Ginkgo biloba attenuated detrimental inflammatory and oxidative events due to Trypanosoma brucei rhodesiense in mice treated with melarsoprol.

BACKGROUND: The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB. METHODOLOGY: Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB. RESULTS: Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite. CONCLUSION: Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.

Pharmacokinetics, Trypanosoma brucei gambiense efficacy, and time of drug action of DB829, a preclinical candidate for treatment of second-stage human African trypanosomiasis.

Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies.

Screening compounds for sleeping sickness therapy without relapse.

The finding of an intracellular stage of Trypanosoma brucei in ependymal cells of the choroid plexus (Abolarin et al., 1986) and of the lining of the ventricles (Ormerod and Hussein, 1986) has suggested a new technique for screening trypanocidal compounds against the failure of drugs to eliminate "occult" stages of the infection (Raseroka and Ormerod, 1986). A (donor) mouse, infected for 28 days, is dosed with a drug, or combination of drugs, and samples of blood, cerebral cortex, choroid plexus and lining of ventricle are injected into clean (recipient) mice. The response of recipient mice shows whether the part, under examination, of the donor mouse has been cleared of trypanosomes. Suramin clears the blood and cerebral cortex but not sites containing ependymal cells (i. e. choroid plexus and lining of ventricle). Melarsoprol is active in all sites but is not always effective. DFMO clears the ependymal cells but its action elsewhere is difficult to evaluate. Metronidazole (inactive on its own), when given with suramin is active at all sites. Bleomycin was the most effective single compound. Bleomycin, an anti-cancer agent registered for use in man, should receive clinical evaluation for sleeping sickness: there is evidence, however, of incompatibility with DFMO.