There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.DOI:
http://dx.doi.org/10.7554/eLife.09744.001
A novel series of pyridyl nitrofuranyl isoxazolines were synthesized and evaluated for their antibacterial activity against multiple drug resistant (MDR) Staphylococcus strains. Compounds with piperazine linker between the pyridyl group and isoxazoline ring showed better activity when compared to compounds without the piperazine linker. 3-Pyridyl nitrofuranyl isoxazoline with a piperazine linker was found to be more active than corresponding 2-and 4-pyridyl analogues with MICs in the range of 4-32µg/mL against MDR Staphylococcus strains. The eukaryotic toxicity of the compounds was tested by MTT assay and were found to be non-toxic against both non-tumour lung fibroblast WI-38 and cervical cancer cell line HeLa. The most active pyridyl nitrofuranyl isoxazoline compound showed improved activity against a panel of Staphylococcus strains compared to nitrofuran group containing antibiotic nitrofurantoin.
While testing the toxicity of acid o. I per cent. salvarsan solution when injected intravenously in rabbits, 1 it was noticed that the animals stood a second injection after an interval of two to four weeks just as well as the first one. This was of some interest because, if the drug sensitized the animals, that is, rendered them anaphylactic, this second injection ought to have produced symptoms characteristic of this interesting condition. In order to test still further whether or not salvarsan can produce a state of hypersensitiveness, a number of guinea pigs also were used, for these animals can be sensitized more readily and more certainly than rabbits, at least as far as horse serum is concerned.It must be emphasized at once, however, that the main object of this investigation was not to establish whether anaphylaxis of any degree could be obtained with salvarsan, but only to find out whether a second or third injection could produce dangerous and fatal consequences.Both acid and alkaline solutions were used, and the strength was chiefly o.i per cent. The alkaline solution was prepared by adding one cubic centimeter of normal sodium hydrate for every o.I gram of the drug which had been ground into solution with a small amount of o. 9 per cent. saline. This solution was then further diluted by o. 9 per cent. saline.As criteria for the state of acute anaphylaxis, the clinical signs and pathological picture which Lewis and I s have proven to be characteristic for guinea pigs were to be used; for rabbits, the train of symptoms and physiological findings which I have de-*
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.