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PubMed1990

Trypanosoma congolense: an in vitro assay to distinguish drug-resistant from drug-sensitive populations.

An in vitro assay to distinguish drug-resistant from drug-sensitive populations of Trypanosoma congolense has been developed. The incorporation of radiolabelled hypoxanthine by procyclic trypanosomes in vitro was measured after 48 h exposure to different concentrations of trypanocides. In the presence of either isometamidium chloride (Samorin) or diminazene aceturate (Berenil), the ability of procyclics of a drug-sensitive stock (TREU 1627) to incorporate hypoxanthine at 28 degrees C was impaired to a much greater extent than that of procyclics of a drug-resistant stock (TREU 1467), when compared with control organisms grown in the absence of drugs. Serum from a rabbit given 1 mg/kg Samorin also inhibited incorporation of radiolabel in TREU 1627 procyclics more severely than in TREU 1467 procyclics, although the difference between stocks was not substantial. When used with cultured blood-stream forms maintained at 35 degrees C, the assay could distinguish the stocks in the presence of Samorin, but no difference was detected between the populations in their incorporation of hypoxanthine after exposure to Berenil.

Amidines↗
PubMed1992

Trypanosoma congolense: the in vitro akinetoplastic induction sensitivity assay.

Incubation of Trypanosoma congolense in diminazene aceturate (Berenil) or isometamidium chloride (Samorin) induced akinetoplastic (AK) forms in vitro. The AK values (expressed in percent) obtained were found to be useful for rapid assessment of relative drug sensitivities. In susceptible clones, AK forms were induced at all drug concentrations tested, whereas in resistant clones they were induced only at higher concentrations. The Berenil-resistant clone exhibited AK values of 0.9% +/- 0.6%--8.9 +/- 2% at concentrations of 1-100 micrograms/ml at 4-10 h post-inoculation (p.i.), whereas the Berenil-susceptible clone displayed values of 9.3% +/- 13%--19.2% +/- 5% at 0.1-50 micrograms/ml. Motile trypanosomes were not seen at 100 micrograms/ml at 4 h p.i. or at 10 or 50 micrograms/ml at 10 h p.i. The Samorin-resistant clone showed AK values of 0.5% +/- 0.1%--43% +/- 3% at concentrations of 0.1-100 micrograms/ml at 4 and 10 h p.i., whereas the Samorin-susceptible clone exhibited values of 5.3% +/- 2%--45% +/- 4% at 0.0005-100 micrograms/ml. These results were supported by the findings obtained using a mouse infectivity test.

Animals↗
PubMed1989

Bovine trypanosomiasis in southern Tanzania: investigation into the incidence of infection and duration of chemoprophylaxis.

Before implementing chemoprophylaxis to control bovine trypanosomiasis it is essential to have epidemiological data upon which to base control regimes. A study was conducted under natural tsetse challenge with two groups each of 12 calves grazing their first season. Group 1 received isometamidium treatments prophylactically at intervals during the rainy season and calves in group 2 were treated individually with diminazene as they become infected with trypanosomes. Infections were first detected in the unprotected calves and indicated that the onset of challenge was approximately four weeks after the rainy season began. Trypanosoma vivax accounted for 21 of the 30 infections detected in blood smears, and although one infection remained unspeciated, the remaining eight were T. congolense. It was concluded that a prophylactic regime beginning one month after the start of the rains with repeat treatments of isometamidium at 1 mg/kg at intervals of 10 weeks could be expected to give good control of trypanosomiasis at this location.

Age Factors↗
PubMed1984

Maintaining zebu Maure cattle in a tsetse infested area of Mali.

A study was initiated to evaluate two trypanocidal drugs, the prophylactic isometamidium chloride (Trypamidium) and the curative diminazene aceturate (Berenil) as to their potential for long-term maintenance of zebu cattle in a tsetse infested area of Mali. Trypamidium was administered quarterly and Berenil was administered only as animals were found to be positive for trypanosomes. During the 21-month study trypanosomiasis was the most frequently encountered disease in the cattle in the Berenil treatment group with an average of 5.5 reinfections. The predominant trypanosome species encountered was Trypanosoma vivax and the most important vector was Glossina palpalis gambiensis. The results indicate that, even though the direct costs for drugs under the two maintenance regimens were almost identical, the use of Trypamidium resulted in a significantly greater annual weight gain, prevented death loss due to trypanosomiasis and resulted in a herd with a greater market value.

Animals↗
PubMed1997

Susceptibility of three breeds of Ugandan goats to experimental infection with Trypanosoma congolense.

This study has indicated that differences in susceptibility to Trypanosoma congolense infection exist among the 3 main breeds of goats in Uganda namely, Kigezi, Mubende and Small East African (SEA). The Kigezi goats appeared to be the most susceptible suffering more severe anaemia, greater retardation of growth and more deaths than the other 2 breeds following experimental infection with Try-panosoma congolense. The Small East African goats appeared to be least susceptible. Following treatment after 84 days of infection, the SEA goats responded much better than the other 2 breeds. By 4 weeks after treatment with diminazene aceturate, the packed red cell volumes of the treated SEA goats were similar to those of control SEA goats while those of the Mubende and Kigezi goats were still much lower than those of control animals.

Anemia↗
PubMed1990

Homidium bromide as a chemoprophylactic for cattle trypanosomiasis in Kenya.

Homidium bromide was used in a strategic chemoprophylactic regime to control trypanosomiasis in Boran cattle in Kenya. Trypanosome infection rates in cattle receiving homidium bromide prophylaxis were compared with those in control cattle which received no prophylaxis but were treated with diminazene aceturate when infected. Homidium bromide was administered twice during the year after which no infections were detected for periods of nineteen weeks and seventeen weeks respectively. The drug sensitivity of the infecting trypanosomes is believed to be a major factor in determining the duration of prophylaxis.

Animals↗
PubMed1990

Trypanosoma brucei evansi: dyskinetoplasia and loss of infectivity after long-term in vitro cultivation.

Bloodstream forms of a stock of Trypanosoma brucei evansi were propagated in vitro for more than 14 months. After that period, all organisms were dyskinetoplastic and had lost their infectivity for mice. An increase in diminazene aceturate resistance in vitro was observed whereas the susceptibility to isometamidium chloride, quinapyramine sulphate and suramin was unaltered. Trypanosomes derived from the long term culture had a surface coat.

Animals↗
PubMed1991

Cymelarsan in the treatment of buffaloes naturally infected with Trypanosoma evansi in south China.

Forty buffaloes naturally infected with Trypanosoma evansi in the South of China were treated with a single dose of a new arsenical. Cymelarsan (Mel Cy) at 0.25 mg/kg to 3.0 mg/kg by intramuscular injection. All animals were cured, with the exception of two out of four animals treated with 0.25 mg/kg Mel Cy which relapsed two months after drug administration. Two out of eight buffaloes in control groups treated with a single dose of diminazene aceturate (Berenil), 3.5 mg/kg, relapsed two months after treatment. All cured animals showed no trypanosomes in their blood when tested within one to three years after administration. A scleroma about 2 to 3.5 cm in diameter was found at the site of injection at the dose of 1.5 mg/kg Mel Cy in three of eight animals. At a dose of 3 mg/kg, Mel Cy induced obvious necrosis of the tissue at the site of injection. The results of field application proved that Mel Cy is a very active trypanocidal drug against T. evansi.

Animals↗
PubMed1993

Pharmacology of existing drugs for animal trypanosomiasis.

Lack of much interest by the pharmaceutical industry to venture into development of new antitrypanosomal drugs has been a major stimulus to an intensification of research into the few existing drugs. Those indicated for animal trypanosomiasis include: isometamidium, homidium and diminazene, used primarily against Trypanosoma congolense, T. vivax and T. brucei; and quinapyramine, mainly indicated for use against T. evansi infections. A great deal of research effort has focused on development of pharmacological and parasitological methodologies, which have considerably advanced our understanding on the efficacy, resistance, disposition and toxicological mechanisms of these drugs. While a clinical breakthrough has been made in the recent past, in the field of chemotherapy of T. evansi infections by the introduction of a new arsenic compound, melarsenoxide cysteamine, chemotherapy of T. simiae infections in pigs still remains a major challenge because the existing drugs are either ineffective or too toxic for economic use. Further research into the existing drugs is a prerequisite for their optimal usage in the overall effort of improving animal health and productivity through control of trypanosomiasis.

Animals↗
PubMed1993

Trypanosoma simiae: in vitro studies on drug susceptibility.

Two Trypanosoma simiae stocks were initiated in culture with tsetse-derived metacyclics. They were propagated axenically as trypomastigote forms at 35 degrees C in 4% CO2 in air. Populations of trypanosomes were incubated with various concentrations of antitrypanosomal compounds. Growth was monitored after 24 h of incubation and the growth inhibition was calculated. Diminazene aceturate, quinapyramine sulphate, DL-alpha-difluoromethylornithine, and Ro 15-0216 showed activity against the stocks. Suramin and Mel Cy showed little effect upon the growth of the parasite populations. Isometamidium chloride gave questionable results in the 24 h growth inhibition test, but the results of a long-term viability assay indicated some degree of drug resistance (or drug tolerance). The results obtained herein correlate with observations obtained from in vivo studies in pigs. It is thus concluded that in many cases the cryptic nature of T. simiae rather than drug resistance is responsible for the failure of chemotherapy of simiae-trypanosomiasis in pigs.

Animals↗
PubMed1992

In vivo assessment of drug sensitivity of African trypanosomes using the akinetoplastic induction test.

Following treatment of mice infected with Trypanosoma congolense or T brucei brucei with various doses of isometamidium chloride or diminazene aceturate, the induction of akinetoplastic (AK) forms was observed in the trypomastigotes of both species within 10 hours of drug administration. The levels of AK-induction were closely correlated with the levels of resistance to each compound found using a standard in vivo drug assay in mice. In general, ineffective doses of either compound conferred AK-induction rates of less than 30 per cent; relapsing cases had between 30 and 50 per cent while curative doses had AK-induction rates of 50 per cent or more. In vivo determination of AK-induction rates using ordinary light microscopy is thus a potentially feasible alternative indicator to the conventional use of mice infection and treatment methods for assessing drug sensitivity in African trypanosomes.

Animals↗
PubMed1984

Arsenic and old taxa: subspeciation and drug sensitivity in Trypanosoma brucei.

Resistance to the trypanocidal drugs atoxyl and tryparsamide was traditionally considered to be a diagnostic feature of rhodesian sleeping sickness and, consequently, of Trypanosoma rhodesiense. In examining the tryparsamide sensitivity of 13 isoenzymically defined stocks of the subgenus Trypanozoon, typical West African stocks showed no greater drug sensitivity than did those of East and Central Africa. The greatest resistance to tryparsamide was shown by two stocks isolated in the Ivory Coast. There was no evidence of strain differences in drug sensitivity to melarsoprol (Mel B) among 26 tested populations; none the less, differential melarsoprol sensitivity was evident in clones from a single mixed population. By contrast, isoenzymically defined West African stocks appeared to be less sensitive to pentamidine and diminazene aceturate (Berenil) than were typical East African stocks. Drug sensitivity was measured in a novel in vivo test designed to minimize the influence of host-parasite interactions, in particular trypanosome penetration of drug-inaccessible sites and host-antibody induced remission of parasitaemia. Drug effect was expressed as the DS0.1, the dose required to suppress parasitaemia to 0.1% of that in untreated control mice.

Animals↗
PubMed1987

Development of Trypanosoma brucei in suckling mouse brain following intracerebral injection.

Intracerebral inoculation of Trypanosoma b. brucei and T. b. rhodesiense into suckling mice produced infection of brain tissue which subsequently gave rise to an infection of the blood and other tissues, in which a normal histopathological picture was observed. Treatment of other intracerebrally infected sucklings with 5 mg/kg diminazene aceturate (Berenil) to clear the infection from the blood permitted a study of the course of the infection in the brain without interference from pathological processes induced by bloodstream infections. There was rapid multiplication and migration of trypanosomes throughout the brain of mice. Pathological processes normally seen in experimental central nervous system infections were absent, except in a single mouse treated earlier with Berenil which developed meningo-encephalitis with trypanosomes present in the choroid plexus. The possible use of such a model system in chemotherapeutic studies is discussed.

Animals↗
PubMed1992

Subcurative chemotherapy and fatal post-treatment reactive encephalopathies in African trypanosomiasis.

The treatment of late-stage African sleeping sickness in man is often complicated by a post-treatment reactive encephalopathy. The bases of this pathological reaction was investigated in a mouse model of African trypanosomiasis. Subcurative treatment with diminazene aceturate, which did not clear parasites from the central nervous system, resulted in a post-treatment meningoencephalitis similar to that seen in man. By contrast, a curative regimen of melaminylthioarsenite and 5-nitroimidazole, which cleared parasites from the central nervous system, did not cause any pathological reaction in the mice. This result indicates that subcurative treatment leads to the development of the post-treatment encephalopathy. Evidence that this may also be the case in man was provided by the detection of trypanosome DNA with the polymerase chain reaction in the brains of 9 patients who had died as the result of a post-treatment reaction. Our findings suggest that more aggressive treatment regimens, which ensure the elimination of trypanosomes from the central nervous system, may prevent post-treatment reactions in patients.

Adolescent↗
PubMed1995

A diamidine-resistant Trypanosoma equiperdum clone contains a P2 purine transporter with reduced substrate affinity.

Following the demonstration that the transport of melaminophenyl arsenical drugs in Trypanosoma brucei is dependent upon an unusual adenosine nucleoside transporter (Carter and Fairlamb, Nature 361 (1993) 173-175) we have investigated adenosine transport in the related parasite Trypanosoma equiperdum (Botat1.1) and a cloned derivative resistant to the diamidine drug berenil (diminazene aceturate) with limited cross-resistance to the melaminophenyl arsenical cymelarsen. The parental strain possesses a bipartite adenosine transport system consisting of one component which is inhibited in a dose-dependent and saturable manner with increasing concentrations of inosine and a second component which is similarly inhibited by adenine. Uptake of adenosine on this second transporter is also inhibited in a dose-dependent fashion by berenil and cymelarsen. Both transporters have high affinity for adenosine (apparent Km values of 0.60 and 0.70 mM and Vmax values of 8.4 and 6.9 pmol (s (10(8) trypanosomes))-1 at 25 degrees C, respectively). Thus T. equiperdum shares with T. brucei a system comprising two adenosine transporters named P1 and P2, respectively. The P1 transporter is similar in the sensitive and resistant T. equiperdum clones, whereas the P2 transporter has reduced transport capacity at physiological adenosine concentration and decreased affinity for adenosine in the drug-resistant clone.

Adenosine↗
PubMed1990

A drug incubation infectivity test (DIIT) for assessing resistance in trypanosomes.

Blood stream forms of drug-resistant and sensitive Trypanosoma brucei brucei, Trypanosoma brucei evansi and Trypanosoma vivax were incubated in a liquid medium for 24 h at 37 degrees C in the presence of various concentrations of diminazene aceturate (Berenil) or isometamidium chloride (Samorin), and assayed for infectivity in mice. Whereas the infectivity to mice of all Samorin-sensitive trypanosomes was decreased after incubation with 1 ng Samorin ml-1, the Samorin-resistant stocks remained infective for mice. Two of the Samorin-resistant stocks remained infective after incubation with Samorin concentrations of up to 50 ng ml-1. The infectivity of Berenil-resistant trypanosome stocks were also retained after incubation with drug concentrations (0.5 or 1.0 micrograms ml-1) which otherwise inhibited the infectivity of Berenil-sensitive trypanosome stocks. In addition, differences in infectivity were observed when Berenil-resistant and sensitive trypanosome stocks were incubated in medium supplemented with serum from goats previously treated with Berenil. Thus, drug-resistant and sensitive trypanosomes can be clearly distinguished using the drug incubation infectivity test.

Amidines↗
PubMed1991

Therapeutic effect of Berenil and Samorin in mice infected with four trypanosome populations isolated from Zambian cattle.

Four populations of Trypanosoma congolense and Trypanosoma brucei brucei were isolated from cattle under different management practices and environments in Zambia. All four isolates had varied responses to both diminazene aceturate (Berenil) and isometamidium chloride (Samorin) as curative drugs in infected mice. Trypanosomes from a traditionally managed herd in a high-tsetse-challenge area had the strains most resistant to Berenil, with maximum curative dose of 45 mg kg-1 body weight. Another isolate from a high-tsetse-challenge area was evidently resistant both to Berenil at 40 mg kg-1 and to Samorin at 4 mg kg-1. The strains most susceptible to both Berenil and Samorin were from a commercially managed herd of cattle under medium tsetse challenge. They responded to recommended cattle standard doses of 3.5 mg kg-1 or 7 mg kg-1 Berenil and to as little as 0.25 mg kg-1 Samorin. It is evident that trypanosome strains resistant to Berenil and/or partially resistant to Samorin exist, and that both T. congolense and T. b. brucei are implicated.

Animals↗
PubMed1993

The effect of trypanocidal drug treatment on the haematological changes in Trypanosoma brucei brucei infected splenectomised dogs.

Twenty adult mongrel dogs of both sexes were used. Ten of the dogs were splenectomised and the remaining dogs were left intact. Five dogs each from the splenectomised and non-splenectomised (intact) animals were infected intravenously with Trypanosoma brucei brucei while the rest served as uninfected controls. All the infected dogs developed trypanosomosis between Days 4 and 8 postinfection. The packed cell volume, haemoglobin concentration, total red blood cell count and white blood cell count decreased progressively indicating anaemia and leucopenia. The absolute reticulocyte counts were increased. Splenectomy enhanced fever, reticulocytosis and parasitaemia but delayed the onset of anaemia and leucopenia. It also shortened the prepatent period of the infection. The treatment of the infected dogs with diminazene aceturate (Berenil at the dose rate of 7.0 mg kg-1 body weight on Day 21 postinfection cleared the parasites in blood within 24 h and resulted in complete reversal of all the haematological aberrations observed. Splenectomy did not enhance or inhibit the recovery rate in the animals after treatment.

Animals↗