RESUMO
BACKGROUND: Acute vulvovaginal candidiasis (VVC) is common among women, but current azole antifungal treatments are often associated with safety and resistance issues. VT-1161 (oteseconazole) is an oral agent with increased selectivity for fungal CYP51. In this phase 2 clinical study, we evaluated the efficacy and safety of VT-1161 vs fluconazole in participants with moderate to severe acute VVC. METHODS: Participants presenting with an acute episode of VVC (nâ =â 55) were randomized to receive VT-1161 300 mg once daily (q.d.) for 3 days, 600 mg q.d. for 3 days, or 600 mg twice daily (b.i.d.) for 3 days or to receive a single dose of fluconazole 150 mg (FDA-approved dose to treat acute VVC). Participants were followed for 6 months. The primary outcome was the proportion of participants with therapeutic (clinical and mycological) cure at day 28. RESULTS: A larger proportion of participants in the per-protocol population experienced therapeutic cure in the VT-1161 300 mg q.d. (75.0%), VT-1161 600 mg q.d. (85.7%), and VT-1161 600 mg b.i.d. (78.6%) groups vs the fluconazole group (62.5%); differences were not statistically significant. At 3 and 6 months, no participants in the VT-1161 groups vs 28.5% and 46.1% in the fluconazole group, respectively, had evidence of mycological recurrence. No serious adverse events or treatment-emergent adverse events leading to discontinuation were reported. CONCLUSIONS: The majority of participants across all treatment groups achieved therapeutic cure at day 28. VT-1161 was well tolerated at all dose levels through 6 months of follow-up. CLINICAL TRIALS REGISTRATION: NCT01891331.
Assuntos
Candidíase Vulvovaginal , Administração Oral , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Feminino , Fluconazol/uso terapêutico , Humanos , Piridinas/uso terapêutico , Tetrazóis/uso terapêuticoRESUMO
BACKGROUND: Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period. STUDY DESIGN: Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of ≥3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with ≥1 culture-verified acute vulvovaginal candidiasis episodes through week 48. RESULTS: In the intent-to-treat population, the proportion of subjects with ≥1 acute vulvovaginal candidiasis episodes ranged from 0-7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings. CONCLUSION: In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis.
Assuntos
Inibidores de 14-alfa Desmetilase/administração & dosagem , Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Piridinas/administração & dosagem , Tetrazóis/administração & dosagem , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Método Duplo-Cego , Feminino , Fluconazol/uso terapêutico , Humanos , Quimioterapia de Indução , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Recidiva , Adulto JovemRESUMO
A phase 1 trial of fusidic acid (CEM-102), an oral fusidane class antibiotic under development for treatment of gram-positive acute bacterial skin and skin structure infections, evaluating pharmacokinetics and safety is described. A randomized, double-blinded, placebo-controlled, dose escalation study was conducted in healthy adult subjects in the fasting state. Plasma exposure after multiple doses was higher than for single doses, indicating accumulation. Loading doses designed to optimize pharmacodynamic effects were well tolerated and achieved near-steady state concentrations of CEM-102 at 24 h. CEM-102 was safe and generally well tolerated at all single, multiple, and loading doses administered.
Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Ácido Fusídico/efeitos adversos , Ácido Fusídico/farmacocinética , Administração Oral , Adolescente , Adulto , Antibacterianos/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Ácido Fusídico/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple-center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142.
Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Ácido Fusídico/efeitos adversos , Ácido Fusídico/uso terapêutico , Cocos Gram-Positivos/efeitos dos fármacos , Dermatopatias Bacterianas/tratamento farmacológico , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Acetamidas/uso terapêutico , Doença Aguda , Administração Oral , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/microbiologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Ácido Fusídico/administração & dosagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Linezolida , Masculino , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Oxazolidinonas/efeitos adversos , Oxazolidinonas/uso terapêutico , Dermatopatias Bacterianas/microbiologia , Resultado do Tratamento , Adulto JovemRESUMO
The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 µg/ml to 19.647 µg/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC0-t) ranged from 0.0402 µg·h/ml to 28.599 µg·h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 µg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 µg·h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median Tmax values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.
Assuntos
Macrolídeos/administração & dosagem , Macrolídeos/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Método Duplo-Cego , Jejum/sangue , Feminino , Humanos , Macrolídeos/sangue , Masculino , Pessoa de Meia-Idade , Triazóis/sangue , Adulto JovemRESUMO
Cation-exchange HPLC analysis of urine from dogs given large daily doses of pyridoxamine revealed an unidentified metabolite hypothesized to be N-methylpyridoxamine. Identity was established by N-methylpyridoxamine synthesis and HPLC comparison to the canine metabolite. Compound synthesis was confirmed by IR, NMR, UV-vis and emission spectroscopy. It seems to have less fluorescent character than other routinely-measured vitamin B(6) metabolites. Upon administration of substantial pyridoxamine doses, N-methylpyridoxamine appears to be a quantifiable canine urine metabolite, although, at either pharmacological or dietary pyridoxamine intakes, its relevance to vitamin B(6) metabolism in other species, including humans, is not yet determined.
Assuntos
Cães/urina , Piridoxamina/análogos & derivados , Vitamina B 6/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piridoxamina/urina , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
BACKGROUND/AIMS: Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation. METHODS: The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr)
Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Piridoxamina/farmacologia , Complexo Vitamínico B/farmacologia , Adolescente , Adulto , Idoso , Creatina/sangue , Nefropatias Diabéticas/sangue , Método Duplo-Cego , Feminino , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Humanos , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Nonenzymatic reactions between sugars or lipids and protein and formation of advanced glycation and lipoxidation end products (AGE/ALEs) contribute to the chemical modification and cross-linking of tissue proteins with age. Accelerated formation of AGE/ALEs during hyperglycemia is implicated in the development of diabetic complications. In this study, we examined the effect of the AGE/ALE inhibitor pyridoxamine on chemical modification and cross-linking of collagen and development of renal disease in the streptozotocin-diabetic rat. METHODS: Diabetic rats were treated with pyridoxamine; parallel experiments were conducted with aminoguanidine, the prototype AGE inhibitor. Progression of renal disease was evaluated by measurements of albuminuria and plasma creatinine concentration. Plasma triglycerides, cholesterol, lactate and pyruvate were measured by enzymatic assays, and AGE/ALEs in skin collagen by HPLC and GC-MS assays. RESULTS: Pyridoxamine significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia and plasma lactate/pyruvate ratio in diabetic rats, without an effect on blood glucose or glycated hemoglobin. AGE/ALEs, fluorescence and cross-linking of skin collagen increased approximately twofold in diabetic versus control rats after seven months of diabetes. Pyridoxamine caused a significant (25 to 50%) decrease the AGE/ALEs, carboxymethyllysine and carboxyethyllysine, cross-linking and fluorescence in skin collagen of diabetic rats, but did not affect pentosidine. CONCLUSIONS: Pyridoxamine inhibits the progression of renal disease, and decreases hyperlipidemia and apparent redox imbalances in diabetic rats. Pyridoxamine and aminoguanidine had similar effects on parameters measured, supporting a mechanism of action involving AGE/ALE inhibition.