Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity

Abstract

Leishmaniasis is a public health issue. It is among the top five parasitic illnesses worldwide and is one of the most neglected diseases. The current treatment disease includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. LASSBio-1736 was described as antileishmanial drug-candidate to cutaneous leishmaniasis, displaying plasma stability and with no preliminary signals of hepatic or renal toxicity. In this paper, we described the in vitro pharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it is in vitro and in vivo leishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and low in vitro systemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmed in vitro and in vivo. It exhibited no cytotoxic effect to mammalian cells and displayed good in –vivo effect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

“…The metabolic stability of compound 5f (LASSBio-2252) was studied as previously described [ 30 ], and 1 mg/mL of human rat microsomes was incubated with compound 2f (10 μM) in the presence and in the absence of the cofactor (i.e., NADPH generating system). After mixing and incubation at 37 °C in a shaking water bath for 1 h, 500 µL cold acetonitrile containing the internal standard was added to terminate the reaction at different time intervals (0, 15, 30, 45 and 60 min).…”

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

“…After each reaction time, 1 mL of cold acetonitrile containing 2 uM internal standard was added to the wells to stop the reaction. The solution was mixed and centrifuged at 24,500× g for 15 min (Universal Centrifuge 320R Hettich) [ 43 , 44 ]. The supernatant (1 mL) was filtrated and placed in vials to be analysed by HPLC.…”

Avaliação Da Prevalência De Cólera Em Dados Hospitalares: Um Estudo Comparativo Entre 2021 E 2022

“…O quadro sintomatológico, por sua vez, é comumente dividido em três períodos: início ou da diarreia premonitória, cólera propriamente dita e o estágio de reação. São nesses períodos em que são diferenciados os sinais sintomas mais evidentes, tais como a diarreia com fezes líquidas acompanhadas de uma particular coloração na fase inicial, vômitos frequentes e câimbras gástricas durante o estágio de cólera e o desaparecimento dos sintomas de algidez e normalização da circulação e das funções orgânicas ao longo da etapa de reação ( QUEIRÓZ, 1911).…”

“…Nesse sentido, a correlação entre um saneamento de qualidade junto à diminuição de doenças de veiculação hídrica é imperativa quando se trata de políticas de prevenção (QUEIRÓZ, 1911).…”