresponding pentavalent compounds.The bonding of arsenic with sulfur atoms tends toreduce host toxicity, increase chemical stability (to oxidation),and improve distribution of the compound to the arsenoxide.Melarsoprol shares the toxic properties of other arsenicals, however, so its use must be monitored for signsof arsenic toxicity.

Clinical Use

Late-stage sleeping sickness caused by T. brucei gambiense and T. brucei rhodesiense
It is not recommended for early-stage disease, in which alternatives with less serious side effects are available.

Side effects

The propylene glycol formulation can cause tissue trauma and long-term damage to veins. Drug-induced reactions include fever on first administration, abdominal colic pain, dermatitis and arthralgia. Polyneuropathy has been reported in about 10% of patients. Reactive arsenical encephalopathy is a serious side effect that occurs in around 10% of those treated, with death in 1–3% of cases. The frequency of encephalopathy increases with a rise in the white cell count or the presence of trypanosomes in the CSF. The causes of the immunological responses involved in the encephalopathy and the possible existence of two forms (reactive and hemorrhagic) are not completely resolved. Studies to identify antiinflammatory approaches to reduce reactive encephalopathy in late-stage T. brucei gambiense infection have produced limited results.

Metabolism

Melarsoprol is administered IV in multiple doses and multiple sessions. Its major metabolite in humans is the lipophilic melarsen oxide, which can penetrate into the CNS. This metabolite apparently is responsible for the protein-binding characteristic for melarsoprol.

Raw materials

Preparation Products