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PubMed2006

Chemotherapy against babesiosis.

Babesiosis is caused by a haemotropic protozoal parasite of the genus Babesia, member of the phylum Apicomplexa and transmitted by the bite of an infected tick. There are many Babesia species affecting livestock, dogs, horses and rodents which are of economic significance. Infections can occur without producing symptoms, but babesiosis may also be severe and sometimes fatal caused by the intraerythrocytic parasite development. The disease can cause fever, fatigue and haemolytic anemia lasting from several days to several months. There are a number of effective babesiacides, but imidocarb dipropionate (which consistently clears the parasitaemia; often the only available drug on the market) and diminazene aceturate are the most widely used. Some Babesia spp. can infect humans, particularly Babesia microti and Babesia divergens, and human babesiosis is a significant emerging tick-borne zoonotic disease. Clinical manifestations differ markedly between European and North American diseases. In clinical cases, a combination of clindamycin and quinine is administered as the standard treatment, but also administration of atovaquone-azithromycin is successful. Supportive therapy such as intravenous fluids and blood transfusions are employed when necessary. More specific fast-acting new treatments for babesiosis have now to be developed. This should be facilitated by the knowledge of the Babesia spp. genome and increased interest for this malaria-like parasite.

Animals↗
PubMed2006

The pathogenesis of anaemia in goats experimentally infected with Trypanosoma congolense or Trypanosoma brucei: use of the myeloid:erythroid ratio.

The present study examined the development of anaemia in Small East African goats experimentally infected with Trypanosoma congolense or Trypanosoma brucei. Experimental goats received a primary trypanosome challenge on day 0, treated with diminazene aceturate on day 49 and received a secondary trypanosome challenge on day 77 of the 136-day experiment. Both primary and secondary challenges were characterised by reduced peripheral erythrocyte counts, fall in packed cell volume (PCV), hypohaemoglobinaemia and reductions in the myeloid:erythroid ratios (M:E) compared with the uninfected goats. The progressive reduction in the M:E ratios denoted increased erythrogenesis in response to increased destruction of erythrocytes in blood by infecting trypanosomes or their products. The more rapid fall in M:E ratio in T. congolense infections shows that this parasite causes more severe clinical pathological effects in goats than T. brucei.

Anemia↗
PubMed2001

Uptake of pentamidine in Trypanosoma brucei brucei is mediated by the P2 adenosine transporter and at least one novel, unrelated transporter.

Diamidine drugs such as pentamidine and berenil (diminazene aceturate) are vital drugs for the treatment of early stage human African trypanosomiasis and the corresponding veterinary condition, respectively. The action of diamidines on trypanosomes is critically dependent on their efficient uptake by the parasite. We have therefore investigated the mode of uptake of pentamidine by Trypanosoma brucei brucei, using [(125)I]iodopentamidine as a permeant. [(125)I]Iodopentamidine uptake was linear for up to 15 min and inhibited by adenosine with a K(i) value of 0.64+/-0.03 microM to a maximum of 50-70%. The adenosine-sensitive flux was also inhibited by adenine with a K(i) value of 0.44+/-0.04 microM. Iodopentamidine uptake was saturable, with the adenosine-insensitive flux displaying a K(m) of 22+/-2 microM and a V(max) of 2.2+/-0.9 pmol(10(7) cells)(-1)s(-1), whereas the adenosine-sensitive flux was inhibited by much lower iodopentamidine concentrations. These results clearly demonstrate that iodopentamidine is taken up by at least two different T. b. brucei transporters, an adenosine-sensitive pentamidine transporter (ASPT1) and a low-affinity pentamidine transporter (LAPT1). The identity of these transporters was investigated, and their significance for drug uptake and resistance in African trypanosomes is discussed.

Adenosine↗
PubMed1997

The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro.

Alamar Blue, an indicator for metabolic cell function, was evaluated as a fluorescent and as a colorimetric dye in drug sensitivity assays for human pathogenic African trypanosomes, Trypanosoma brucei rhodesiense and T.b. gambiense. The experimental conditions were adjusted to find those where the relationship between trypanosome number and Alamar Blue signal was linear over the widest possible range. Fluorescent signals correlated to trypanosome numbers from 10(4) trypanosomes/ml (T.b. rhodesiense) and 10(5) trypanosomes/ml (T.b. gambiense) up to 2-3 x 10(6) trypanosomes/ml when trypanosomes were incubated for 2 h with 10% Alamar Blue. Trypanocidal activity of common drugs (melarsoprol, DFMO, suramin, pentamidine and diminazene aceturate) was determined employing this assay. The IC50 values obtained were comparable to those obtained with another fluorochrome, BCECF-AM. The Alamar Blue assay can be applied for drug screening, since it is simple, reproducible and economical. The assay can also be used in field sites with less equipped laboratories, because in addition to fluorometric endpoint determination, a colorimetric reading is possible.

Animals↗
PubMed1996

Equine piroplasmosis an update on diagnosis, treatment and prevention.

Two haemoprotozoan parasites, Babesia caballi and Babesia equi, can cause equine piroplasmosis. Due to the presence of potential tick vectors in areas so far unaffected by equine babesias, import and export regulations often require the serum testing of animals for evidence of infection. Although the complement fixation test (CFT) has been recommended for detecting the presence of antibodies to Babesia spp., it has been demonstrated to have several disadvantages, including false-positive results and low sensitivity for detecting latent infections. An enzyme-linked immunosorbent assay (ELISA) may be an alternative for increased and sensitive detection of acute and latent babesial infections, but its development to date has been hindered by a limited antigen supply and poor specificity. In vitro cultivation of both parasite species and the identification of parasite proteins for diagnostic use has facilitated the development of a highly sensitive and specific ELISA. For the direct detection of the parasites, DNA probes are now available. Several drugs are available for the treatment of equine piroplasmosis. For instance, diminazene diaceturate is effective in the chemosterilization of B. caballi and in the elimination of clinical signs in B. equi infections. Antitheilericidal drugs such as buparvaquone have been demonstrated to be effective in combatting disease due to B. equi and may--in combination with imidocarb--also eliminate the parasite. The control of equine piroplasmosis must include effective tick control, seromonitoring of animals and the application of chemotherapy.

Animals↗
PubMed1998

In vitro antifilarial activity of organometallic complexes against infective larvae of Molinema dessetae and adult females of Brugia pahangi.

New organometallic complexes having protozoocidal properties were evaluated for their in vitro antifilarial activity using two models: infective larvae of Molinema dessetae and adult females of Brugia pahangi. The compound most active on the M. dessetae model was Ir(I)-COD-pentamidine tetraphenylborate with an EC50 = 6 +/- 1 microM after 7-day-incubation. In the 2-aminobenzothiazole series, Ruthenium was more potent than Iridium for antifilarial activity. A dithiocarbamate function significantly enhanced the antifilarial activity. The compounds derived from benzimidazole were inactive whatever the metal (Iridium or Rhodium). The other compounds exhibited EC50 ranging from 10 to 31 microM. On adult female Brugia pahangi in vitro, Pt-DDH-N-acetylleucine, Pt-diminazene and Pd-Cl4-piperazine at 20 microM began to kill both microfilariae and the developing embryos within the mothers on day 2. The compounds, except for Pd-Cl4-piperazine, killed the adults after 5 days. Rh-Cl-2-chloropyridine caused obvious slowing of the adults from day 3 onward but did not affect the viability of adults, microfilariae or developing embryos. In vivo antifilarial investigations are necessary to appreciate the real advantage of heavy metal complexes in the experimental treatment of filariasis.

Animals↗
PubMed2003

The leucocytic and parasitaemic profiles and immune response of rats treated with retinyl palmitate before infection with Trypanosoma brucei.

The effects of oral administration of retinyl palmitate (30,000 IU/kg bodyweight) for 3 days to rats before infection with Trypanosoma brucei were investigated by examining the leucocytic and parasitaemic profiles, and the antibody response to sheep red blood cells. The pretreatment significantly (P<0.01) improved the leucocytic profile (especially the absolute lymphocyte count) from day 7 post-infection to the time of death. It also significantly delayed the onset of parasitaemia (i.e., lengthened the pre-patent period) and led to reduced levels of parasitaemia throughout the period of infection. Pretreatment significantly increased the antibody response to sheep red blood cells (P<0.01) throughout the infection, even after treatment with diminazene aceturate, to levels that more than compensated for the immunosuppressive effect of the T. brucei. Further studies are warranted on the possible use of retinyl palmitate in overcoming immunosuppression associated with trypanosome infections in man and animals in endemic areas.

Animals↗
PubMedDate not supplied

Relapses following treatment of early-stage Trypanosoma brucei gambiense sleeping sickness with a combination of pentamidine and suramin.

616 patients with early Trypanosoma brucei gambiense trypanosomiasis (no trypanosomes in the cerebrospinal fluid [CSF] and a CSF white cell count [WCC] of 1-5/mm3) were treated with a combination of pentamidine (6 intramuscular [i.m.] injections of 4 mg/kg) and suramin (2 intravenous [i.v.] injections of 20 mg/kg) in Nioki hospital, Zaire, between 1983 and 1992; 46 (7.5%) of them subsequently relapsed. There was no increase in the frequency of treatment failure during this 10 years' period. Relapses were more frequent in children aged 0-17 years (19/163 [11.7%]) than in adults (26/420 [6.2%] (relative risk [RR] = 1.88, 95% confidence interval [CI] 1.07-3.31, P = 0.04). Even within this small range of CSF WCC, the risk of treatment failure increased in parallel with the WCC count and reached 10/36 (27.8%) in patients with a CSF WCC of 5/mm3. Treatment failures were more frequent (5/30 [16.7%]) in a small group of patients treated with a combination of diminazene (3 i.m. injections of 7 mg/kg) and suramin (one i.v. injection of 20 mg/kg) than in the pentamidine/suramin group (RR = 2.23, 95% CI 0.96-5.21, P = 0.08). Our data support the view that central nervous system involvement occurs early in Gambian trypanosomiasis, which in turn raises doubts about the usefulness of adding suramin to pentamidine, as the former drug, which is more expensive than pentamidine and has to be administered intravenously, penetrates poorly into the CSF and may potentially decrease free pentamidine levels in blood and CSF.

Adolescent↗
PubMed2001

A comparative evaluation of parasitological tests and a PCR for Trypanosoma evansi diagnosis in experimentally infected water buffaloes.

In this study five parasitological methods and a polymerase chain reaction (PCR) were compared for the diagnostic sensitivity for Trypanosoma evansi in experimentally infected water buffaloes over a period of 15 weeks. The combined estimates of sensitivity (CE(se)) of the PCR proved to be highest at 78.2%, closely followed by the mouse inoculation (MI), the micro-haematocrite centrifugation technique (MHCT) and the mini-anion-exchange centrifugation technique (MAECT) with CE(se) of, respectively, 74.0, 69.6 and 62.4%. The CE(se) of the buffy-coat technique (BCT) at 38.6% and the sodium dodecyl sulfate (SDS) clarification technique at 25.1% were considerably lower. PCR detected consistently all buffaloes infected from week 3 post-infection (PI) onwards. For MI this occurred after 5 weeks PI while for MHCT and MAECT these sustainable high levels were reached in the 7th week PI. BCT and SDS never detected all buffaloes infected. The influence of time and temperature on the viability of T. evansi in heparinized blood from water buffalo was also studied. In general we observed that the survival time tends to be longer when blood is kept at 4 degrees C. In samples kept in direct sunlight parasites became undetectable with the MHCT after 30min. After treatment of the water buffaloes with diminazene aceturate, the PCR signal disappeared within 24h.

Animal Diseases↗
PubMed1997

Phenotypic characterization of Leishmania mexicana pentamidine-resistant promastigotes. Modulation of the resistance during in-vitro developmental life cycle.

Two clones of Leishmania mexicana resistant to 5 microM (LmR5CL2) and 20 microM (LmR20CL1) pentamidine, derived from a parental wild-type clone (LmWTCL3) were selected in vitro using a continuous drug pressure protocol. Both resistant clones expressed a cross-resistance to diminazene aceturate. No differences in their in-vitro infectivity for mouse peritoneal macrophages between wild-type and pentamidine-resistant promastigotes were observed. During these experiments, promastigotes of LmR20CL1 derived from intramacrophagic amastigote forms reverted to the pentamidine-sensitive phenotype, unlike the lower resistant ones. In the same way, when a complete developmental sequence of L. mexicana was achieved in axenic cultures, LmR20CL1 promastigotes derived from axenically growing amastigotes expressed an IC50 value close to the wild-type one, whereas resulting LmR5CL2 promastigotes remained pentamidine resistant. This modulation of the chemoresistance during the developmental life cycle could be significant in the transmission of drug-resistant strains by Phlebotominae as well as in basic research to follow drug resistance during the in-vitro and in-vivo life cycle of Leishmania.

Animals↗
PubMed2002

Screening of acyl hydrazide proteinase inhibitors for antiparasitic activity against Trypanosoma brucei.

The major cysteine proteinase (brucipain) of Trypanosoma brucei is a target for chemotherapy of African Sleeping Sickness. We have screened a non-peptidyl acyl hydrazide proteinase inhibitor library of 500 compounds for inhibition of brucipain. Those 21 compounds with IC(50) values of <40 microM were tested for efficacy against bloodstream forms of T. brucei in cell culture. Eight acyl hydrazides showed 50% or more inhibition of trypanosome replication at <1 microM. The trypanocidal acitivity of the most effective compounds was comparable with those of the commercial antitrypanosomal drugs suramin and diminazene aceturate. However, these acyl hydrazides exhibited varying cytotoxicity towards human HL-60 cells and therefore, only less favourable selectivity indices compared with the commercially available drugs. Nevertheless, the data support the potential of acyl hydrazides as antitrypanosomal chemotherapeutic agents for treatment of sleeping sickness.

Animals↗
PubMed1975

Antiparasitic nitroimidazoles. 9. Synthesis of some 2-(4-dialkylaminomethylstyryl)-and 2-(4-amidinostyryl)5-nitro-1-vinylimidazoles.

A series of 2-styryl-5-nitro-1-vinylimidazoles carrying alkylaminomethyl or amidino functions in the 4 position of the styryl ring was prepared and evaluated for antitrypanosomal activity in mice infected with Trypanosoma rhodesiense. The alkylaminomethyl compounds were found inactive against Trypanosoma cruzi infections in mice. One compound, 2-(4-methylamidinostyryl)-5-nitro-1-vinylimidazole hydrochloride, showed antitrypanosomal activity comparable to the standard drugs suramin, pentamidine, diminazene, and melarsoprol when tested ip against T. rhodesiense infected mice and also showed some activity when tested ip against T. cruzi infected mice.

Amidines↗
PubMed1984

Trypanocidal 1,3-arylene diketone bis(guanylhydrazone)s. Structure-activity relationships among substituted and heterocyclic analogues.

Based on the antitrypanosomal activity of 1,3-diacetylbenzene bis(guanylhydrazone) (4) and 2,6-diacetylpyridine bis(guanylhydrazone) (17), a number of substituted and heterocyclic 1,3-arylene diketone bis(guanylhydrazone)s were prepared and tested against Trypanosoma brucei infections in mice. A wide range of ED50 values was observed among 5-substituted derivatives of 4. The 5-amino analogue 5 and 5-acetamido analogue 6 were about twice as active as 4. 1,3,5-Triacetylbenzene tris(guanylhydrazone) (12) was about 9 times as active as 4 and was approximately one-half as active as the currently used trypanocide diminazene aceturate in this test system. Other 5-derivatives had activity equivalent to or less than that of the parent compound 4. Three new heterocyclic analogues were all less active than 2,6-diacetylpyridine derivative 17 and benzene derivative 4. Ring substitution ortho to the guanylhydrazone side chains was invariably detrimental to activity. Side-chain homologues 1,3-dipentanoylbenzene bis(guanylhydrazone) and 1,3-diacetylbenzene bis(2-imidazolin-2-ylhydrazone) were essentially inactive.

Animals↗
PubMed2002

Financial implications of rearing sheep and goats under natural trypanosomosis challenge at Galana ranch, Kenya.

A study to compare the profitability of rearing sheep and goats under natural trypanosomosis challenge was carried out on Galana ranch in south-eastern Kenya between July 1996 and October 1997. Seventy-nine male weaner sheep and 79 male weaner goats were monitored monthly for weight changes and fortnightly for trypanosomosis. The animals of each species were divided into two groups. Group 1 was an untreated control, while group 2 was treated with isometamidium chloride (Samorin) at 0.5 mg/kg body weight every 3 months. In both groups, trypanosome infections were detected by microscopy and treated with diminazene aceturate (Veriben), at 3.5 mg/kg body weight, when the packed cell volume reached 17% or below. The profitability of each drug regime was expressed as the marginal revenue over the cost of trypanosomosis (MOT). There were greater losses occasioned by trypanosomosis in sheep than in goats. Animals of both species on chemoprophylaxis gave higher MOT values than those that received chemotherapy on diagnosis. However, the MOT values for the chemoprophylactic regime were higher for sheep than for goats, suggesting that the greater weight gain by sheep more then compensated for the higher cost of maintaining them under high trypanosomosis challenge. Thus, a Galana rancher would be better off keeping sheep rather than goats, other things being equal. The marginal revenue per dose of Samorin was lower than that of Veriben for both species, suggesting that strategic use of Samorin timed to precede the peak incidence of trypanosomosis might be a better option to raise the overall profitability in sheep and goats.

Animal Husbandry↗
PubMed1994

Drug resistance and Acanthamoeba keratitis: the quest for alternative antiprotozoal chemotherapy.

Trophozoites and cysts of 20 isolates of Acanthamoeba from the cornea and five from related samples were tested in vitro for sensitivity to ten drugs (three aromatic diamidines, two aminoglycosides, two macrolides, a polyene macrolide antibiotic, an organoarsenical and an antimetabolite) and two cationic antiseptics (chlorhexidine and polyhexamethylene biguanide, PHMB). Only chlorhexidine and PHMB showed uniform amoebacidal activity. Aromatic diamidines (pentamidine isethionate, propamidine isethionate and diminazene aceturate) generally proved effective against both forms of the amoeba; only pentamidine gave synergy with the biguanide while propamidine gave an additive effect. Other drugs tested proved erratic or ineffective against different isolates. Chlorhexidine alone, or together with propamidine, was subsequently used in two patients with proven Acanthamoeba keratitis; the causative isolates were sensitive to the individual compounds and to the combination in vitro. The treatment provided resolution of the clinical disease; amoebae were shown to be nonviable by histology and culture. The combination of chlorhexidine and propamidine is recommended for treatment of proven Acanthamoeba keratitis.

Acanthamoeba↗
PubMed1993

Susceptibility for infection-related glomerulopathy depends on non-MHC genes.

BALB/c mice infected with Trypanosoma brucei and treated seven days after inoculation with Diminazene aceturate develop polyclonal B-cell stimulation, including production of antibodies to known nephritogenic autoantigens and glomerular disease associated with severe albuminuria. To investigate if the susceptibility for glomerular disease in this model is linked to MHC or non-MHC genes, we studied this disease in six mouse strains that were partly congenic for their MHC and partly congenic for their non-MHC genes. The course of the infection was measured by parasitemia and related to (auto)antibody production, proteinuria and glomerular deposition of immunoglobulins. The mouse strains could be divided into two groups. The first group consisted of the C57BL/6 (H-2b), C57BL/10 (H-2b) and B10.D2 (H-2d) strains, which proved to be relatively resistant to infection with Trypanosoma brucei (that is, spontaneous survival > 25 days). In sera of these mice antibodies to a broad range of antigens could be found 14 days after inoculation; no proteinuria was observed. The second group consisted of the BALB/c (H-2d), BALB.B (H-2b) and DBA/2 (H-2d) strains, which were relatively susceptible to the infection. In these animals proteinuria occurred and a broad polyclonal B-cell stimulation was seen 42 days after inoculation. No correlation was found between the specificity of circulating antibodies and the occurrence of proteinuria or a glomerular fluorescence pattern. These results indicate that in this model non-MHC genes govern the outcome of the infection as well as the development of polyclonal B-cell stimulation and proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed2003

Intra-uterine Infection with Babesia bovis in a 2-day-old Calf.

Infection with Babesia bovis was diagnosed in a 2-day-old female calf apparently transmitted in utero. The calf was born as the second calving to a cross-bred beef cow permanently on pasture. Diagnosis was based upon identification of B. bovis in peripheral blood smears and clinical signs which included fever, jaundice, pale mucous membranes and convulsions. Anaemia, leucocytosis, thrombocytopenia and lymphocytosis were noted at the febrile acute stage of the disease. The blood smears revealed evidence of regeneration of toxic neutrophils with a left shift, severe spherocytosis and high degree of basophilic stippling. Elevated concentration of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase were also noted, and were probably the result of haemolysis, dehydration and muscle damage because of recumbancy. Elevated total bilirubin concentration following haemolysis resulted in jaundice. The neurological symptoms observed were probably caused by sludging of parasitized erythrocytes in the brain capillaries. The calf recovered following treatment with diminazene aceturate and the recovery was followed up clinically, haematologically and biochemically.

Animals↗
PubMed2001

In vitro effect of alkaloids on bloodstream forms of Trypanosoma brucei and T. congolense.

The effect of 34 alkaloids of the piperidine, pyridine, tropane, isoquinoline, indole, quinolizidine, quinoline, purine, and steroidal types on the growth of Trypanosoma brucei, T. congolense, and human HL-60 cells was investigated in vitro. Berbamine, berberine, cinchonidine, cinchonine, emetine, ergotamine, quinidine, quinine, and sanguinarine showed trypanocidal activities with ED(50) (50% effective dose) values below 10 microM. Berberine, emetine, and quinidine were the most active compounds found; their ED(50) values and minimum inhibitory concentrations were comparable to those of the antitrypanosomal drugs suramin and diminazene aceturate. However, most of these compounds were also cytotoxic. In the case of emetine, the ratio of cytotoxic/trypanocidal activity was only 3 while for quinidine it was 300 indicating that this alkaloid could be a candidate for further drug development. DNA intercalation in combination with protein biosynthesis inhibition, which is the major mode of action of the active alkaloids, could be responsible for the observed trypanocidal and cytotoxic effects.

Alkaloids↗