Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
| Autor: | Rolf W. Winter, Tracey L. Schultz, Vern B. Carruthers, Aaron Nilsen, Sovitj Pou, Alyssa J. Miller, Michael K. Riscoe, Rozalia Dodean, Lev N. Zakharov, Igor Bruzual, J. Stone Doggett |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Cmax Carbonates Pharmacology Quinolones Carbonate ester 03 medical and health sciences chemistry.chemical_compound Mice Medicine Animals Pharmacology (medical) Experimental Therapeutics Prodrugs Adverse effect 030304 developmental biology 0303 health sciences biology 030306 microbiology business.industry Area under the curve Toxoplasma gondii Brain Esters Prodrug Quinolone biology.organism_classification medicine.disease Toxoplasmosis 3. Good health Bioavailability Infectious Diseases Toxoplasmosis Animal chemistry business Toxoplasma |
| Zdroj: | Antimicrob Agents Chemother |
| Popis: | Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|