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At least 19 recordsLinked to original sources
PubMed1994

Response of diminazene-resistant and diminazene-susceptible Trypanosoma congolense to treatment with diminazene when occurring as a mixed infection in goats.

A study was carried out to determine whether a drug-resistant trypanosome population could influence the survival of a drug-sensitive population in mixed infections in goats. To identify both populations during the course of a mixed infection, a system for distinguishing them was developed; using a nucleotide sequence of a cDNA that was derived from Trypanosoma congolense ILNat 3.3 (IL 1616), a pair of 20-mer primers was designed which, in a PCR, amplified a 900-bp sequence from the diminazene-sensitive trypanosome, T. congolense IL 1180, but not the diminazene-resistant trypanosome, T. congolense IL 3247. The PCR technique detected 100 pg of IL 1180 DNA when mixed with 25 ng of total genomic DNA of IL 3274, as determined by gel electrophoresis and ethidium bromide-staining of the PCR products. Using the 900-bp PCR product as a 32P-labelled probe on Southern blots, the sensitivity was increased 100-fold. Three groups of five goats each were infected with IL 1180 (group A), IL 3274 (group B) or both clones simultaneously (group C), and treated with diminazene aceturate at a dose of 7.0 mg/kg body weight following detection of trypanosomes. Three other groups of three goats each were similarly infected and kept as untreated controls. All group A animals were cured, while all in group B and four animals in group C relapsed. Trypanosomes were harvested from all animals at regular intervals up to 60 days post treatment. Using the PCR techniques, IL 1180 DNA could not be detected in any post-treatment trypanosome DNA sample. It therefore appeared, on the basis of the sensitivity of the DNA detection systems used, that IL 1180 is unable to survive treatment with diminazene aceturate when mixed with IL 3274 in goats.

Animals↗
PubMed1995

Apparent rarity of diminazene-resistant trypanosomes in goats infected with a diminazene-resistant population of Trypanosoma congolense.

Experiments were carried out in goats to determine the frequency with which diminazene-resistant trypanosomes occur in parasite populations before and after the intramuscular treatment of the goats with diminazene aceturate. Trypanosoma congolense IL 3274, a diminazene-resistant clone, was used to initiate infections in three groups of five goats. The goats in the first group were treated with diminazene aceturate at a dose of 7.0 mg kg-1 bodyweight within 10 seconds of infection; one of the goats was cured. All of the second group, which received no treatment, became parasitaemic. The third group of goats received the same dose of drug as the first group but three days after all of them were first detected parasitaemic; trypanosomes reappeared in all the five goats. When this third group was treated, the frequency of trypanosomes resistant to the drug dosage was estimated to be less than 1 in 10(3). The parasites which reappeared after the treatment of these animals were used to infect two additional groups of five goats intravenously. The goats in one group were treated with the same dose of drug as before, within 10 seconds of infection and were all cured. In contrast, the five goats in the second, untreated, group became parasitaemic. Finally, when the goats in which the infections had relapsed were retreated with diminazene aceturate at the same dose rate, the level of parasitaemia temporarily decreased by at least 10(3) trypanosomes ml-1. These findings suggest that diminazene-resistant T congolense occur at low levels in trypanosome populations despite attempts to select for a population resistant to the dose of drug used.

Animals↗
PubMed1995

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate.

The frequency of trypanosomes resistant to diminazene aceturate at a dose of 25 mg/kg of body weight was investigated for populations of Trypanosoma congolense IL 3274 which reappeared in infected mice after intraperitoneal treatment with diminazene aceturate at the same dosage. At inoculum sizes of 10(2), 10(3), 10(4), 10(5), and 10(6) trypanosomes per mouse, the relapse populations were used to initiate infections in five groups of 100 mice each by the intravenous route. Immediately after infection, 50 mice in each group were treated intraperitoneally with diminazene aceturate at the aforementioned dosage; the other 50 mice functioned as untreated controls. Thereafter, all animals were monitored for 100 days for the presence of trypanosomes. In each group, trypanosomes were detected in 50 of 50 control mice, indicating 100% infectivity for all five inoculum sizes. In contrast, in the groups of 50 mice infected with 10(2), 10(3), 10(4), 10(5) and 10(6) trypanosomes and treated with diminazene aceturate, trypanosomes were detected in 4, 11, 13, 28, and 39 of 50 mice, respectively. By logistic regression, a good fit was found between the number of mice identified as parasitemic and the inoculum sizes. Maximum likelihood estimates for the proportions of trypanosomes resistant to diminazene aceturate at 25 mg/kg of body weight for the inoculum of 10(2), 10(3), 10(4), 10(5), and 10(6) organisms were 8.335 x 10(-4), 2.485 x 10(-4), 3.02 x 10(-5), 8.3 x 10(-6), and 1.6 x 10(-6), respectively. These finding indicate that the majority of the relapse trypanosomes were susceptible the the drug dosage used for selecting the population and that, surprisingly, the calculated proportion of organisms which survived drug exposure varied inversely with the inoculum size. Further experiments with mice indicated that the inverse relationship did not result from alterations in the pharmacokinetics of the drug with different inoculum sizes. The data therefore suggest that parasite inoculum size and drug dosage are important factors in estimating the apparent frequency of diminazene-resistant trypanosomes in populations of T. congolense occurring in vivo.

Animals↗
PubMed1995

The chemotherapeutic efficacy of diminazene aceturate and lithium chloride against relapse infection of Trypanosoma brucei brucei in rats.

The chemotherapeutic efficacy of diminazene aceturate (Berenil) and lithium chloride (LiCl) in relapse infection of trypanosomiasis was investigated in rats experimentally infected with Trypanosoma brucei brucei. The study showed that the combination of diminazene aceturate at (7 mg/kg) and LiCl (10 micrograms/kg) appeared more effective therapeutically than diminazene aceturate, or diminazene aceturate and LiCl and dexamethasone group, as more of the rats in the diminazene aceturate and LiCl treated-group remained aparasitaemic for longer days (60 days). Relapse parasitaemia occurred on days 10 and 12 in diminazene aceturate (7 mg/kg); diminazene aceturate (7 mg/kg) and LiCl (10 micrograms/kg) plus dexamethasone (1 mg/kg) treated group respectively, while relapse parasitaemia did not occur in the diminazene aceturate and LiCl treated group until day 20. Histopathological examination of the brain did not show any signs of inflammatory reaction in the diminazene aceturate and LiCl and dexamethasone treated group. However lesions associated with meningoencephalitis, such as cellular infiltration of mononuclear cells, perivascular cuffings and perivascular congestion and oedema were observed in the diminazene aceturate; diminazene aceturate and LiCl treated groups.

Animals↗
PubMed1996

Pharmacokinetics of diminazene in plasma and lymph of goats.

OBJECTIVE: To characterize the pharmacokinetics of diminazene in plasma and pseudo-afferent lymph of East Africa X Galla goats. DESIGN: The efferent prescapular lymphatic duct of 3 goats was cannulated 8 weeks after surgical removal of the lymph node. Thereafter, 3.5 mg of diminazene base/ kg of body weight was administered to these goats and to 3 noncannulated goats. PROCEDURE: Using high-performance liquid chromatography, concentration of diminazene was determined in plasma and lymph collected up to 96 hours after treatment. RESULTS: Maximal concentrations of diminazene in plasma of noncannulated goats (median [range], 4.30 [4.28 to 5.01] micrograms/ml), plasma of cannulated goats (3.94 [2.94 to 4.06] micrograms/ml), and lymph (1.06¿0.73 to 1.86] micrograms/ml) were significantly different (P < 0.05); values in lymph were considerably lower than those in plasma from noncannulated and cannulated animals. Time to reach maximal concentration did not differ significantly between lymph and plasma of noncannulated and cannulated goats. Over the first 24 hours after drug administration, concentration of diminazene in plasma of noncannulated goats was generally higher than that in lymph, but thereafter was similar. Apparent volume of distribution of diminazene in the plasma of noncannulated (2.57 [1.93 to 2.60] L/kg) and cannulated (2.30 [1.04 to 2.40] L/kg goats did not differ significantly. Penetration ratio of diminazene into lymph, compared with plasma, of cannulated goats was 1.69:1. CONCLUSIONS: Disposition of diminazene in goats is characterized by higher concentration in plasma than in lymph. However, the drug persists longer in lymph than in plasma. CLINICAL RELEVANCE: The longer persistence of diminazene in lymph than in plasma may account for the enhanced therapeutic efficacy of diminazene in the early stage, compared with later stages, of a tsetse fly-transmitted trypanosome infection.

Animals↗
PubMed1993

Pharmacology of diminazene: a review.

Chemotherapy for trypanosomiasis in domestic livestock depends on only a few compounds, of which several are chemically closely related. Of these compounds, the most widely used therapeutic agent in cattle, sheep and goats is diminazene aceturate. Diminazene was first described in 1955. Subsequently, a substantial body of data has been generated on various pharmacological aspects of the compound. In this review, we consider the current status of knowledge concerning the therapeutic spectrum of diminazene, resistance to diminazene in trypanosomes, and combination therapeutic regimens in which diminazene has been administered together with other compounds. Analytical techniques for diminazene, the pharmacokinetics of diminazene, data concerning diminazene's toxicity, and the different molecular mechanisms by which diminazene may exhibit trypanocidal action are also considered.

Animals↗
PubMed2006

A diminazene-resistant strain of Trypanosoma brucei brucei isolated from a dog is cross-resistant to pentamidine in experimentally infected albino rats.

Trypanosomosis is a major cause of mortality for dogs in Nigeria and treatment with diminazene aceturate has steadily become less effective, either as a result of low quality of the locally available diminazene preparations or of drug resistance. To investigate these alternatives, samples of locally obtained drugs were analysed for diminazene aceturate content and a strain of Trypanosoma brucei brucei was isolated from a diminazene-refractory dog in Nsukka, south-eastern Nigeria, and used to infect albino rats. The quality of diminazene aceturate-based preparations was variable, with two preparations containing less than 95% of the stated active compound. Rats infected with T. brucei isolated from the dog were treated 7 and 10 days after infection either with 7 mg/kg diminazene aceturate (intraperitoneally, once) or with 4 mg/kg pentamidine isethionate (intramuscularly, 7 consecutive days). Relapse rates were 100% for both trypanocides in the groups of rat treated 10 days post-infection, and 83% and 50% of rats treated 7 days after infection relapsed to diminazene aceturate and pentamidine isethionate, respectively. Careful consideration of physiological parameters showed that pentamidine was only marginally superior to diminazene aceturate as applied in this study. It was concluded that dogs in Nigeria are infected with genuinely diminazene aceturate-resistant trypanosomes that appear to be cross-resistant to pentamidine isethionate.

Animals↗
PubMed2004

The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in african trypanosomes.

Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [(3)H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a K(m) of 0.45 +/- 0.11 micro M, which was dose dependently inhibited by pentamidine and adenosine. The K(i) values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up [(3)H]diminazene and [(3)H]pentamidine. TbAT1-null mutants had lost almost all capacity for [(3)H]diminazene transport. However, this cell line still displayed a small but detectable rate of [(3)H]diminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates [(3)H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates.

Adenosine↗
PubMed1992

Metabolic N-hydroxylation of diminazene in vitro.

The two N-hydroxylated derivatives (amide oximes) and the corresponding amides of the trypanocidal diamidine diminazene (Berenil, CAS 536-71-0) have been synthesized. These reference compounds made it possible to investigate the in vitro metabolism of the amidine functionalities of diminazene. Diminazene metabolites were detected for the first time, in the form of the corresponding mono- and di(amide oxime), after incubation with 12000 g supernatants from rabbit liver homogenates and careful workup (freeze drying). The identification was based on the behavior in thin-layer chromatography and on comparison of the mass spectral data for the metabolites with those for synthetic material. The N-hydroxylation of diminazene showed the properties typical of a reaction catalyzed by a microsomal monoxygenase. Diminazene amides did not occur as metabolites. The di(amide oxime) of diminazene was tested for its trypanocidal and leishmanicidal activity on various laboratory strains of trypanosomes in mice and on Leishmania donovani in hamsters. The studies showed that the di(amide oxime) has a trypanocidal effect on various strains of trypanosomes (T. brucei, T. vivax, T. congolense and T. evansi), but this is distinctly weaker than that of diminazene. A diminazene-resistant strain of T. rhodesiense is also unaffected by the di(amide oxime). The di(amide oxime) also has a leishmanicidal effect, but this again is distinctly less than that of diminazene.

Animals↗
PubMed2002

A competitive enzyme-linked immunosorbent assay for diminazene.

Diminazene aceturate has remained a very important therapeutic drug for trypanosomosis in cattle, sheep and goats since its introduction into the market in 1955. Despite its continued use, the methods available for its detection in body fluids are lengthy and inefficient for routine monitoring of drug levels in treated animals. A competitive enzyme linked immunosorbent assay (ELISA) has now been developed and optimized for the detection of diminazene in bovine serum. In the assay, diminazene in the test samples and that in a newly developed diminazene-horseradish peroxidase conjugate compete for antibodies to diminazene raised in rabbits and immobilized on a microtitre plate. Tetramethylbenzidine-hydrogen peroxide (TMB/H(2)O(2)) is used as chromogen-substrate system. The assay has a detection limit of 0.8 ng/ml of serum with a high specificity for diminazene. Cross-reactivity with either homidium bromide and quinapyramine sulphate/chloride of 0.0004% is negligible while that with isometamidium chloride is 0.71%. The assay was able to detect diminazene levels in normal Boran steers for at least two weeks after intramuscular injection with the drug at a dose of 3.5 mg/kg bw. The assay will be useful in monitoring diminazene use, and development of resistance in trypanosomosis endemic areas.

Animals↗
PubMed2005

The pharmacokinetics of diminazene aceturate after intramuscular administration in healthy dogs.

The pharmacokinetics of diminazene aceturate following intramuscular (i.m.) administration at 4.2 mg/kg was evaluated in 8 healthy German Shepherd dogs. Blood samples were collected at 19 intervals over a period of 21 days. Diminazene plasma concentrations were measured using a validated HPLC method with UV detection and a sensitivity of 25 ng/ml. The in vitro and in vivo binding of diminazene to blood elements was additionally determined. Diminazene pharmacokinetics showed a large inter-individual variation after i.m. administration. It had a short absorption half-life (K01-HL of 0.11 +/- 0.18 h), resulting in a C(max) of 1849 +/- 268.7 ng/ml at T(max) of 0.37 h and a mean overall elimination half-life (T1/2beta) of 5.31 +/- 3.89 h. A terminal half-life of 27.5 +/- 25.0 h was measured. At 1 h after i.m. injection, 75% of the diminazene in whole blood was in the plasma fraction. The results of this study indicate that diminazene is rapidly distributed and sequestered into the liver, followed by a slower terminal phase during which diminazene is both redistributed to the peripheral tissues and/or renally excreted. It is recommended that diminazene administered i.m. at 4.2 mg/kg should not be repeated within a 21-day period.

Absorption↗
PubMed1999

Comparative pharmacokinetics of diminazene in lactating goats and sheep.

The pharmacokinetic aspects of diminazene aceturate were studied in lactating goats and sheep after single intravenous and intramuscular administrations of 3.5 mg/kg b.wt. Plasma and milk concentrations were determined by use of reversed phase high-performance liquid chromatography (HPLC) after ion-pair extraction. Following intravenous injection, the disposition of diminazene in goats and sheep conformed to a two-compartment model with rapid distribution and slower elimination phases. Values of (t1/2 beta) were obtained indicating a slower final disappearance of the drug from plasma of sheep (21.17 h) than in goats (16.39 h). Diminazene concentrations were maintained for more than 4 days in the plasma of goats and sheep. In both species of animals, diminazene was rapidly absorbed following intramuscular administration of 3.5 mg/kg b.wt. The peak plasma concentrations (Cmax) were 7.00 and 8.11 micrograms/ml and were attained at (Tmax) 0.92 and 1.12 hours in goats and sheep, respectively. The elimination half-life (t1/2el) of diminazene after intramuscular administration was shorter in goats (16.54 h) than in sheep (18.80 h). Systemic bioavailabilities (F%) of diminazene after intramuscular administration were 94.94% and 82.64% in goats and sheep, respectively. Diminazene could be detected in milk of goats and sheep within 10 min post-injection. Milk concentrations of the drug were lower in goats than in sheep and were detected for 5 and 6 days following both routes of administration, respectively.

Animals↗
PubMed1993

Comparative pharmacokinetics of diminazene in noninfected Boran (Bos indicus) cattle and Boran cattle infected with Trypanosoma congolense.

The pharmacokinetics of diminazene in five female Boran (Bos indicus) cattle before and then during acute and chronic phases of experimental infections with Trypanosoma congolense were investigated. A 7.0% (wt/vol) solution of diminazene aceturate (Berenil) was used in all three phases of the study and administered as a single intramuscular dose of 3.5 mg of diminazene base per kg of body weight. There were no significant differences between the values of pharmacokinetic parameters for the noninfected cattle and the values for cattle with a chronic T. congolense infection. However, the maximum concentration of the drug in plasma during the acute phase of infection (8.25 +/- 1.72 micrograms/ml) was significantly (P < 0.01) greater than that during chronic infection (5.04 +/- 0.26 micrograms/ml) and that in the noninfected state (4.76 +/- 0.76 micrograms/ml). Similarly, the time to maximum concentration of the drug in plasma when diminazene was administered during the acute phase of infection (18.00 +/- 6.71 min) was significantly (P < 0.02) shorter than that for noninfected cattle (36.00 +/- 8.22 min) and that during chronic infection (33.75 +/- 7.50 min). The volume of distribution at steady state during acute infection (1.01 +/- 0.31 liter/kg) was significantly (P < 0.01) smaller than that in the noninfected state (1.37 +/- 0.17 liter/kg) and that in chronic infection (1.51 +/- 0.24 liter/kg). Eight hours after the drug had been administered, the concentration-time data profiles for each of the three study phases were very similar. Mean concentrations of diminazene in plasma 48 h after administration of the drug were 0.43 +/- 0.07 microgram/ml in noninfected cattle, 0.43 +/- 0.11 microgram/ml during the acute phase of trypanosome infection, and 0.44 +/- 0.09 microgram/ml during the chronic phase of the infection. Results of the present study indicate that the area under the concentration-time curve for diminazene in trypanosome-infected cattle did not differ significantly for noninfected cattle. It, therefore, appears that the total amount of diminazene attained and maintained in the plasma of cattle is not significantly altered during infection with T. congolense.

Acute Disease↗
PubMed1987

Effect of tetracycline administration on the efficacy of diminazene aceturate therapy and prophylaxis in Trypanosoma brucei infections of mice.

The simultaneous administration, to Trypanosoma brucei infected mice, of rolitetracycline or oxytetracycline and diminazene aceturate appeared to have no effect on the initial trypanocidal action of the diminazene aceturate in that trypanosomes were cleared from the circulation. It also had no effect on the duration of the aparasitaemic period which follows diminazene aceturate treatment and the mice remained free of circulating trypanosomes for some time. However, if used prophylactically, relatively large amounts of tetracyclines (4 x 10 mg kg-1) administered with 40 mg kg-1 diminazene aceturate caused a reduction of the prophylactic period compared with those mice given only diminazene aceturate. This reduction in the prophylactic period is unlikely to have any practical significance in the combination diminazene aceturate/tetracycline treatment of domestic animals as diminazene aceturate is used therapeutically and not prophylactically in the control of trypanosomiasis.

Amidines↗
PubMed1991

In vivo and in vitro sensitivity of Trypanosoma evansi and T. equiperdum to diminazene, suramin, MelCy, quinapyramine and isometamidium.

The sensitivity of three Trypanosoma equiperdum clones and thirteen Trypanosoma evansi clones originating from the People's Republic of China, the Philippines, Ethiopia and elsewhere to a series of drugs was determined in vivo and in vitro. The drugs tested were diminazene aceturate (Berenil), suramin (Naganol), MelCy (Cymelarsan), quinapyramine sulfate (Trypacide) and isometamidium chloride (Samorin). The activity of each drug was expressed as: 1) in vitro: the minimal effective concentration which killed trypanosome population by 100% within 24 h of drug exposure (MEC100); the maximum tolerated concentration in which trypanosomes could propagate at the same rate as the controls during 48 h of drug exposure (MTC100); 2) in vivo: the curative dosage in 100% of infected mice (CD100); the highest ineffective dosage: 100% of infected mice remain infected (ID100). MEC100 values of diminazene aceturate ranged from 0.0556 microgram/ml to 14.24 micrograms/ml for the eleven tested clones (differed by 256-fold); CD100 values of this drug ranged from 2.25 mg/kg to greater than 89 mg/kg (differed by greater than 40-fold). Diminazene aceturate at up to 89 mg/kg had no effect on T. evansi SHBR, T. equiperdum PBR (Berenil resistant organisms selected by continual passage of the organisms through mice treated with increasing concentrations of drug), or T. evansi AH (strain isolated in the field). Comparable MEC100 values for other trypanocides tested were 1-8 micrograms/ml for suramin, 0.005-0.04 microgram/ml for MelCy, 1-16 micrograms/ml for quinapyramine sulfate and 1-4 micrograms/ml for isometamidium chloride. Clones selected for resistance to diminazene aceturate were not cross-resistant to suramin and isometamidium chloride. In contrast, the clones resistant to diminazene were shown to be more sensitive to quinapyramine sulfate than the normal strains in in vivo tests. The results indicate that resistance to diminazene aceturate by T. evansi and T. equiperdum clones in vivo also occurred in vitro. Resistance to isometamidium chloride in the clones tested in vivo was not observed in vitro, except for T. equiperdum SA. It therefore appears that drug bioavailability is altered or drug biotransformation occurs during the in vivo test. We conclude that the in vitro assay procedure may be of potential use for screening new trypanocides and also for the rapid detection of drug resistant isolates of T. evansi and T. equiperdum.

Animals↗
PubMed1995

The effects of hyperosmolar agents lithium chloride and sucrose on the brain concentration of diminazene aceturate in rats.

The concentrations of diminazene aceturate in the brain of Trypanosoma brucei brucei infected and uninfected rats treated with diminazene aceturate (3.1 mg/kg, im) and either LiCl (2.5, 5.0 and 10 micrograms/kg) or sucrose (0.25, 0.5 and 1.0 g/kg) were determined. When diminazene aceturate was administered at a standard dose of 3.1 mg/kg (im), the addition of LiCl (10 micrograms/kg, im) increased significantly (P < 0.05) the concentration of the drug in the brains of both trypanosome infected and normal infected rats. The addition of sucrose (1.0 g/kg, im) instead of LiCl failed to give any significant increase in diminazene aceturate levels in the brain. The diminazene aceturate levels were significantly (P < 0.05) higher in the organs (brain, kidney, liver and spleen) of trypanosome infected compared to uninfected rats. The concentration of diminazene aceturate in the organs increased significantly (P < 0.05) with increasing concentrations of LiCl.

Animals↗
PubMed2006

Confirmation of diminazene diaceturate in bovine plasma using electrospray liquid chromatography-mass spectrometry.

Diminazene diaceturate is used as a trypanocide for cattle in tropical regions. This paper describes a LC-MS(n) method to confirm the presence of diminazene in bovine plasma. Bound diminazene in plasma samples was freed with dilute phosphoric acid, then concentrated on a bonded C(18) SPE cartridge. The LC-MS(n) method utilized electrospray ionization coupled with an ion trap mass spectrometer. Ions observed in MS(2) and MS(3) product ion spectra, as well as those from the MS(1) spectrum, were monitored. The method was validated with plasma samples fortified with diminazene diaceturate (4-100ng/mL). Diminazene was confirmed in samples fortified with diminazene diaceturate at levels of 6.4ng/mL or higher.

Animals↗
PubMed1997

Susceptibility of Ugandan Trypanosoma brucei rhodesiense isolated from man and animal reservoirs to diminazene, isometamidium and melarsoprol.

Thirty-six Trypanosoma brucei spp. stocks isolated from man and domestic animals in south-east Uganda were studied for susceptibility to diminazene, isometamidium and melarsoprol in vitro. All stocks were susceptible to melarsoprol. One T.b. rhodesiense stock isolated from a sleeping sickness patient showed reduced susceptibility to the veterinary drugs diminazene and isometamidium. More than 100 ng/ml diminazene or 0.78 ng/ml isometamidium were required to eliminate that stock during 10 days drug exposure. In contrast, the remaining stocks were eliminated by 0.8-6.3 ng/ml diminazene and 0.01-0.20 ng/ml isometamidium. Clones derived from the resistant T. b. rhodesiense stock showed reduced susceptibility to isometamidium and diminazene comparable to the parental population. Control of sleeping sickness by treatment of the animal reservoir could, therefore, face serious problems since drug-resistant stocks as reported here would most likely not be eliminated by recommended doses of diminazene and isometamidium.

Animals↗