Melarsoprol Treatment Research Articles

Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda.

Culture adapted T. b. gambiense isolated from Northwest Uganda were exposed to 0.001-0.14 microg/ml melarsoprol or 1.56-100 microg/ml DL-alpha-difluoromethylornithine (DFMO). Minimum inhibitory concentrations (MICs) of each drug were scored for each isolate after a period of 10 days drug exposure. The results indicate that T. b. gambiense isolates from Northwest Uganda had elevated MIC values for melarsoprol ranging from 0.009 to 0.072 microg/ml as compared with T. b. gambiense isolates from Cote d'Ivoire with MIC values ranging from 0.001 to 0.018 microg/ml or with T. b. rhodesiense from Southeast Uganda with MIC values from 0.001 to 0.009 microg/ml. All MIC values obtained fell below expected peak melarsoprol concentrations in serum of treated patients. However, it may not be possible to maintain constant drug concentrations in serum of patients as was the case in our in vitro experiments. Importantly, the MIC of 0.072 microg/ml exhibited by one of the isolates from Northwest Uganda was above levels attainable in CSF indicating that this isolate would probably not be eliminated from CSF of treated patients. PCR amplification of the gene encoding the P2-like adenosine transporter followed by restriction digestion with Sfa NI enzyme revealed presence of fragments previously observed in a trypanosome clone with laboratory-induced arsenic resistance. From our findings it appears that reduced drug susceptibility may be one factor for the frequent relapses of sleeping sickness after melarsoprol treatment occurring in Northwest Uganda.

Effect of Melarsoprol Treatment on Circulating IL-10 and TNF-α Levels in Human African Trypanosomiasis

The pathogenesis of human African trypanosomiasis (HAT) has been the object of considerable research interest but has remained incompletely understood. The importance of cytokines in the pathophysiology of this protozoan infection is now widely recognized, but the full spectrum of cytokines involved has yet to be determined. In the present investigation we compared the plasma concentrations of TNF-α and IL-10 in normal African controls and patients suffering from advanced meningocephalic (late-stage)Trypanosomiasis brucei (T. b.) gambienseinfections, before and after treatment with the arsenical trypanocide melarsoprol. We found that patients with late-stageT. b. gambienseexhibit chronically elevated circulating levels of both of these cytokines, and that these levels quickly decline following melarsoprol treatment. These findings confirm that TNF-α is involved in the immunopathogenesis of late-stage African trypanosomiasis and suggest that IL-10 may also play an important regulatory role in this disease.

Cost-effectiveness analysis of alternative treatments of African gambiense trypanosomiasis in Uganda.

African trypanosomiasis, or sleeping sickness, is a tropical disease caused by trypanosome parasites transmitted by tsetse flies. The focus of this paper is on the cost-effectiveness of alternative drug treatments for patients in the late stage of the disease. Melarsoprol has been used for many decades. More recently, eflornithine has been developed. It has fewer side effects and improves the overall cure rate. It is much more expensive than melarsoprol, however. The objective of the present cost-effectiveness is to identify the costs and benefits that would be involved in switching from melarsoprol to eflornithine in the treatment of late stage sleeping sickness. Benefits are expressed in lives saved as well as in disability adjusted life years (DALYs). The analysis is applied to the case of Uganda. The implications for affordability are also considered, by taking account of how the treatment costs would be shared between the national government, donors and patients. The baseline results indicate that melarsoprol treatment is associated with an incremental cost per life and DALY saved of $209 and $8, respectively. Each additional life saved by switching from melarsoprol alone to a combination of melarsoprol and eflornithine would cost an extra $1,033 per life saved, and an extra $40.9 per DALY gained. Shifting from this second alternative to treatment of all patients with eflornithine leads to an incremental cost per life saved of $4,444 and an incremental cost of $166.8 per DALY gained.

Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness

This paper reviews the incidence of, and risk factors for, drug-induced encephalopathy and mortality (from all causes) during treatment with melarsoprol of 1083 patients with Trypanosoma brucei gambiense sleeping sickness in Nioki hospital (Zaire) between 1983 and 1990. Sixty-four patients (5.9%) developed encephalopathy and 62 (5.7%) died: 43 from reactive encephalopathy and 19 from other causes. Univariate and multivariate analyses showed that the administration of prednisolone reduced significantly the incidence of encephalopathy and mortality during treatment, especially in patients with trypanosomes observed in the cerebrospinal fluid (CSF) and/or with a CSF white blood cell (WBC) count of 100 or more per mm 3. The risk of encephalopathy was associated more strongly with the CSF WBC count than with the presence of CSF trypanosomes. In the subgroup of patients with a CSF WBC count of 100 or more mm 3, changing the melarsoprol regimen to 3 series of 3 injections instead of 3 series of 4 injections halved the mortality rate during treatment. Treatment of patients who do develop reactive encephalopathy with the heavy metal chelator dimercaprol, in addition to intravenous steroids and anticonvulsants, may be harmful. The data suggest that a further reduction of the total dose of melarsoprol may decrease toxicity without jeopardizing efficacy.

Gambiense trypanosomiasis: frequency of, and risk factors for, failure of melarsoprol therapy

1083 patients with late-stage Trypanosoma brucei gambiense sleeping sickness were treated with melarsoprol in Nioki hospital, Zaire, between 1983 and 1990. Sixty-two (5·7%) died during treatment. Of the 1021 patients who survived the treatment, 63 (6·2%) subsequently relapsed, 58 (92%) of whom were diagnosed within 2 years of melarsoprol treatment. There was no evidence of an increase in the frequency of treatment failures during the study period, and the rate of relapses that we documented is comparable to that reported from Zaire more than 30 years ago. Relapses were more frequent among patients who had trypanosomes seen in the cerebrospinal fluid (CSF) at the time of the initial diagnosis (odds ratio [OR] = 2·76, 95% confidence interval [CI] = 1·65–4·63, P = 0·0001). Male patients had twice as many relapses as females (OR = 2·00, 95% CI = 1·19–3·36, P = 0·009), which was partly explained by males having trypanosomes in the CSF more often than females. There were important geographical variations in the frequency of relapses within the territory of the Nioki rural health zone, suggesting that the circulation of trypanosomes was geographically limited. Prednisolone treatment did not increase the risk of treatment failure, nor did decreasing the total dose of melarsoprol from 12 to 9 injections for patients with ⩾100 white blood cells/mm 3 of CSF. Since patients with trypanosomes in the CSF are also those who are at the highest risk of melarsoprolinduced encephalopathy, more aggressive treatment regimens cannot be recommended. Indeed our data suggest that there may be a threshold above which further increasing the total dosage of melarsoprol will not reduce the risk of relapse.

Trypanosoma brucei rhodesiense: Effect of immunosuppression on the efficacy of melarsoprol treatment of infected mice

Trypanosoma brucei rhodesiense: Effect of immunosuppression on the efficacy of melarsoprol treatment of infected mice

The use of 2-substituted 5-nitroimidazoles in the treatment of chronic murine Trypanosoma brucei infections with central nervous system involvement.

Chronic infections of Trypanosoma brucei GVR 35/2 in mice, normally relapse after conventional chemotherapy because infective trypanosomes in the brain escape the action of the drug and are able to multiply and eventually re-establish a parasitaemia. However, if treatment consists of a single dose of 1 x 20 mg/kg suramin followed 3 or 4 days later by a 2-substituted 5-nitroimidazole, given intraperitoneally, either as a single dose or as a course of daily injections, relapses rarely occur and the majority of the mice are permanently cured. The minimum effective levels for the three 5-nitroimidazole compounds (Merck Sharp and Dohme, Rahway, NJ, USA) were two doses of 10 mg/kg of L611,744; four doses of 10 mg/kg of MK 436; and three doses of 10 mg/kg of L634,549. Generally it was more effective to divide a given total dose into two or more daily doses, rather than to give the 4-nitroimidazole as a single treatment. The effective dose levels are low enough to be of practical significance and, if the 5-nitroimidazoles were ever licensed for humans, might well prove to be an alternative to melarsoprol treatment for the elimination of trypanosomes from the central nervous system.