The use of a rapid curative chemotherapeutic regimen for experimental infection of the central nervous system (CNS) of mice by Trypanosoma brucei has indicated that this 'aggressive' treatment does not precipitate the development of post-treatment meningo-encephalopathy. If meningoencephalitis is already established at the time of the treatment there is no exacerbation of the reaction and the CNS pathology rapidly returns to normal. Paralysis is not precipitated by the rapid curative treatment of either primary or relapse infections, in contrast to non-curative treatments. Mice showing this overt clinical paralysis in addition to histological meningoencephalitis soon regain mobility and the CNS pathology is rapidly resolved after curative chemotherapy. These experiments provide no support for the concept that the rapid release of trypanosome antigens in situ in the brain exacerbates the post-treatment encephalopathy. They do support the concept that it is viable trypanosomes remaining in the brain which are responsible.

Animals↗

PubMedDate not supplied

Successful treatment of experimental murine Trypanosoma brucei infection with topical melarsoprol gel.

Melarsoprol gel applied topically (0.1 mL for at least 2 d) can cure late-stage Trypanosoma brucei brucei and T. b. rhodesiense infections in mice. The best regimen was 3 applications at approximately 0, 6, and 24 h. The melarsoprol gel retained its activity at room temperature for at least 63 d. There was only minimal skin irritation and no sign of toxicity.

Administration, Topical↗

PubMedDate not supplied

Factors affecting blood sampling for anaemia and parasitaemia in bovine trypanosomiasis.

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Anemia↗

PubMedDate not supplied

The influence of dietary protein on live bodyweight, degree of anaemia and erythropoietic responses of Scottish blackface sheep infected experimentally with Trypanosoma congolense.

The present study investigated the influence of dietary protein on the intensity of parasitaemia, degree of anaemia and erythropoietic responses, in sheep experimentally infected with Trypanosoma congolense and given either a high protein diet (116 g digestible crude protein [DCP] per day) or a low protein diet (51.5 g DCP per day). It was observed that infected and control animals on the high protein diet grew at similar rates while infected animals on the low protein diet experienced marked retardation of growth compared with their uninfected controls. Dietary protein had no influence on the degree of anaemia that followed infection. Measurement of blood volumes revealed that low protein infected group had significantly lower mean circulating red cell volume than their controls. Ferrokinetic measurements indicated that plasma iron turnover rates (PITR) and 59Fe incorporation rates were higher in the high protein infected group than in the low protein infected group, although these differences were not significant. These observations indicate that infected animals on a high protein tended to show greater enhancement of erythropoietic activity that infected animals on low protein diet.

Anemia↗

PubMedDate not supplied

Inhibition of hepatic drug metabolism by phenothiazine tranquilizers: quantitative structure-activity relationships and selective inhibition of cytochrome P-450 isoform-specific activities.

Twelve phenothiazine tranquilizers were investigated for the capacity to inhibit rat hepatic microsomal cytochrome P-450 (P-450) isoform-specific drug oxidation in vitro. All congeners were substituted in the 2-(carbocyclic) and 10- (thiazinyl nitrogen of the thiazine ring) positions. Cytochrome P-450 PB-B-mediated 7-pentylresorufin O-depentylase and P-450 BNF-B-mediated 7-ethylresorufin O-deethylase activities were effectively inhibited by most of the compounds. Structure-activity correlations revealed the apparent importance of the lipophilicity of the 2-substituent, and the negative effect of flexibility in the 10-position substituent, on anti-P-450 PB-B potency. On the other hand, inhibition of P-450 BNF-B activity was promoted by bulkiness and branching within the 10-substituent and the shape/bulk of the 2-group. From this analysis it is likely that the active site of P-450 PB-B is relatively small with at least one lipophilic region that may be involved in substrate and inhibitor binding. The active site of P-450 BNF-B is relatively large, and steric properties, rather than lipophilic character, appear to determine inhibition by phenothiazines. Derivatives with piperidinyl and piperazinyl ring systems in the 10-position were relatively active inhibitors of P-450 PCN-E (or an immunochemically related form of P-450) that catalyzes androst-4-ene-3,17-dione 6 beta-hydroxylation, and P-450 UT-A-mediated 16 alpha-hydroxylase activity. In contrast, steroid 7 alpha-hydroxylation (P-450 UT-F) and N-nitrosodimethylamine N-demethylation (P-450j) were refractory to inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Hepatic microsomal metabolism of the anthelmintic benzimidazole fenbendazole: enhanced inhibition of cytochrome P450 reactions by oxidized metabolites of the drug.

Potentiation of the anthelmintic action of benzimidazole carbamates, such as fenbendazole [methyl 5(6)-(phenylthio)-1H-benzimidazol-2-ylcarbamate], has been noted during concurrent administration of benzimidazoles that possess no intrinsic anthelmintic activity. This study investigated the possibility that inhibition of P450 enzymes by fenbendazole and its metabolites could play a role in the potentiation phenomenon. Fenbendazole underwent P450-mediated oxidation in microsomes from untreated rat liver to the sulfoxide and (4'-hydroxyphenyl)thio metabolites [2.92 and 2.87 nmol/(mg of protein.h)]. Pretreatment of rats with phenobarbital or dexamethasone enhanced sulfoxidation by 1.9- and 2.9-fold, respectively. 4'-Hydroxylation was increased slightly (by 28%) by phenobarbital and decreased slightly (by 41%) by dexamethasone. Induction also promoted further metabolism of the sulfoxide to fenbendazole sulfone. Immunoinhibition and chemical inhibition studies suggested that P450 3A proteins and the flavin-containing monooxygenase are involved in sulfoxide and sulfone formation whereas 4'-hydroxylation involved the P450s 2C11, 2C6, and 2B1, depending on the type of induction. In untreated rat liver, the sulfoxide and (4'-hydroxyphenyl)thio metabolites of fenbendazole were relatively potent inhibitors of P450-mediated androstenedione 16 alpha-, 16 beta-, and 6 beta-hydroxylation (IC50 values of 42, 36, and 74 microM, respectively); 7 alpha-hydroxylase activity was uninhibited. In contrast, fenbendazole and its sulfone metabolite were not inhibitors of these reactions. Mixed-function oxidase activities in phenobarbital-induced rat hepatic microsomes were refractory to inhibition by most compounds, but P450 1A1 mediated activities in microsomes from beta-naphthoflavone-induced rat liver were quite susceptible to inhibition by fenbendazole sulfoxide. Studies with two analogous sulfoxides yielded similar findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗