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At least 19 recordsLinked to original sources
PubMed1998

Discrepancy in plasma melarsoprol concentrations between HPLC and bioassay methods in patients with T. gambiense sleeping sickness indicates that melarsoprol is metabolized.

OBJECTIVE: With the use of a specific high-performance liquid chromatography (HPLC) method and a bioassay which determines trypanocidal activity, concentrations of melarsoprol were assessed in plasma, urine and cerebrospinal fluid (CSF) from 8 patients with late-stage Trypanosoma gambiense sleeping sickness. The aim was to unravel to what extent the bioassay codetermines biologically active metabolites of melarsoprol. METHODS: Subjects were given one dose of melarsoprol i.v. per day for 4 days (1.2, 2.4, 3.0-3.6, 3.0-3.6 mg per kg b.w., respectively). Plasma samples were obtained before the first melarsoprol injection, immediately after and at 1 h, 24 h and 5 days after the 4th injection. Urine was collected before melarsoprol therapy and at 24 h after the 4th injection. CSF samples were taken once before treatment and at 24 h after the 4th injection. RESULTS: HPLC analyses showed that plasma concentrations immediately after the 4th injection varied from 2200 to 15,900 nmol/l; dropping to 0-1800 nmol/l at 1 h; and to undetectable levels at 24 h. In urine small amounts of melarsoprol were recovered. Melarsoprol could not be detected in CSF by HPLC. Immediately after injection, bioassay analyses showed plasma concentrations of the same magnitude as HPLC assays but at 1 h they were 4-65-fold higher than the levels assessed by HPLC. Even 24 h and 5 days after the 4th injection there was significant but decreasing activity. Urine levels were 40-260-fold higher than the measured HPLC concentrations, whereas there was low but detectable activity in CSF. CONCLUSION: Results indicate that melarsoprol is rapidly eliminated from plasma. The significant trypanocidal activity determined by bioassay and simultaneous low or undetectable levels of melarsoprol assayed by HPLC indicate that the compound is transformed into metabolites with parasiticidal activity.

Adolescent↗
PubMed2002

Combination of eflornithine and melarsoprol for melarsoprol-resistant Gambian trypanosomiasis.

OBJECTIVE: To evaluate the efficacy and toxicity of a combination of eflornithine and melarsoprol among relapsing cases of Gambian trypanosomiasis. METHODS: Forty-two late-stage Trypanosoma brucei gambiense trypanosomiasis patients relapsing after initial treatment with melarsoprol were treated with a sequential combination of intravenous eflornithine (100 mg/kg every 6 h for 4 days) followed by three daily injections of melarsoprol (3.6 mg/kg, up to 180 mg). They were then followed-up for 24 months. RESULTS: Two (4.8%) patients died during treatment. Of the 40 surviving patients, two had a treatment failure, 13 and 19 months after having received the combination therapy. By Kaplan-Meier analysis, the 2-year probability of cure was 93.3% (95% confidence interval: 84.3-100%). CONCLUSION: This sequential combination has an efficacy and a toxicity similar to a 7-day course of eflornithine monotherapy, but is easier to administer. Whether such therapeutic success corresponds tosynergism between eflornithine and melarsoprol, or merely means that 4 days of eflornithine monotherapy suffices for such patients, will need to be determined in a comparative trial.

Adolescent↗
PubMed2006

Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness.

BACKGROUND: Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection. METHODS: An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment. RESULTS: A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens. CONCLUSION: A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

Administration, Oral↗
PubMed2006

Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.

OBJECTIVE: To compare the effectiveness of melarsoprol and eflornithine in treating late-stage Gambian trypanosomiasis in the Republic of the Congo. METHODS: We analysed the outcomes of death during treatment and relapse within 1 year of discharge for 288 patients treated with eflornithine, 311 patients treated with the standard melarsoprol regimen and 62 patients treated with a short-course (10-day) melarsoprol regimen between April 2001 and April 2005. FINDINGS: A total of 1.7% (5/288) of patients treated with eflornithine died compared with 4.8% (15/311) of those treated with standard melarsoprol and 6.5% (4/62) of those treated with short-course melarsoprol. Patients treated with eflornithine tended to be younger and were more likely to have trypanosomes or higher white blood cell counts in their cerebrospinal fluid. The cumulated incidence of relapse among patients who attended at least one follow-up visit 1 year after discharge was 8.1% (11/136) for those treated with eflornithine, 14% (36/258) for those treated with standard melarsoprol and 15.5% (9/58) for those treated with shortcourse melarsoprol. In a multivariate analysis, when compared with eflornithine, standard melarsoprol was found to be a risk factor for both death (odds ratio (OR) = 2.87; 95% confidence interval (CI) = 1.03-8.00) and relapse (hazard ratio (HR) = 2.47; 95% CI = 1.22-5.03); when compared with eflornithine, short-course melarsoprol was also found to be a risk factor for death (OR = 3.90; 95% CI = 1.02-14.98) and relapse (HR = 6.65; 95% CI = 2.61-16.94). CONCLUSION: The effectiveness of melarsoprol treatment appears to have diminished. Eflornithine seems to be a better first-line therapy for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.

Adolescent↗
PubMed2002

Human African trypanosomiasis: potential therapeutic benefits of an alternative suramin and melarsoprol regimen.

Treatment of late-stage human African trypanosomiasis is complicated by the presence of trypanosomes within the central nervous system (CNS). The regimen commonly prescribed to treat CNS-stage disease involves the use of the trypanocidal drugs suramin and melarsoprol. Suramin does not cross the blood-brain barrier efficiently and therefore, at normal dosages, will not cure CNS-stage infections. An initial treatment with suramin is given to eliminate the parasites from the peripheral tissues. This is followed by a course of intravenous melarsoprol, which can enter the CNS. However, melarsoprol not only produces severe adverse reactions but also is extremely painful to administer. One possible method to help alleviate these problems is to reduce the total amount of melarsoprol in the treatment regimen. This study indicates a synergism between suramin and melarsoprol and demonstrates that experimental murine CNS-trypanosomiasis can be cured with a single intraperitoneal dose of 20 mg/kg suramin followed almost immediately by 0.05 ml (4.5 micromol) topical melarsoprol. These dosages will not cure the infection when administered as monotherapies. Moreover, the timing of the drug administration appears to be crucial to the successful outcome of the regimen. If the interval between injection of suramin and application of topical melarsoprol is extended from 15 min to 3 or 7 days, the infections are not cured. Although extended relapse times occur following these regimens when compared with monotherapy approaches. Thus, there is strong evidence that injected suramin and topical melarsoprol should be given almost simultaneously to achieve the most effective combination of the two drugs.

Animals↗
PubMed2005

Melarsoprol-cyclodextrins inclusion complexes.

Melarsoprol, a water-insoluble drug, is mainly used in the treatment of trypanosomiasis and has demonstrated an in vitro activity on myeloid and lymphoid leukemia derived cell lines. It is marketed as a very poorly tolerated non-aqueous solution (Arsobal). The aim of our work was to develop melarsoprol-cyclodextrin complexes in order to improve the tolerability and the bioavailability of melarsoprol. Phase-solubility analysis showed A(L)-type diagrams with beta-cyclodextrin (betaCD), randomly methylated beta-cyclodextrin (RAMEbetaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), which suggested the formation of 1:1 inclusion complexes. The solubility enhancement factor of melarsoprol (solubility in 250 mM of cyclodextrin/solubility in water) was about 7.2x10(3) with both beta-cyclodextrin derivatives. The 1:1 stoichiometry was confirmed in the aqueous solutions by the UV spectrophotometer using Job's plot method. The apparent stability constants K(1:1), calculated from mole-ratio titration plots, were 57 143+/-4 425M(-1) for RAMEbetaCD and 50 761+/-5 070 M(-1) for HPbetaCD. Data from 1H-NMR and ROESY experiments provided a clear evidence of inclusion complexation of melarsoprol with its dithiaarsane extremity inserted into the wide rim of the cyclodextrin torus. Moreover, RAMEbetaCD had a pronounced effect on the drug hydrolysis and the dissolution rate of melarsoprol. However, the cytotoxic properties of melarsoprol on K562 and U937 human leukemia cell lines was not modified by complexation.

Antineoplastic Agents↗
PubMedDate not supplied

Risk factors for treatment failure after melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda.

We evaluated the treatment failure rate among late-stage human African trypanosomiasis (HAT) patients treated with melarsoprol in Arua, northern Uganda, between September 1995 and August 1996, and identified the risk factors for treatment failure. We conducted a retrospective cohort study in October 1998, and performed a survival analysis. A treatment failure was defined as a late-stage HAT patient fully treated with melarsoprol and classified as an HAT case at any follow-up visit within 2 years after treatment. Among 428 patients treated in the study period, 130 (30.4%) were identified as treatment failure within 2 years after discharge. The multivariate analysis showed that patients who experienced treatment failure after melarsoprol were more likely to have been admitted as a relapsing case (relative hazard, RH = 11.15 [6.34-19.61]), and to have been diagnosed with trypanosomes in the lymph nodes (RH = 3.19 [2.10-4.83]) or in the cerebrospinal fluid (CSF) (RH = 1.66 [1.09-2.53]). The risk of treatment failure also increased with the number of cells in the CSF. The treatment failure rate after melarsoprol observed in Arua is greatly above the expected figures of 3-9%. More research is needed to confirm whether it is related to the variation of melarsoprol pharmacokinetics between individuals, or if it is associated with a reduced susceptibility of the trypanosomes to melarsoprol. The study emphasizes the need for second-line drugs to treat patients that have already received one or several full course(s) of melarsoprol.

Adolescent↗
PubMed1997

Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines.

Inorganic arsenic trioxide (As2O3) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non-EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10(-7) to 10(-9) mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10(-7) mol/L) exhibited morphologic characteristics of apoptosis. 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. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.

Antineoplastic Agents↗
PubMed2005

The role of Trypanosoma brucei MRPA in melarsoprol susceptibility.

We previously showed that over-expression of Trypanosoma brucei MRPA, a member of the multidrug resistance protein family in T. brucei, reproducibly resulted in resistance to the anti-trypanosomal drug melarsoprol in vitro. MRPA is predicted to mediate efflux of melarsoprol as a conjugate with trypanothione, a glutathione-spermidine conjugate which is the major small thiol in trypanosomes. Here, we show that depletion of MRPA by RNA interference resulted in moderate hypersensitivity to both melarsoprol and melarsen oxide. Over-expression of MRPA alone is not sufficient to cause melarsoprol resistance in vivo, although it is sufficient in vitro. This discrepancy is not an effect of drug metabolism since over-expression of MRPA alone conferred resistance to melarsoprol and its principle metabolite, melarsen oxide, in vitro. Over-expression of MRPA was not detected in four melarsoprol-resistant trypanosome isolates from sleeping sickness patients.

Animals↗
PubMed1998

Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARalpha independent manner.

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. As2O3 has been proposed to principally target PML and PML-RARalpha proteins in APL cells. We investigated the activity of As2O3 and melarsoprol in a broader context encompassing various myeloid leukemia cell lines, including the APL cell line NB4-306 (a retinoic acid-resistant cell line derived from NB4 that no longer expresses the intact PML-RARalpha fusion protein), HL60, KG-1, and the myelomonocytic cell line U937. To examine the role of PML in mediating arsenical activity, we also tested these agents using murine embryonic fibroblasts (MEFs) and bone marrow (BM) progenitors in which the PML gene had been inactivated by homologous recombination. Unexpectedly, we found that both compounds inhibited cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10(-7) to 10(-5) mol/L. As2O3 relocalized PML and PML-RARalpha onto nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60 and U937 cell lines. Although melarsoprol was more potent in inhibiting growth and inducing apoptosis, it did not affect PML and/or PML-RARalpha nuclear localization. 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. 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.

Animals↗
PubMed1989

Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness.

In a prospective randomised trial, 620 patients who had Trypanosoma brucei gambiense trypanosomiasis with central nervous system involvement were treated either with prednisolone plus melarsoprol or with melarsoprol only. 598 patients were evaluable: morbidity and death associated with melarsoprol-induced encephalopathy was reduced in patients who were given prednisolone. The two groups did not differ either in the incidence of other complications of melarsoprol therapy or in relapse rate after melarsoprol therapy. The cost of prednisolone would be outweighed by savings on the treatment of encephalopathies in such patients.

Administration, Oral↗
PubMed2002

Slow-release melarsoprol microparticles.

The present study compares two methods of preparation of microparticles of melarsoprol for the treatment of the human trypanosomiasis. Melarsoprol is poorly soluble in water and in organic media. Microparticles were formulated with modified O/W and W/O/W methods, Poly(epsilon -caprolactone) microparticles were prepared either with a suspension-in-oil-in-water (S/O/W) solvent evaporation method or by complexation of melarsoprol with methyl ss-cyclodextrin followed by a water-in-oil-in-water (W(CD)/O/W) solvent evaporation method. Results showed a poor incorporation of melarsoprol (2.89 +/- 0.20 microg mg(-1)) using the W(CD)/O/W process, while the S/O/W process allowed achieving 161 +/- 5 microg mg(-1) and seemed to be very effective for the preparation of a sustained release form of melarsoprol. Moreover S/O/W microparticles showed a slow release of the drug in 70% of phosphate buffer pH 7.4, 0.1 M and 30% of propylene glycol (about 50% in 2 h and 80% after 7 h).

Chemistry, Pharmaceutical↗
PubMedDate not supplied

Pharmacokinetic properties of the trypanocidal drug melarsoprol.

With a biological assay and atomic absorption spectrometry we determined the level of melarsoprol in the serum and cerebrospinal fluid of 19 patients treated with melarsoprol in Daloa, Ivory Coast. Most serum levels were between 2 and 4 micrograms/ml 24 h after administration, and were still > or = 0.1 microgram/ml after 120 h. Levels in the cerebrospinal fluid were between 0 and 0.1 microgram/ml. Elimination was biphasic, with a pronounced beta 1 phase. Mean terminal elimination half-life of melarsoprol was about 35 h, volume of distribution was about 100 l and total clearance was about 50 ml/min. The results of these first pharmacokinetic studies on melarsoprol were used to simulate possible alternative therapy schemes which might avoid some of the problems that arise with melarsoprol use.

Adult↗
PubMed1999

Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients.

Recent data have renewed the interest for arsenic-containing compounds as anticancer agents. In particular, arsenic trioxide (As2O3) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing programmed cell death in leukemic cells both in vitro and in vivo. 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. At pharmacological concentrations (10(-8) to 10(-6) mol/L), As2O3 and melarsoprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyelocytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis, as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosphatidylserine at the cell surface using annexin V, and by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. 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. In nonseparated bone marrow samples, both arsenical compounds triggered death in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myeloma cells as in cell lines, interleukin 6 did not prevent arsenic-induced cell death or growth inhibition, and no synergistic effect was observed with IFN-alpha. In contrast to As2O3, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen. Both pokeweed mitogen-induced normal plasma cells and malignant plasma cells showed a normal nuclear distribution of PML protein, which was disrupted by As2O3 but not by melarsoprol, suggesting that the two arsenical derivatives acted by different mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.

Antineoplastic Agents↗
PubMed2006

The antitrypanosomal drug melarsoprol competitively inhibits thiamin uptake in mouse neuroblastoma cells.

Melarsoprol is the main drug used for the treatment of late-stage sleeping sickness, although it causes severe side-effects such as encephalopathy and polyneuropathy leading to death in some patients. Recent data suggest that melarsoprol and its active metabolite melarsenoxide interfere with thiamin transport and metabolism in E. coli and yeast, but there are no data concerning their possible effects on thiamin metabolism in mammalian cells. We tested both drugs on thiamin transport in cultured mouse neuroblastoma cells using (14)C-labeled thiamin. Melarsoprol, competitively inhibits high-affinity thiamin transport in mouse neuroblastoma cells with a K(i) of 44 micromol/L. However, the active compound melarsenoxide has no inhibitory effect. This suggests that the side effects of melarsoprol treatment are unlikely to be due to inhibition of thiamin transport by melarsenoxide, its main metabolite in the brain.

Animals↗
PubMedDate not supplied

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 > or = 100 white blood cells/mm3 of CSF. Since patients with trypanosomes in the CSF are also those who are at the highest risk of melarsoprol-induced encephalopathy, more aggressive treatment regimens cannot be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

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.

Animals↗
PubMed2000

Investigations of the metabolites of the trypanocidal drug melarsoprol.

BACKGROUND: Melarsoprol remains the first-choice drug for trypanosomiasis (human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse reactions, we investigated the metabolism of this 50-year-old organoarsenic compound. 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. One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes. The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours. Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy. Because of the poor pharmaceutical properties of melarsoprol, the therapeutic potential of melarsen oxide was investigated. In a rodent model of acute infection, 20 of 20 mice were cured (0.1 to 1 mg/kg intravenously or 2.2 mg/kg intraperitoneally). In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier. CONCLUSION: The prospects for the future of trypanosomiasis treatment are deplorable. Investigations on the improvement of the use of the old drugs are therefore required. The results of this study may build a basis for further research on the cause of severe adverse reactions.

Adult↗