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PubMed1994

Generation of monoclonal antibodies to the anti-trypanosomal drug isometamidium.

Mice were immunized with either an isometamidium-human serum albumin (HSA) conjugate or an isometamidium-porcine thyroglobulin conjugate (PTG). Thereafter, monoclonal antibodies (MAbs) IL-A 1001, IL-A 1002, IL-A 1003, 5F7.B7, and 5F7.C9 were generated and selected on the basis that they recognized conjugated and unconjugated isometamidium, but lacked cross-reactivity with the carrier molecules. All five MAbs were of the IgG1 isotype. Each of the five MAbs was assessed in a competitive ELISA for isometamidium; in each case, the minimum level of detection was approximately 10 ng/ml. Each MAb exhibited approximately 0.1% cross-reactivity with the anti-trypanosomal compound diminazene. However, based on their cross-reactivity with the anti-trypanosomal compound homidium, the MAbs could be divided into two groups; IL-A 1001, IL-A 1002, and IL-A 1003, produced using an isometamidium-HSA conjugate as an immunogen, exhibited low levels of cross-reactivity (approximately 0.1%). In contrast, 5F7.B7 and 5F7.C9, produced using an isometamidium-PTG conjugate as an immunogen, exhibited high levels of cross-reactivity.

Animals↗
PubMed2003

Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice.

Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1-/- mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1-/- mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1-/- mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1-/- mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.

Animals↗
PubMed1992

The use of azathioprine to ameliorate post-treatment encephalopathy associated with African trypanosomiasis.

The treatment of human African sleeping sickness is complicated by a post-treatment meningoencephalitis that may be fatal. Using a mouse model this study assesses the use of the non-steroidal anti-inflammatory drug, azathioprine, in the management of this post-treatment reaction. Female NIH mice treated with the trypanocidal compound diminazene aceturate (40 mg/kg), 28 days after infection, developed a similar post-treatment reaction to that seen in humans. Administration of azathioprine (100 mg/kg) for 5 days before and 5 days after trypanocidal chemotherapy abrogated the pathology in the central nervous system although this returned approximately 15 days after cessation of azathioprine. Activated astrocytes associated with the later stages of the infection did not appear to be affected by the use of azathioprine.

Animals↗
PubMed1995

Use of monoclonal antibodies for detecting T brucei brucei infection in splenectomised dogs.

A monoclonal antibody against a plasma membrane antigen of Trypanosoma rhodesiense was used for the detection of T brucei group-specific circulating antigen in 24 adult local dogs experimentally infected with T brucei brucei strain 8/18. Ten of the dogs were splenectomised and the remainder non-splenectomised (intact). Five dogs each from the splenectomised and intact groups were inoculated intravenously with trypanosomes. The infected dogs developed trypanosomiasis between days 4 and 8 after infection. The circulating antigens were detected as early as six days after infection and remained high until two weeks after treatment, when the circulating antigen declined. The detection of the antigens showed the existence of infection unlike the antibody test. The treatment of the infected dogs with diminazene aceturate (Berenil; Hoechst) at a dose of 7.0 mg/kg on day 21 after infection cleared all the parasites but elevated the circulating antigen levels. The antigen capture enzyme-linked immunosorbent assay is a useful diagnostic tool for complementing parasitological diagnosis, for detecting infection in the field and for ascertaining the efficacy of trypanocidal drugs.

Animals↗
PubMed2003

Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei.

Sleeping sickness, caused by Trypanosoma brucei spp., has become resurgent in sub-Saharan Africa. Moreover, there is an alarming increase in treatment failures with melarsoprol, the principal agent used against late-stage sleeping sickness. In T. brucei, the uptake of melarsoprol as well as diamidines is thought to be mediated by the P2 aminopurine transporter, and loss of P2 function has been implicated in resistance to these agents. The trypanosomal gene TbAT1 has been found to encode a P2-type transporter when expressed in yeast. Here we investigate the role of TbAT1 in drug uptake and drug resistance in T. brucei by genetic knockout of TbAT1. Tbat1-null trypanosomes were deficient in P2-type adenosine transport and lacked adenosine-sensitive transport of pentamidine and melaminophenyl arsenicals. However, the null mutants were only slightly resistant to melaminophenyl arsenicals and pentamidine, while resistance to other diamidines such as diminazene was more pronounced. Nevertheless, the reduction in drug sensitivity might be of clinical significance, since mice infected with tbat1-null trypanosomes could not be cured with 2 mg of melarsoprol/kg of body weight for four consecutive days, whereas mice infected with the parental line were all cured by using this protocol. Two additional pentamidine transporters, HAPT1 and LAPT1, were still present in the null mutant, and evidence is presented that HAPT1 may be responsible for the residual uptake of melaminophenyl arsenicals. High-level arsenical resistance therefore appears to involve the loss of more than one transporter.

Adenine↗
PubMed1988

Plasma histamine levels in rats treated with trypanocidal diamidines.

The histamine levels in rat plasma treated with various new trypanocidal diamidines and diimidazolines were evaluated by HPLC and fluorometric detection. Equimolar doses (10 mumol/kg) of the new compounds raised the plasma histamine level to a much smaller degree than pentamidine or diminazene.

Amidines↗
PubMed1987

Pathobiochemical alterations in experimental chronic and acute trypanosomal infection in mice.

During an experimental chronic infection of inbred mice with Trypanosoma congolense several physiological parameters become altered. Splenomegaly followed later by hepatomegaly are predominant. Lactate dehydrogenase and aminotransferase activities of the plasma are elevated, the number of erythrocytes and thrombocytes decreases, whereas monocytic cells are detected in higher concentrations. Gamma-Globulins and transferrin become elevated. Some of the pathobiochemical alterations depend directly on the parasitaemia and are reversed to normal values after chemotherapy with diminazene aceturate (Berenil). The curative effect of this drug depends largely on when it is administered. In acute T. congolense infections, leading to the death of the animals in 3-4 days, pathobiochemical alterations are found only shortly before the exitus.

Alkaline Phosphatase↗
PubMed1999

Therapeutic effects of some antihaematozoal drugs against Haemoproteus columbae in domestic pigeons.

Three antihaematozoal drugs were tested for the treatment of pigeons naturally infected with Haemoproteus columbae. Butalex (Buparvaquone) was found effective against the parasite either by using the recommended dose (R. D.) or the double (D. D.) dosis. The R. D. of Berenil (Diminazene aceturate) was not effective while the D. D. reduced the number of gametocytes circulating in the infected blood. Triquine was found very toxic to the pigeons both the R. D. and the D. D.

Animals↗
PubMed1976

Immunity to monomorphic Trypanosoma brucei: humoral response.

Trypanosome-agglutinating antibodies, predominantly of the IgM class, are formed in T. brucei-infected rats cured with Berenil (diminazene). The duration of Berenil prophylaxis following administration of a minimum curative dose is approximately 28 days. Rechallenge of drug-cured animals with homologous organisms results in the production of IgG, indicating an apparent absence of interference under these conditions with B-cell, T-cell cooperativity.

Animals↗
PubMed1992

Pathogenesis of trypanosomiasis-induced glomerulonephritis in mice.

We investigated the pathogenesis of glomerulonephritis in mice that had been infected with Trypanosoma brucei. Polyclonal B cell activation was evaluated, with special attention to the presence of autoantibodies, which are known to be involved in other models for glomerulonephritis. The BALB/c mice studied developed severe albuminuria. Light-microscopy of the kidneys showed increase of mesangial matrix and thickening of the glomerular capillary walls. Immunofluorescence studies showed immunoglobulins in a mixed linear-granular pattern along the glomerular capillary wall and in the mesangium. Trypanosomal antigens were not found in these aggregates. Electron-microscopy revealed mesangial, subendothelial, and subepithelial electron-dense deposits. During the course of this infection, significant levels of antibodies directed against known nephritogenic renal autoantigens, i.e. GBM, laminin, RTE, and gp330, were measured in serum and glomerular eluates. These findings led us to conclude that mice infected with T. brucei and treated with diminazene aceturate develop an autoimmune-mediated glomerulonephritis, characterized by mesangial, subendothelial, and subepithelial immune aggregates. This murine model seems to offer a useful tool for the study of immunological aspects of polyclonal B cell activation in infection-related glomerular disease.

Animals↗
PubMed1989

Antigen-detection enzyme immunoassays for the diagnosis of Trypanosoma vivax, T. congolense and T. brucei infections in cattle.

Species-specific monoclonal antibodies against Trypanosoma vivax, T. congolense and T. brucei were used to develop antigen-capture enzyme-linked immunosorbent assays (antigen-ELISA) for the diagnosis of bovine trypanosomiasis. Each assay was subsequently used for the detection of species-specific circulating antigens in sera of cattle experimentally infected by tsetse transmission. In T. vivax and in T. congolense-infected animals, circulating antigens were detected as early as 10-12 days post-infection while for T. brucei infections, the antigens were detected 8-14 days after challenge. The appearance of the antigens in peripheral blood generally coincided with the onset of first parasitaemia. The antigen levels increased and were persistently present in circulation even on occasions where parasitaemia was not detectable by the buffy coat technique. Following treatment with Berenil (diminazene aceturate, Hoechst, W. Germany) at a dose of 7.0 mg/kg body weight, T. vivax and T. congolense antigens were cleared from circulation within 2 weeks. The rate of removal was slower but variable in T. brucei infections. In one group of 3 animals infected with T. congolense, however, the initial decline in "antigenaemia" was followed, several weeks later, by another rise in antigenaemia, possibly heralding a relapse of the infection. Parasitaemia was not demonstrable at this stage by the buffy coat technique. The circulating antigens were partly in the form of free antigens and partly as immune complexes. Not only are these antigen-detection ELISA assays likely to be of diagnostic importance, but they may also be useful as tools for evaluation of the efficacy of treatment.

Animals↗
PubMed1988

Babesiosis in a litter of pups.

Babesia canis infection was diagnosed in a litter of seven 3-week-old Mastiff pups kept in a north Florida kennel. The pups were evaluated because of poor weight gain; the smallest pup also was markedly lethargic. Six of the pups were anemic and thrombocytopenic. A positive linear correlation between PCV and absolute reticulocyte count suggested that the variation in PCV may have been related more to the ability of a pup to increase erythrocyte production than to a difference in magnitude of erythrocyte destruction. All pups recovered from clinical signs and hematologic abnormalities attributable to babesiosis within 2.5 weeks after treatment with diminazene aceturate. Transient neurologic signs observed in 1 pup 3 days after treatment were believed to represent an adverse drug reaction. The dam of the litter had a serum titer of 1:640 for B canis, but appeared healthy, as did approximately 30 other adult dog in the kennel. The strain of B canis infecting dogs in the kennel caused severe illness and death in some pups, but clinically inapparent disease in adult dogs.

Animals↗
PubMed1983

Relapsed parasitaemia following chemotherapy of chronic T. brucei infections in mice and its relation to cerebral trypanosomes.

Mice infected with Trypanosoma brucei can be easily cured using the available trypanocidal drugs, provided treatment is given soon after the infection; however, if infection is allowed to continue for some time then it is extremely difficult to obtain a permanent cure, and after an aparasitaemic period the infection eventually relapses. It has been shown that a relatively small number of infective trypanosomes in the brain have escaped the action of the drug and these are able to replicate and eventually they re-establish a circulating parasitaemia. The number of infective trypanosomes remaining after chemotherapy varied according to the stabilate of T. brucei, but using the stabilate T. brucei GVR 35 there were up to, 5,000 infective trypanosomes 2 days after treatment, and this rapidly increased up to 50,000 trypanosomes at 7 days. Infected mice on histological examination exhibited a mild meningitis and this was exacerbated by Berenil therapy and 7 days posttreatment the mice had an acute meningoencephalitis. It would appear that if the infective trypanosomes are completely eliminated from the brain this exacerbated reaction does not occur. It has been found that combined treatment of chronic T. brucei infections with either diminazene aceturate or suramin followed by 5-substituted nitroimidazoles at appropriate dose levels will completely eliminate the infective trypanosomes from the brain and the mice are permanently cured.

Animals↗
PubMed1982

Clinical observations on Babesia gibsoni and Babesia canis infections in dogs.

Thirty-five cases of Babesia gibsoni infection and 11 cases of Babesia canis infection were diagnosed and treated in dogs at Kadena Air Base in Okinawa, Japan, between April 1979 and February 1980. Diagnosis was made by demonstrating the organisms in blood smears and by serologic examination, using an indirect fluorescent antibody test. Serologic findings correlated well with the occurrence of infection in mature dogs, but poorly in young (1- to 3-month-old) dogs. Although these 2 intraerythrocytic parasites were readily distinguishable on Giemsa-stained blood smears and by the indirect fluorescent antibody test, the clinical syndromes were similar. Most dogs were anorectic and depressed and were found to have regenerative anemia. Of 37 dogs tested, 31 were Coomb's test-positive, and most of these became Coombs' test-negative after treatment and disappearance of clinical signs. Specific treatment consisted predominantly of the use of diminazene aceturate. Pentamidine isethionate also used. Although these drugs were effective in halting and reversing the clinical progression of the disease, they usually were ineffective in clearing the blood of B gibsoni organisms, and relapses commonly occurred. Both drugs appeared to be more effective against B canis. It was concluded that some of the several hundred dogs arriving in the United States annually from Okinawa are carriers of B gibsoni, a parasite only recently discovered in North America.

Animals↗
PubMed1980

Pharmacotherapeutics of drugs used in treatment of anaplasmosis and babesiosis.

Treatment of anaplasmosis and babesiosis in cattle is practical and effective when given early in the course of infection, before the onset of severe anemia or neurologic disorders. The tetracyclines (usually oxytetracycline or chlortetracycline) are the only effective specific compounds approved for use against anaplasmosis in the United States. Oxytetracycline, at the rate of 6.6 to 11 mg/kg of body weight given one to three times IM or IV, effectively moderates the course of infection. Chlortetracycline administered orally in dosages as small a 1.1 mg/kg will prevent infection and in dosages ranging from 2.2 to 11 mg/kg for 30 to 90 days will eliminate carrier infection. Babesiosis in cattle is effectively treated by a large number of babesiacidal compounds, but in practice, diminazene aceturate (3 to 5 mg/kg, IM), amicarbalide (5 to 10 mg/kg, IM), and imidocarb (1 to 3 mg/kg, IM) are most often used. However, none of these compounds is approved for use in treating babesiosis in cattle in the United States. Larger amounts of these compounds are usually required for the treatment of babesiosis in the horse and in the dog, and the elimination of babesiosis in these species is much more difficult than it is for babesiosis in cattle.

Amidines↗
PubMed1980

An unidentified Babesia of the domestic cat (Felis domesticus).

An unidentified Babesia was seen in a blood smear from a cat showing signs of anaemia. The cat responded to treatment with diminazene (Berenil). The morphology of the parasite is described and a comparison is made with other Babesia which have been described from the domestic cat and wild felids. This parasite most closely resembled B. herpailuri described from a jaguarundi in South America.

Animals↗
PubMed1985

Amidoximes of pentamidine: synthesis, trypanocidal and leishmanicidal activity.

For the study of the biotransformation of pentamidine and the evaluation of its trypanocidal and leishmanicidal properties the N-hydroxylated derivatives II and III were prepared. In II and III, one or both the terminal amidine moieties of pentamidine are replaced by an amidoxime. These amidoximes II and III were tested against various Trypanosoma species and Leishmania donovani in mice and golden hamsters, respectively. The studies demonstrate that the pentamidine derivatives II and III were active against various trypanosomes (T. brucei; T. vivax; T. congolense). However, besides having a pronounced activity against Trypanosoma rhodesiense compounds II and III exhibit a less action on other Trypanosomes than the standard drugs diminazene and in some cases the parent compound pentamidine. Derivatives II and III were also distinctly active against Leishmania donovani but their leishmanicidal effect was slightly less marked than that of pentamidine.

Animals↗
PubMed1997

Trypanosoma brucei brucei: a long-term model of human African trypanosomiasis in mice, meningo-encephalitis, astrocytosis, and neurological disorders.

The search for a chronic experimental model for human African trypanosomiasis (HAT) in animals with cerebral lesions and neurological disorders has been difficult. Models with meningo-encephalitis have been proposed using Trypanosoma brucei gambiense or T. b. rhodesiense. Meningo-encephalitis is rare in infection with T. b. brucei. It has been shown that the treatment of mice infected with T. b. brucei with diminazene aceturate (Berenyl) led to development of a rapid meningo-encephalitis. In this study, we report the development of a chronic experimental model of HAT in mice infected with T. b. brucei AnTat 1.1E. To obtain a chronic evolution of the infection, on Day 21 postinfection, mice were treated with a dose of suramin (Moranyl) at 20 mg x kg(-1) body weight, a dose which failed to eliminate trypanosomes in the central nervous system (CNS). This treatment, repeated after each parasitemic relapse in the blood, allowed animals to survive more than 300 days postinfection. After a few weeks of infection, mice displayed neurological signs. Histological studies showed the appearance of increasing inflammatory lesions, from meningitis to meningo-encephalitis, with progression of lesions throughout the perivascular spaces in cerebral and cerebellum parenchyma. No demyelination or neuronal alteration were observed except in the necrotic spaces. Trypanosomes were observed in different structures in CNS. An immunohistochemical study of glial fibrillary acidic protein (GFAP) showed an increasing astrocytosis according to the duration of the infection. This model reproduces neurological and histological pathology observed in the human disease and can be useful for further immunopathological, neurohistological and therapeutic studies on this condition.

Animals↗