Disease relevance of MELARSOPROL

• Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5% [1].
• Topical melarsoprol for trypanosomiasis [2].
• Also essential for both forms of HAT is accurate determination of the disease stage because of the high toxicity of melarsoprol, the drug most widely used during the neurological stage of the illness [3].
• Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARalpha independent manner [4].
• Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic leukemia (APL) and chronic B-cell leukemia cell lines, respectively [4].

Psychiatry related information on MELARSOPROL

• The trypanosomicide action of melarsoprol led to a reduction in the number of sleep episodes, except in one patient whose health condition worsened during the third treatment session: sleep onset REM sleep phases (SOREMPs) decreased and the number of SWS episodes during a sleep episode increased [5].

High impact information on MELARSOPROL

• Calcium also has a synergistic effect on melarsoprol, the only drug available for treating sleeping sickness patients with central nervous system involvement, and the concentration of calcium has been reported to be depressed inthe serum of experimentally infected animals [6].
• 598 patients were evaluable: morbidity and death associated with melarsoprol-induced encephalopathy was reduced in patients who were given prednisolone [7].
• Moreover, both As2O3 and melarsoprol comparably inhibited growth and induced apoptosis of PML+/+ and PML-/- MEFs, and inhibited colony-forming unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of PML+/+ and PML-/- progenitors [4].
• Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10(-7) to 10(-5) mol/L [4].
• Together, these results show that As2O3 and melarsoprol inhibit growth and induce apoptosis independent of both PML and PML-RARalpha expression in a variety of myeloid leukemia cell lines, and suggest that these agents may be more broadly used for treatment of leukemias other than APL [4].

Chemical compound and disease context of MELARSOPROL

• The original model is extended by using two additional strains of outbred mice and by demonstrating that melarsoprol, an arsenical and currently the only drug used for human African trypanosomiasis involving the brain, was also curative for these brain infections [8].
• African trypanosomes are pathogens of humans and livestock in equatorial Africa. There is a great deal of resistance to present front line drugs for treating African trypanosomiasis such as melarsoprol (Arsobal) and pentamidine [9].
• Eflornithine has been successfully used in patients with human trypanosomiasis failing melarsoprol therapy however expense and availability have limited its potential [10].
• Another drug, nifurtimox is licensed for South American trypanosomiasis but also been used in trials against melarsoprol-refractory late sage disease [11].
• We have investigated the anti-tumour activities of Mel-B either with or without all-trans-retinoic acid (ATRA) using the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human prostate cancer cells both in vitro and in vivo [12].

Biological context of MELARSOPROL

• We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death [13].
• We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells [13].
• The overexpression of TbMRPA resulted in a 10-fold increase in the IC50 of melarsoprol [14].
• Recently, a high proportion of patients with late-stage Trypanosoma brucei gambiense trypanosomiasis, who had been treated with melarsoprol in some disease-endemic areas, subsequently relapsed [15].
• Given the breadth of this activity, we initiated a clinical study to evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in patients with refractory or resistant leukemia [16].

Anatomical context of MELARSOPROL

• Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines [13].
• In contrast to As2O3, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen [17].
• As2O3 and melarsoprol also inhibited viability and growth and induced apoptosis in plasma-cell enriched preparations from the bone marrow or blood of myeloma patients [17].
• One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes [18].
• Investigations ruled out the usual major causes of such a syndrome in our setting in northern Tanzania. Examination of his cerebrospinal fluid revealed trypanosomes, and he made a slow but dramatic improvement after a full course of suramine and melarsoprol [19].

Associations of MELARSOPROL with other chemical compounds

• This prompted us to study the in vitro effects of As2O3 and of another arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells [17].
• Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients [17].
• However, genetic disruption in Trypanosoma brucei brucei of the gene encoding P2, TbAT1, reduced the susceptibility to melarsoprol and pentamidine by only a factor of approximately 2 [20].
• Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection.Methods [21].
• The melaminophenyl arsenicals melarsoprol and melarsen oxide interfere with thiamine metabolism in the fission yeast Schizosaccharomyces pombe [22].

Gene context of MELARSOPROL

• Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity [23].
• Effect of melarsoprol treatment on circulating IL-10 and TNF-alpha levels in human African trypanosomiasis [24].
• In the present investigation we compared the plasma concentrations of TNF-alpha and IL-10 in normal African controls and patients suffering from advanced meningocephalic (late-stage) Trypanosomiasis brucei (T.b.) gambiense infections, before and after treatment with the arsenical trypanocide melarsoprol [24].
• After 24 hours, all three cell lines treated with melarsoprol (10(-7) mol/L) exhibited morphologic characteristics of apoptosis [13].
• Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy [25].

Analytical, diagnostic and therapeutic context of MELARSOPROL

• The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series [26].
• RESULTS: The half-life of melarsoprol determined by HPLC was <1 hour compared with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating the existence of active metabolites [18].
• Of 65 T. b. gambiense isolates analyzed from a focus in north-western Uganda with high treatment failure rates following melarsoprol therapy, 38 had a mutated TbAT1 [25].
• C3 levels increased after treatment with melarsoprol (Mel B) [27].
• Further evaluation of the PCR method is required, in particular to determine whether PCR assays could be used in studies on patients who fail to respond to melarsoprol, as observed in several foci [28].

References