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PubMed1997

A substance P antagonist, RP-67,580, ameliorates a mouse meningoencephalitic response to Trypanosoma brucei brucei.

Mice infected with the protozoan parasite Trypanosoma brucei brucei and treated subcuratively with the trypanocidal drug diminazene aceturate develop an acute inflammatory meningoencephalitis with associated astrocytic proliferation. This reaction is very similar to that seen in the fatal posttreatment reactive encephalopathies that can occur in human African trypanosomiasis. The 11-amino acid neuropeptide substance P (SP) has recently been identified as a mediator in many inflammatory responses, and the development of potent, highly specific, nonpeptide SP antagonists has provided a new opportunity to investigate the possible involvement of SP in a variety of pathological conditions. We therefore postulated that SP may play a role in the development of the posttreatment inflammatory encephalopathy found in this experimental mouse model of African trypanosomiasis. In the present study RP-67,580, a SP antagonist that binds specifically to NK-1 receptors, was given intraperitoneally at a dose of 2 mg/kg twice daily to mice in which a severe meningoencephalitis had been produced. A significant reduction in both the severity of the inflammatory response (P = 0.0001) as well as the degree of astrocyte activation (P < 0.001) was found in the brains of these animals as compared with control mice that had not received RP-67,580. An inactive enantiomer of this SP antagonist, RP-68,651, had no effect on the central nervous system inflammatory reaction. We conclude from these findings that the neuropeptide SP plays a key role in the development of the severe central nervous system inflammatory response associated with African trypanosomiasis.

Analgesics↗
PubMed1976

The immune response of zebu cattle infection with Trypanosoma congolense and T. vivax.

Zebu cattle were infected with Trypanosoma congolense and T. vivax and changes in the levels of serum immunoglobulins were measured during infection and after treatment. Increases in the levels of IgM occurred within 14 days of infection coincidentally with the first appearance of trypanosomes in the peripheral blood. IgM levels rose to 2-10 times preinfection levels and remained high until the animals were treated with diminazene aceturate. Levels then declined to approximately pre-infection levels within 25 days. IgG levels showed little change. In one animal infected with T. congolense which died of trypanosomiasis, there was an initial increase in IgM levels but subsequently both IgM and IgG levels declined until the animal died. The neutralizing activity of whole serum, and serum IgM and IgG fractions from an ox infected with T. congolense were examined. High levels of neutralizing antibodies against trypanosomes isolated on the eighth day after infection were found in sera collected 12-29 days after infection. Most of the antibody activity was located in IgG fractions which showed a peak in neutralizing activity between day 17 and 22. IgG fractions of the sera showed only slight antibody activity.

Animals↗
PubMed1980

The experimental chemotherapy of leishmaniasis, IV. The development of a rodent model for visceral infection.

A description is given of two methods for investigating the action of drugs against a viscerotropic Leishmania in mice. The parasite employed was isolated from a patient with kala-azar in Ethiopia. It is designated 'L. infantum LV9' and produces a visceral infection in NMRI mice. The biochemical typing characters of the parasite are described. In Method A, infected animals were treated from the 5th or 6th day after infection (D + 5 or D + 6) for five consecutive days. They were sacrificed 24 hours after the completion of drug treatment and an estimate was made of the amastigote load in the liver. A comparison of this with untreated controls gives an index of activity of a test drug, from 0 to 3. Method B is similar except that the ED50 and ED90 are determined by graphic analysis of data from graded drug doses. A comparison is made with sodium stibogluconate used as a positive drug control to yield a 'Pentostam Index'. The course of infection in BALB/c and NMRI mice is compared with that in random-bred Swiss mice in which 'L. infantum LV9' produces an inconsistent infection. An inoculum of 10(7) amastigotes produces a peak parasite intensity between D + 15 and D + 20. The ED50 and ED90 of sodium stibogluconate (Pentostam) (as Sbv) in Method B are 22 x 5 and 46 x 5 mg/kg sc daily x 5. (By Method A the single dose figures are 65 and 280 mg/kg.) For routine use a standard dose level of 120 mg/kg sc daily x 5 of Pentostam (Sbv) is used in Method B. The ED50 and ED90 of meglumine antimoniate (Glucantime) (as Sbv) in Method B are 11 x 6 and 66 x 7 mg/kg sc daily x 5. Data are given for other antimonials in Method A. Pentamidine and diminazene aceturate proved to have a slow action which was more readily demonstrated if the observation period was prolonged. Amphotericin B was moderately active but toxic to the host. The relevance of these models and a comparison of data found in the mouse and hamster are debated.

Amphotericin B↗
PubMed1989

Neurochemical measurements in the brains of mice infected with Trypanosoma brucei brucei (TREU 667).

Trypanosoma brucei brucei (TREU 667) infected mice were used as a model of African trypanosomiasis, a disease in which neuropsychiatric manifestations occur. To study the possible neurochemical basis of these abnormalities, we measured brain acetylcholine receptor numbers, activities of the cholinergic enzymes, choline acetyltransferase (CAT), and acetylcholinesterase (AChE), and regional concentrations of the monoamines, dopamine (DA), serotonin (5-HT), and norepinephrine (NE), and their acid metabolites, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) in mice infected with T. b. brucei. There were no significant changes in CAT or AChE activities or acetylcholine receptor numbers at either 35 or 50 days post-infection (PI). At day 35 PI, the only significant finding was a decrease in 5-HIAA concentration in the brain stem, a change which did not persist to day 50 PI. At day 50 PI there were, however, significant increases in DA concentration in the brain stem and NE concentrations in the hippocampus, cerebellum, brain stem and striatum. To establish a chronic relapsing murine model, mice were treated with diminazene aceturate (Berenil) at day 60 PI and killed 60 days later (120 days PI). In these mice, 5-HT concentrations were significantly increased in the hypothalamus and decreased in the cortex. In addition, 5-HIAA concentrations were increased in the striatum and hypothalamus and HVA concentrations were increased in the striatum and hippocampus. Our data, taken together with that of others, suggests that there are alterations in the monoaminergic, but not in the cholinergic, neuronal system, in African trypanosomiasis. These data may form the basis for the neuropsychiatric abnormalities that are associated with this disease.

Acetylcholinesterase↗
PubMed1987

Potential value of localized skin reactions (chancres) induced by Trypanosoma congolense transmitted by Glossina morsitans centralis for the analysis of metacyclic trypanosome populations.

Goats infected with Trypanosoma congolense transmitted by Glossina morsitans centralis and then treated with the trypanocidal drug diminazene aceturate are immune to tsetse-transmitted infection with a homologous, but not heterologous trypanosome clone. Immune animals fail to develop localized skin reactions (chancres) and do not become infected, whereas on heterologous challenge chancres appear followed by parasitaemia. In this study, the feasibility of using chancre reactions to characterize several different metacyclic populations of T. congolense was evaluated. Provided goats were immunized, it was found that the chancre reaction could be used to distinguish different populations of T. congolense. However, problems were encountered when attempts were made to induce immunity against more than one trypanosome population. When goats were infected by tsetse flies with four antigenically unrelated metacyclic populations of T. congolense, either simultaneously or at 4 day intervals, adequate immunological priming was not always achieved. In fact, goats exposed to superinfection 8 to 12 days after a primary infection did not develop chancres or an immune response to the second infection (although they were immune to the organism used for primary infection). Following trypanocidal treatment these animals were subsequently completely susceptible to homologous infection with the metacyclic population used for superinfection, indicating that some form of interference phenomenon effective at the level of the skin appears to prevent or delay the development of the second trypanosome population following superinfection of infected animals.

Animals↗
PubMed1991

Susceptibility of N'Dama and Boran cattle to tsetse-transmitted primary and rechallenge infections with a homologous serodeme of Trypanosoma congolense.

Eight trypanotolerant N'Dama cattle controlled an infection of Trypanosoma congolense ILNat 3.1 transmitted by Glossina morsitans centralis, more efficiently than a group of similarly infected trypanosusceptible Boran cattle. All eight N'Damas maintained their PCV above 15% throughout the primary infection whereas the PCV of six of the eight Borans dropped below 15%; these latter animals were treated with diminazene aceturate to prevent possible death. Lymphocyte, neutrophil and platelet counts also decreased in the Boran during the primary infection. In contrast, a lymphocytosis was observed in the N'Dama; and although the neutrophil and platelet counts decreased, the drop was less severe than in the Boran. Two years after the primary infection and immediately prior to a homologous rechallenge infection, all eight N'Damas had neutralizing anti-metacyclic trypanosome variant-specific antibodies present in their sera compared to five of the eight Borans. Following the homologous rechallenge infection the eight N'Damas became parasitaemic but there were no alterations in their erythrocyte or leukocyte counts. The Borans became highly parasitaemic and developed severe, chronic anaemia and leukopaenia. Thus, the trypanotolerant N'Damas controlled a primary infection of T. congolense more efficiently than trypanosusceptible Boran cattle and eliminated a homologous rechallenge infection without the pathology associated with the disease.

Animals↗
PubMed1996

Use of insecticide-impregnated targets for the control of tsetse flies (Glossina spp.) and trypanosomiasis occurring in cattle in an area of south-west Ethiopia with a high prevalence of drug-resistant trypanosomes.

In the Ghibe valley, south-west Ethiopia, a tsetse control trial using deltamethrin-impregnated targets was started in May 1990. The mean relative density of the main vector, Glossina pallidipes, fell from 2.1 flies per trap per day in the 12 months prior to introduction of tsetse control to 0.41 flies per trap per day in the 12 months after tsetse control was initiated. The annual mean prevalence of Trypanosoma congolense infections in cattle fell from 32% in the 2 years before tsetse control to 13% in the 2 years following deployment of targets. The largest reduction occurred in the first quarter of 1991 when the mean monthly trypanosome prevalence was 5%. There was also a decrease of approximately 75% in the estimated rate of relapse of trypanosome infections in cattle after treatment with diminazene aceturate. However, in June 1991, socio-political disturbances occurred in Ethiopia and were associated with substantial thefts of targets. Following these thefts, the mean relative density of G. pallidipes rose from 0.41 flies per trap per day in the period May 1990-April 1991, to 1.29 flies per trap per day in the period April 1992-March 1993. Associated with this rise, the mean trypanosome prevalence in cattle increased from 13% in the period May 1991-April 1992 to 28% in the period May 1992-April 1993. This was similar to the mean trypanosome prevalence in cattle during the pre-control period. Thus, while effective tsetse control methods can be used to reduce the transmission of trypanosomes their long-term impact is dependent on their sustainability.

Animals↗
PubMedDate not supplied

Endemic visceral leishmaniasis in a dog from Texas.

Visceral leishmaniasis was diagnosed by cytology and positive indirect immunofluorescent antibody titers to Leishmania donovani in a 7-month-old female Basenji dog from Texas. Clinical and laboratory findings included weight loss, hematochezia, hyperglobulinemia, hypoalbuminemia, anemia, and neutrophilic leukocytosis. Evidence of response to treatment with diminazene aceturate and ketoconazole included improvement in the abnormal clinical, hematologic, and biochemical findings, decreased serum globulin concentration and antibody titer to Leishmania donovani, and absence of organisms in examined tissues. Several foci of endemic leishmaniasis have been reported in the United States. Because of its zoonotic potential and the lack of approved treatments for dogs with leishmaniasis in the United States, the development of effective treatment strategies is needed.

Animals↗
PubMed1980

Chemotherapy of Babesia microti infections in Mongolian Jirds.

For identifying drugs which might be effective in the treatment of human Babesia microti infections, 20 selected antiprotozoal agents or combinations of agents were tested for activity against B. microti in Mongolian jirds (meriones unguiculatus). 4-Methyl-primaquine and aromatic diamidines, including diminazene and pentamidine, were the most effective compounds tested.

Animals↗
PubMed1996

In vivo trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors.

A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for trypanocidal activities in human and veterinary trypanosomes of African origin. One agent, CGP 40215A, a bicyclic analog of MGBG which also resembles the diamidines diminazene (Berenil) and pentamidine, was curative of infections by 19 isolates of Trypanosoma brucei subspecies as well as a Trypanosoma congolense isolate. Several of these isolates were resistant to standard trypanocides. Curative doses were < or = 25 mg/kg of body weight/day for 3 days in these acute laboratory model infections. In addition, CGP 40215A also cured a model central nervous system infection in combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl, eflornithine). Curative combinations were 14 days of oral 2% DFMO (approximately 5 g/kg/day) plus 5, 10, or 25 mg/kg/day for 3 or 7 days given by intraperitoneal injection or with a miniosmotic pump. Combinations were most effective if CGP 40215A was given in the second half or at the end of the DFMO regimen. MGBG has modest activity as an inhibitor of trypanosome S-adenosylmethionine decarboxylase (50% inhibitory concentration [IC50]. 130 microM), while CGP 40215A was a more active inhibitor (IC50, 20 microM). Preincubation of trypanosomes with CGP 40215A for 1 h caused a reduction in spermidine content (36%) and an increase in putrescine content (20%), indicating that one possible mechanism of its action may be inhibition of polyamine biosynthesis.

Adenosylmethionine Decarboxylase↗
PubMed1997

Cross-resistance associated with development of resistance to isometamidium in a clone of Trypanosoma congolense.

Resistance to isometamidium was increased 94-fold in a clone of Trypanosoma congolense (clone IL 1180) by repeated subcurative treatment of infected mice for 11 months. This was associated with 3.4-, 33-, and 4.2-fold increases in resistance to diminazene, homidium, and quinapyramine, respectively. Both T. congolense IL 1180 and the resistant derivative were able to undergo cyclical development in Glossina morsitans centralis tsetse flies, producing hypopharyngeal infection rates of 40.0 and 39.8%, respectively.

Animals↗
PubMed1997

In vitro life cycle of pentamidine-resistant amastigotes: stability of the chemoresistant phenotypes is dependent on the level of resistance induced.

Using a continuous drug pressure protocol, we induced pentamidine resistance in an active and dividing population of amastigote forms of Leishmania mexicana. We selected in vitro two clones with different levels of resistance to pentamidine, with clone LmPENT5 being resistant to 5 microM pentamidine, while clone LmPENT20 was resistant to 20 microM pentamidine. Resistance indexes (50% inhibitory concentration [IC50] after drug presure/IC50 before drug pressure) of 2 (LmPENT5) and 6 (LmPENT20) were determined after drug selection. Both resistant clones expressed significant cross-resistance to diminazene aceturate and primaquine. Pentamidine resistance was not reversed by verapamil, a calcium channel blocker known to reverse multidrug resistance (A. J. Bitonti, et al., Science 242:1301-1303, 1988; A. R. C. Safa et al., J. Biol. Chem. 262:7884-7888, 1987). No difference in the in vitro infectivity for resident mouse macrophages was observed between the wild-type clone (clone LmWT) and pentamidine-resistant clones. During in vitro infectivity experiments, when the life cycle was performed starting from the intramacrophagic amastigote stage, the drug resistance of the resulting LmPENT20 amastigotes was preserved even if the intermediate promastigote stage could not be considered resistant to 20 microM pentamidine. In the same way, when a complete developmental sequence of L. mexicana was achieved axenically by manipulation of appropriate culture conditions, the resulting axenically grown LmPENT20 amastigotes remained pentamidine resistant, whereas LmPENT5 amastigotes lost their ability to resist pentamidine, with IC50s and index of resistance values close to those for the LmWT clone. These results strongly indicate that the level of pentamidine tolerated by resistant amastigotes after the life cycle was dependent on the induced level of resistance. This fact could be significant in the in vivo transmission of drug-resistant parasites by Phlebotominae. Particular attention should be given to the finding that the emergence of parasite resistance is a potential risk of the use of inadequate doses as therapy in humans.

Animals↗
PubMed1998

Antitrypanosomal activity of a new triazine derivative, SIPI 1029, In vitro and in model infections.

A recently developed diaminotriazine derivative [O,O'-bis(1, 2-dihydro-2,2-tetramethylene-4,6-diamino-S-triazin-1-yl)-1, 6-hexanediol dihydrochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems. In vitro, SIPI 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense at 0.15 to 2.15 nM (50% inhibitory concentrations). In in vivo mouse laboratory models of T. b. rhodesiense clinical isolate infections, SIPI 1029 was curative for 12 of 13 isolates at </=10 mg/kg of body weight/day for 3 days. In eight infections, a single dose was >/=60% curative, and in six of these, a dose of </=5 mg/kg was sufficient for >/=60% cure rates. A number of these isolates were resistant to the standard trypanocide melarsoprol (Arsobal) and/or the diamidines diminazene aceturate (Berenil) and pentamidine. SIPI 1029 was also curative in combination with DL-alpha-difluoromethylornithine (Ornidyl) in a T. b. brucei central nervous system model infection. Some evidence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 or 3 days in which deaths were observed in 6 of 65 animals given this dosage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.

Acute Disease↗
PubMed1998

Field evaluation of the prophylactic effect of an isometamidium sustained-release device against trypanosomiasis in cattle.

In order to compare the prophylactic effect provided by a poly(D,L-lactide) sustained-release device (SRD) containing isometamidium (ISMM) with that provided by the classical intramuscular injection of the drug, a field trial was carried out at the Madina Diassa Ranch in Mali. One- to 3-year-old N'Dama cattle were randomly divided into three groups. The first group (n = 42) was treated with ISMM at a dose of 1 mg/kg of body weight, the second group (n = 44) received the same dose of the drug via an SRD, which was subcutaneously implanted in the shoulder region, and the third group (n = 36) was kept as an untreated control group. All animals were treated with diminazene aceturate (7 mg/kg of body weight) 2 weeks before the start of the experiment and were tested monthly by the buffy coat technique for a period of 8 months. Glossina morsitans submorsitans was the most important tsetse species, with apparent densities (number of catches/trap/day) varying between 11.9 and 38.7 over the experimental period. Eight months after treatment the cumulative infection rates were 27.7, 58.5, and 77.4% in the group with the SRD implant, the group receiving the intramuscular injection, and the control group, respectively. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower (P = 0.006) in the group which received ISMM via the SRD than in the one which was treated with ISMM intramuscularly.

Animals↗
PubMed1974

Susceptibility of an insect Leptomonas and Crithidia fasciculata to several established antitrypanosomatid agents.

Growth inhibition of the lower trypanosomatids Crithidia fasciculata and a Leptomonas from a hemipteron by several established trypanocides and leishmanicides were compared in four complex and one defined media. The Leptomonas was more susceptible than C. fasciculata in all media, especially to phenanthridines (ethidium, prothidium, isometamidium) and diamidines (pentamidine, diminazene diaceturate [Berenil], hydroxystilbamidine, stilbamidine); concentrations of these drugs required for 50% inhibition of the Leptomonas were <5 mug/ml. In contrast, C. fasciculata was uninhibited by <20 mug of diamidines per ml and was three- to sixfold less susceptible than the Leptomonas to isometamidium and prothidium. Both trypanosomatids were susceptible to nucleoside antibiotics, e.g., nucleocidin. Neither was inhibited by suramin, melarsen, melarsen oxide, or tryparsamide. The Leptomonas was more susceptible to standard trypanocides than five other insect trypanosomatids in a complex medium; it was the only one inhibited by <20 mug of stilbamidine and hydroxystilbamidine per ml.

Animals↗
PubMed1975

Drug-resistant Leptomonas: cross-resistance in trypanocide-resistant clones.

A Leptomonas of insect origin was highly susceptible to several standard trypanocides and leishmanicides in vitro. Resistance was induced to some of these drugs; clones were isolated from each strain. Cross-resistance patterns of the clones were derived for diamidines, quinapyramine (Antrycide), acriflavin, phenanthridines, and other drugs active against trypanosomes and leishmanias. Clones tested included two each that were resistant to acriflavin, Antrycide, diminazene aceturate (Berenil), and pentamidine and one that was resistant to stilbamidine. Appreciable cross-resistance was evident for all clones. Differences were observed between clones from the same parent strain. Collateral susceptibility towards isometamidium and oxophenarsine was detected in most clone-derived populations. In clones passaged without drug to test for drug fastness, acriflavin and pentamidine clones lost resistance within 10 transfers, whereas Berenil and Antrycide clones retained considerable resistance after 20 to 30 subcultures without drug. Considerations of differences in life cycles suggest that the clone collection may be useful in screening for agents effective against leishmanias and stercorarian trypanosomes rather than against salivary trypanosomes.

Clone Cells↗
PubMed2006

Porcine eperythrozoonosis in China.

Eperythrozoonosis of swine (also designated as porcine mycoplasmosis) is a disease of swine under stress, expressed as a febrile condition with development of an acute ictero-anemia. It is caused by Eperythrozoon suis and usually causes a subclinical infection with a latent carrier state that persists for extended periods. In China, this disease has gradually developed as an important intercurrent disease and an emerging swine disease that, in recent years, has spread throughout all provinces except Tibet. Classical swine fever (hog cholera), porcine influenza, swine enzootic pneumonia, porcine reproductive and respiratory syndrome (blue ear disease), streptococci, and toxoplasmosis were detected in Eperythrozoonosis-infected pig herds, and caused serious economic losses. National epidemiology surveillance in 2002 revealed that this disease caused a total morbidity of 30% and a mortality of 10-20%. Total mortality (which includes culling sick pigs) was more than 60%. The morbidity within infected herds was near 100%, has spread throughout with a total mortality rate usually over 50%. Mortality of piglets in some districts was as high as 50%. The highest infection rate on pig farms was more than 90%. The farms with higher infection rates occurred in pig-raising areas during epidemic seasons. New diagnostic tests, such as ELISA and PCR, have been developed for the detection of porcine eperythrozoonosis, but traditionally the diagnosis of the disease is still based on clinical history and optical microscopic examination of the causative agent in blood smears. Efficient preventive and control measures include the detection of carriers in pig herds and treatment of sick pigs with drugs, such as long-acting oxytetracycline, doxycycline, or aceturate of diminazene. Oxytetracyclines as feed additives have been introduced for eperythrozoonosis prevention in uninfected pig herds, and pig producers have taken measures to reduce stress and improve sanitary conditions.

Animals↗
PubMed1990

Increased erythrophagocytic activity of macrophages in dogs with Babesia gibsoni infection.

To elucidate the mechanism of anemia caused by Babesia gibsoni infection in dogs, the erythrophagocytic activity of macrophages in infected dogs was investigated in vitro. In the present study, macrophages obtained from peripheral blood (PB-macrophages) and bone marrow (BM-macrophages) of splenectomized dogs with chronic B. gibsoni infection were examined. The BM-macrophages in the splenectomized dogs with chronic babesiosis exhibited an increased erythrophagocytic activity compared with those from splenectomized, non-infected dogs. In the infected dogs, erythrophagocytic activities of macrophages against both auto- and iso-erythorcytes from normal dogs were almost the same. Administration of an anti-protozoal drug, diminazene diaceturate, resulted in a decrease of the erythrophagocytic activity of BM-macrophages associated with an increase of the hematocrit value in splenectomized dogs with chronic babesiosis. In splenectomized dogs with acute babesiosis, erythrophagocytic activity of BM-macrophages was also elevated. Such a phenomenon was not, however, observed in splenectomized dogs with onion-induced hemolytic anemia. These results suggest that the erythrophagocytic ability of macrophages in the infected dogs might be accelerated by parasites per se through an unknown mechanism, resulting in severe anemia in spite of low parasitemia.

Anemia↗