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PubMed2002

Drug sensitivity of trypanosome populations from cattle in a peri-urban dairy production system in Uganda.

Cattle from 50 farms in Mukono County, Uganda, were monitored for trypanosomes every second month over an 18-month period (1995-1996) by mini-anion exchange chromatography and haematocrit centrifugation techniques. Eighteen trypanosome isolates collected from cattle during this period were characterised in cattle, goats and mice for their sensitivity to homidium, isometamidium and diminazene; 10 of the isolates were selected randomly, 8 were from animals that had the highest serum isometamidium concentrations at the time the isolates were collected. All the isolates contained only Trypanosoma brucei and/or T. vivax. In nai;ve Boran (Bos indicus) cattle the isolates exhibited low pathogenicity and were sensitive to diminazene aceturate at 3.5 mg/kg body weight (bw) and isometamidium chloride at 0.5 mg/kg bw. In goats, 5 of 8 isolates were highly pathogenic, producing clinical signs indicative of central nervous system involvement within 60 days of infection; all such isolates contained T. brucei. However, all 8 populations were sensitive in goats to diminazene aceturate at 3.5 mg/kg bw. In contrast, 4 populations were refractory to treatment with isometamidium chloride at 0.5 mg/kg bw in at least 1 out of 3 goats each. Furthermore, 5 populations were refractory to treatment with homidium chloride at 1.0 mg/kg bw in a minimum of 2 out of 3 goats each. In mice, the 50% curative dose values for 11 Mukono isolates that contained T. brucei ranged from 0.30 to 1.89 mg/kg bw for diminazene aceturate, from 0.02 to 0.17 mg/kg bw for isometamidium chloride and from 0.90 to 4.57 mg/kg bw for homidium chloride. Thus, by comparison to reference drug-sensitive populations, all the stabilates were highly sensitive to diminazene and isometamidium, while some expressed low levels of resistance to homidium.

Animals↗
PubMed2006

Drug-resistance of Trypanosoma b. rhodesiense isolates from Tanzania.

OBJECTIVE: To determine the drug resistance of Trypanosoma brucei rhodesiense strains isolated from sleeping sickness patients in Tanzania. METHOD: We first screened 35 T. b. rhodesiense strains in the mouse model, for sensitivity to melarsoprol (1.8, 3.6 and 7.2 mg/kg), diminazene aceturate (3.5, 7 and 14 mg/kg), suramin (5, 10 and 20 mg/kg) and isometamidium (0.1, 1.0 and 2 mg/kg). A 13 isolates suspected to be resistant were selected for further testing in vitro and in vivo. From the in vitro testing, IC(50) values were determined by short-term viability assay, and MIC values were calculated by long-term viability assay. For in vivo testing, doses higher than those in the initial screening test were used. RESULTS: Two T. b rhodesiense stocks expressed resistance in vivo to melarsoprol at 5 mg/kg and at 10 mg/kg. These strains had high IC(50) and MIC values consistent with those of the melarsoprol-resistant reference strain. Another isolate relapsed after treatment with 5 mg/kg of melarsoprol although it did not appear resistant in vitro. One isolate was resistant to diminazene at 14 mg/kg and another was resistant at both 14 and 28 mg/kg of diminazene. These two isolates had high IC(50) values consistent with the diminazene-resistant reference strain. Two isolates relapsed at a dose of 5 mg/kg of suramin, although no isolate appeared resistant in the in vitro tests. Two isolates were resistant to isometamidium at 1.0 mg/kg and had higher IC(50) values. Two isolates were cross-resistant to melarsoprol and diminazene and one isolate was cross-resistant to suramin and isometamidium. CONCLUSION: The reduced susceptibility of T. b. rhodesiense isolates to these drugs strongly indicates that drug resistance may be emerging in north-western Tanzania.

Animals↗
PubMed1997

Concentrations of isometamidium chloride (Samorin) in sera of Zebu cattle which showed evidence of hepatotoxicity following frequent trypanocidal treatments.

The concentrations of isometamidium circulating in poorly nourished Zebu cattle which showed morbidity, mortality, and biochemical and histopathological evidence of hepatotoxicity, following frequent treatments with isometamidium chloride and diminazene aceturate were investigated using the isometamidium-ELISA. As few as two isometamidium treatments one month apart were associated with significant weight loss, and cattle treated with diminazene aceturate after three or four isometamidium treatments suffered a 50% mortality. Although there were no obvious, marked elevations in isometamidium concentration which might have allowed the use of the ELISA as a predictor of a potential toxicity problem, concentrations did increase significantly with the number of monthly treatments administered, suggesting drug accumulation, and the increases were significantly higher in cattle to which diminazene had also been administered. In cattle treated with both trypanocides, weight loss and serum glutamate dehydrogenase levels were correlated with isometamidium concentrations. These observations, together with the histopathological findings, support the hypothesis that the morbidity and mortality observed were related to the repeated treatment with isometamidium in conjunction with diminazene aceturate, and that the pathogenesis involved a component of hepatic damage. It is therefore recommended that cattle, particularly those under nutritional stress, are not subjected to repeated treatments with isometamidium at intervals as short as one month, and particularly not with concurrent administration of diminazene.

Animals↗
PubMed2003

Field studies of drug-resistant cattle trypanosomes in Kénédougou Province, Burkina Faso.

Field studies were conducted to assess the occurrence of resistance to isometamidium chloride and diminazene aceturate in trypanosomes infecting cattle in Kénédougou Province of Burkina Faso. Forty-five of the 166 villages in Kénédougou were randomly sampled and visited to assess livestock numbers, trypanosomosis risk, and tsetse challenge. The proportion of cattle infections associated with drug-resistant trypanosomes was assessed in the nine villages with the highest trypanosome infection prevalence and one village with a confirmed history of drug-resistant infections. These studies showed that resistance to both isometamidium and diminazene was widespread. However, there was considerable variation between villages in drug-resistance parameters, with the proportion of treated cattle with trypanosome infections 3 months after isometamidium prophylaxis varying from 6.9 to 63.8% and the proportion of cattle having infections 2 weeks after treatment with diminazene varying from 0 to 36.8%. The demonstration of widespread resistance to both isometamidium and diminazene has important implications, as administration of trypanocides is the most commonly employed method to control trypanosomosis in this area.

Animals↗
PubMed2000

Hydrogen bonding and electrostatic interaction contributions to the interaction of a cationic drug with polyaspartic acid.

PURPOSE: To determine the mechanism and identify forces of interaction between polyaspartic acid and diminazene (a model drug). Such knowledge is essential for the design of polymeric drug delivery systems that are based on molecular self-assembly into complexes or micellar type systems. METHODS: Complex formation was studied by isothermal titration microcalorimetry and the McGhee von Hippel model was applied to obtain K(obs), deltaH(obs), and n(obs). The calorimetry data were compared with both an optical density study and the amount of free/complexed drug. RESULTS: The diminazene-polyaspartic acid interaction is enthalpically driven, whereby one diminazene molecule interacts with two monomers of polyaspartic acid. The dependence of K(obs) on salt concentration reveals a contribution of electrostatic interactions. However, applying Manning's counter ion condensation theory shows that the major driving force for the complex formation is hydrogen bonding, with interfacial water molecules remaining buried within the complex. The modelling of the pH dependence of K(obs) and deltaH(obs) demonstrates that the ionization of carboxylic groups of polyaspartic acid is a prerequisite for the interaction. CONCLUSIONS: Complex formation between diminazene and polyaspartic acid is driven by both electrostatic interactions and hydrogen bonding, with the latter being the dominating force. Although electrostatic interactions are not the major driving force, ionization of the drug and polymer is essential for complex formation.

Cations↗
PubMed1976

Trypanocidal effect of diamidine 98/202 in experimental Trypanosoma rhodesiense infection of the stumptailed macaque (Macaca arctoides).

The trypanocidal effect of preparation 98/202, a 6-Amidino-2-(4'-amidinophenyl)-thionaphthene dilactate, was investigated in 4 stumptailed macaques (Macaca arctoides) infected with Trypanosoma rhodesiense (strain: Hamburg, 1962), of which 2 animals had been treated previously with diminazene and pentamidine, respectively. The curative treatment with preparation 98/202 was carried out in all cases in the late stage of infection; at the beginning of treatment 3 of the 4 animals had already shown malaise with distinct affection of the central nervous system. The individual dose was 5 mg/kg (base) and was given by deep intramuscular injection on 2, 3 or 4 consecutive days. During the trial period elimination of the parasites from the blood was observed in all monkeys, and in 3 out of 4 animals also in the liquor cerebrospinalis. In one animal a parasitological cure could be demonstrated. Two animals died as a result of the very advanced infection, one animal had to be killed prematurely because of numerous deep skin necroses without healing tendency. In 2 animals previously treated with diminazene and pentamidine, respectively, the T. rhodesiense strain developed a distinct resistance to pentamidine, diminazene and preparation 98/202. The resistance induced with pentamidine against diminazene and preparation 98/202, however, was only transitory and disappeared after withdrawal of the preparation. A brief description of the course of infection is given and possible sites of action of preparation 98/202 are discussed.

Amidines↗
PubMed1995

Sensitivity of animal-derived Trypanozoon stocks from sleeping sickness endemic foci of Nigeria to trypanocides and human plasma.

Twelve Trypanozoon stocks isolated from semi-nomadic cattle in known sleeping sickness foci of central and northern Nigeria were studied in terms of susceptibility to two trypanocides, diminazene aceturate (Berenil) and isometamidium chloride (Samorin) and human plasma. In infected small ruminants, three of the stocks were resistant to diminazene aceturate at does of 7.0 -14.0 mg/kg body weight (b.w.) while isometamidium chloride at doses of 1.0 mg/kg b.w. or higher failed to effect parasitological cure of infections with two of the diminazene-resistant stocks. The two isometamidium-resistant stocks were also consistently resistant to the trypanolytic action of human plasma. It is suggested that cattle are reservoirs of Trypanosoma brucei subspecies potentially infective to man and resistant to the therapeutic action of the known sanative pair (diminazene and isometamidium).

Animals↗
PubMed1992

Development of multiple drug resistance of Trypanosoma congolense in Zebu cattle under high natural tsetse fly challenge in the pastoral zone of Samorogouan, Burkina Faso.

Preliminary data from an ongoing epidemiological survey in the pastoral zone of Samorogouan (Kénédougou) indicate the occurrence of multiple-drug-resistant Trypanosoma congolense. Despite frequent trypanocidal drug treatments with diminazene aceturate (Berenil, Hoechst) at 7 mg/kg body weight (bw) at intervals of 2 to 4 weeks, no significant drop in the prevalence of African animal trypanosomosis (AAT) was observed. To examine a suspected drug resistance, 20 Zebu cattle, naturally infected with T. congolense and/or T. vivax, were transferred in December 1989 from Samorogouan into a fly-proof stable. Diminazene aceturate at 7 mg/kg bw cured infections of T. vivax, but was ineffective against T. congolense. Likewise, treatments with homidium bromide (Ethidium, FBC) at 1 mg/kg bw and isometamidium chloride (Trypamidium, Rhône Mérieux) at 1 mg/kg bw, respectively, proved to be ineffective. Corresponding chemotherapeutic trials in previously unexposed Zebu bulls and Sahelian goats infected with one primary T. congolense isolate from Samorogouan demonstrated a high level of resistance to diminazene aceturate (7 mg/kg bw in cattle and 17.5 mg/kg bw in goats), isometamidium chloride (1 and 2 mg/kg bw i.v. in goats) and quinapyramine sulphate (Trypacide'S', Rhône Mérieux) at 5 mg/kg bw in goats. The appearance of a multiple-drug-resistant strain of T. congolense emphasizes the urgent need for new chemical substances as trypanocidal drugs and the increasing importance of efficient vector control.

Animals↗
PubMedDate not supplied

Treatment of experimental trypanosomiasis in pigs.

The therapeutic activity of difluoromethylornithine (DFMO), diminazene aceturate (Berenil) and their combination against chronic trypanosomiasis was investigated in experimental Trypanosoma brucei brucei infections of growing pigs. DFMO (300 mg/kg/day orally for 10 days), diminazene aceturate (7 mg/kg in single intramuscular injection) and a combination of the two agents at the above dosages produced varied periods of aparasitaemia in the treated pigs. Relapse parasitaemia occurred in all treatment groups, with diminazene aceturate providing the longest relief period of 17 days, combination treatment 11 days and DFMO 6 days. The packed cell volume, blood haemoglobin concentration and red cell count values decreased after the pigs were infected with the parasites. The values improved following treatment with the agents and their combination.

Animals↗
PubMed1994

Drug sensitivity of Chinese Trypanosoma evansi and Trypanosoma equiperdum isolates.

The drug sensitivities of eleven Trypanosoma evansi isolates from China were examined using two different in vitro assays, a 3H-hypoxanthine incorporation assay and a long incubation low inoculation test (LILIT). Better discrimination of the drug susceptibility of the strains was observed with the LILIT. The drug responses of all the isolates to the arsenical melarsoprol were very similar. In contrast, for suramin, minimal inhibitory concentrations (MIC) varied within a 27-fold range and for diminazene within a 55-fold range. Comparison of MIC values with expected drug levels in the host as well as in vivo experiments with selected isolates and drugs indicated that all the isolates examined would be sensitive to melarsoprol, diminazene and suramin under in vivo conditions. For isometamidium, the difference in MIC values between the most and the least sensitive isolate was 724-fold. Neither of two isolates tested in mice--the most resistant and the second most sensitive--was cured with the highest acceptable dose of 10 mg kg-1 isometamidium chloride. Comparison of our results with blood levels of drug to be expected in cattle support the assumption that the Chinese T. evansi isolates have more or less innate resistance to isometamidium under in vivo conditions. One Trypanosoma equiperdum isolate was tested in the 3H-hypoxanthine incorporation assay. The results indicated that this isolate was highly sensitive to melarsoprol, isometamidium and suramin; with regard to diminazene, T. equiperdum was not as sensitive as the most sensitive T. evansi strains.

Animals↗
PubMed2000

An analysis of trypanocidal drug use in the Eastern Province of Zambia.

As part of the development of a strategy for the control of bovine trypanosomosis in Zambia, a survey was conducted to quantify and qualify the current use of trypanocidal drugs (diminazene aceturate and isometamidium chloride) in a tsetse-controlled and a tsetse-infested area of the Eastern Province. A total of 207 trypanocide users were interviewed. Questions were posed on herd structure, trypanocidal drug preference, treatment strategy, reason for treatment, method of treatment and treatment frequency. The majority of the cattle owners preferred to use diminazene aceturate rather than isometamidium chloride. Both trypanocides were mainly used to treat clinically sick animals (not necessarily infected with trypanosomes) and preference was given to the treatment of oxen and cows. The proportion of animals treated and the frequency of drug application did not differ between the two areas. Hence, in the tsetse-controlled area, a high proportion of the trypanocide treatments was inappropriate. In the tsetse-infested area, on the other hand, the treatment of clinically sick animals significantly reduced the trypanosomosis-related mortality but was insufficient to boost reproduction in cows. Despite the fact that the cattle owners administered most trypanocides themselves, evidence from the survey suggests that most of the farmers did not under-dose with either diminazene aceturate or isometamidium chloride. Moreover, other factors enhancing the development of resistance to trypanocides in trypanosomes were not present in the areas surveyed. Conclusions are drawn on the usefulness of this type of survey in determining appropriate methods to control bovine trypanosomosis.

Age Factors↗
PubMed2000

Multiple-drug resistant Trypanosoma congolense populations in village cattle of Metekel district, north-west Ethiopia.

Investigations were carried out to determine the prophylactic activity of isometamidium chloride in village populations of cattle naturally infected with trypanosomes in Metekel district, northwest Ethiopia. In a cross-sectional study in March 1997, 484 randomly selected cattle from four villages were examined for trypanosome infections by the dark ground/phase contrast buffy coat technique (BCT). The trypanosome prevalence was 17.2%. Trypanosoma congolense was the dominant species accounting for 47.6% of the overall infections. Fifty parasitaemic cattle from two villages were treated with isometainidium chloride (Trypamidium(R)) at a prophylactic dose of 1.0 mg/kg body weight (b.w.) and thereafter monitored on a monthly basis for parasitaemia. Trypanosomes were detected in six cattle within 1 month and in 18 cattle within 2 months of treatment. Twenty three percent (6/26) of cattle infected with T. congolense at the time of treatment were detected parasitaemic with this trypanosome species 1 month after treatment. Mice were infected with three T. congolense isolates obtained from cattle which were detected parasitaemic within one or 2 months after isometamidium treatment. The mice were subsequently treated with ranges of doses of isometamidium chloride or diminazene aceturate (Berenil(R)) and thereafter monitored for parasitaemia for a period of 60 days. Isometamidium chloride at doses of 0.5-4.0 mg/kg b.w. and diminazene aceturate at doses of 3.5-28.0 mg/kg b.w. failed to cure T. congolense infections in any of the animals. Three clones were derived from one of the isolates; each clone expressed high levels of resistance to both trypanocides when tested in mice. Based on these results it is concluded that the prophylactic activity of isometamidium is greatly reduced for some of the T. congolense populations present in the area, and in addition there is resistance to diminazene aceturate in this trypanosome species.

Animals↗
PubMed1998

Response of a T. b. rhodesiense stock with reduced drug susceptibility in vitro to treatment in mice and cattle.

In vivo drug susceptibility tests involving treatment of infected mice and cattle were performed on two trypanosome stocks, a T. brucei brucei and a T.b. rhodesiense, isolated in South Eastern Uganda. The T. b. rhodesiense stock had expressed reduced susceptibility to diminazene aceturate and isometamidium chloride in vitro, while the other, a T. b. brucei stock was susceptible. Diminazene aceturate at 14 mg/kg was not sufficient to cure all T. b. rhodesiense infected mice. Similarly, in the case of isometamidium chloride, 33% of infected mice treated with 2.0 mg/kg drug were not cured. In contrast, mice infected with the susceptible T. b. brucei and treated similarly with either drug were all cured. However, when cattle infected with the T. b. rhodesiense stock, or the susceptible T. b. brucei stock, or a 1:1 mixture of the two were treated with 7 mg/kg diminazene aceturate, they were all cured. Use of diagnostic PCR employing T. brucei specific primers confirmed that although the cattle had acquired infection pre-treatment, no trypanosome DNA amplification signal was demonstrated in the samples collected 60 days post-treatment. The reduced susceptibility of this T. b. rhodesiense, which could be demonstrated in mice as well as in culture, may indicate the existing potential for evolution of resistance in South Eastern Uganda.

Animals↗
PubMed1988

Efficacy of DL-alpha-difluoromethylornithine in a rat model of Pneumocystis carinii pneumonia.

Pneumocystis carinii pneumonia is often the terminal event for patients with the acquired immunodeficiency syndrome. Eflornithine (DL-alpha-difluoromethylornithine [DFMO]; Ornidyl; Merrell Dow Research Institute, Cincinnati, Ohio) has been used successfully against this protozoan disease in limited clinical trials, although not all patients respond to therapy. In contrast, results of the only reported experiments with DFMO in an animal model were negative. We retested DFMO against P. carinii in an immunosuppressed rat model by inclusion of 3% DFMO in the drinking water, a dose rate about twice that used previously. A combination of trimethoprim and sulfamethoxazole, a proven anti-P. carinii agent, was used as a positive control. After 3 weeks of anti-P. carinii pneumonia therapy, the surviving rats were sacrificed and the degree of parasitosis was judged by examination of lung sections stained with silver methenamine to reveal cysts. In three separate experiments, DFMO showed definite anti-P. carinii pneumonia activity; the parasitosis of DFMO-treated animals was significantly less than that of control animals (P less than 0.001 for all experiments). DFMO was not as active as trimethoprim-sulfamethoxazole, however. Several other experimental therapies were tested, including dapsone and two additional antiprotozoal agents: suramin and diminazene aceturate (Berenil; Farbwerke Hoechst, Frankfurt, Federal Republic of Germany). Diminazene aceturate, a veterinary drug related to the standard anti-P. carinii pneumonia agent pentamidine, was very active (P less than 10(-10]. Suramin and dapsone were weakly active. The combinations suramin-diminazene aceturate and suramin-DFMO were tested, but they were antagonistic rather than synergistic.

Amphotericin B↗
PubMed2004

Trypanocidal drug resistance in eastern province of Zambia.

A survey to investigate resistance to drugs used in the treatment of bovine trypanosomosis was conducted in the eastern province of Zambia between 1996 and 1998. A cross-sectional study was conducted in three districts (Petauke, Katete, Lundazi) at 34 village sampling sites selected at random from villages that had shown greater than 6% prevalence of bovine trypanosomosis during an earlier survey. A longitudinal study was conducted in same three districts over a 1-year period. The study sites were chosen from the cross-sectional study and included eight sites showing high trypanosomosis prevalence and where no control activities were recorded. Use was made of parasitological methods, tests of resistance in cattle and mice and isometamidium-ELISA. Overall mean prevalence of trypanosomosis was 14.4, with 96% of infections caused by Trypanosoma congolense. The remainder was caused by Trypanosoma vivax (2%) and Trypanosoma brucei (2%). Tests in mice showed that of the stabilates collected, 24 (34%) were resistant to only isometamidium chloride, 8 (11.3%) were resistant to only diminazene aceturate, 1 (1.4%) was resistant to both drugs, and 38 (53.5%) were sensitive to both drugs. At least 2 out of 27 stabilates tested in cattle appeared to be resistant to trypanocidal drugs, 1 to isometamidium and 1 to diminazene. Isometamidium could be detected in only 63 (4.1%) of 1526 serum samples from cattle in the study. Only 6 (2.8%) of 212 serum samples from trypanosome-infected cattle had serum levels of the drug above 0.4 ng isometamidium per ml serum which is indicative for drug resistance in the infecting parasite population. Although some drug resistance is apparent, diminazene aceturate and isometamidium chloride can still be expected to be effective as a sanative pair in this area in most cases, since not more than 1 stabilate of 71 investigated showed evidence of resistance to both drugs.

Animals↗
PubMed2001

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.

Drug Delivery Systems↗
PubMed1988

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia.

Cationic compounds used in the treatment of veterinary African trypanosomiasis have structural properties similar to those of pentamidine, which has been used in the therapy of human trypanosomiasis and infection with Pneumocystis carinii. We have compared the activities of these drugs and other antimicrobial agents in an immunosuppressed rat model of P. carinii pneumonia. Diminazene, imidocarb, amicarbalide, quinapyramine, and isometamidium showed efficacy greater than or equal to that of pentamidine in the therapy of P. carinii infection, whereas ethidium and methylglyoxal bis(guanylhydrazone) were only slightly active against the organism. Diminazene and pentamidine also exhibited comparable efficacy in P. carinii prophylaxis, alpha-Difluoromethylornithine (DFMO), a polyamine inhibitor, was ineffective therapy when used alone and did not improve the effectiveness of pentamidine or diminazene. Quinine, quinidine, quinacrine, chlorpromazine, spiramycin, Pentostam, Astiban, dehydroemetine, ampicillin, gentamicin, chloramphenicol, and spectinomycin also showed little or no activity against the organism. Thus, in this model anti-P. carinii activity appears to be a common property of veterinary cationic trypanocidal compounds. This should be important in studying structure-activity relationships and in developing new drugs for the treatment of P. carinii infection in humans.

Amidines↗
PubMed1993

Derivation and characterization of a quinapyramine-resistant clone of Trypanosoma congolense.

Over a period of 208 days a quinapyramine-resistant population was derived in vivo from a quinapyramine-susceptible clone of Trypanosoma congolense: IL 1180. While the dose of quinapyramine sulfate required to cure 50% of mice infected with the parental clone was 0.23 mg/kg of body weight, the 50% curative dose for the resistant derivative, IL 1180/Stabilate 12, was greater than 9.6 mg/kg. This approximately 40-fold increase in resistance to quinapyramine was shown to be associated with an 8-fold increase in resistance to isometamidium, a 28-fold increase in resistance to homidium, and a 5.5-fold increase in resistance to diminazene. Cross-resistance to homidium and diminazene was also demonstrated in goats. Two clones derived from the drug-resistant derivative underwent cyclical development in Glossina morsitans centralis, producing mature infection rates of 39.6 and 23.9%. Thus, induction of resistance to quinapyramine in T. congolense IL 1180 was associated with cross-resistance to isometamidium, homidium, and diminazene and did not compromise the population's ability to undergo full cyclical development in tsetse flies.

Animals↗