RESUMEN
Background: Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods: The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships. Results: F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9-19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan. Conclusions: F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.
Asunto(s)
Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergillus flavus/efectos de los fármacos , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Pirroles/farmacocinética , Pirroles/uso terapéutico , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Aspergilosis Pulmonar Invasiva/microbiología , Aspergilosis Pulmonar Invasiva/patología , Ratones , Triazoles/farmacocinética , Triazoles/uso terapéutico , Voriconazol/farmacocinética , Voriconazol/uso terapéuticoRESUMEN
OBJECTIVE: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response. METHODS: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology. RESULTS: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction. CONCLUSION: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response.
Asunto(s)
Aterosclerosis/complicaciones , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Ácidos Heptanoicos/farmacología , Metabolismo de los Lípidos/genética , Polimorfismo de Nucleótido Simple , Pirroles/farmacología , Atorvastatina , Dislipidemias/complicaciones , Dislipidemias/metabolismo , Femenino , Genotipo , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/uso terapéutico , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Pirroles/farmacocinética , Pirroles/uso terapéutico , Resultado del TratamientoRESUMEN
Because statins and ajoene inhibit the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, we evaluated the hypothesis that the cytotoxic effect of these compounds may be potentiated when both are used in combination on tumor cells. We showed that cotreatment of the murine melanoma B16F10 cell with statins (atorvastatin and pravastatin) and ajoene, all at nontoxic doses, dramatically increased their cytotoxicity. B16F10 cell death induced by statins, but not by ajoene, was prevented by mevalonate and geranylgeranylpyrophosphate. To our knowledge, this is the first report that the combination of statins and ajoene, which alters the mevalonate pathway, might potentiate their cytotoxic effects on tumor cells.
Asunto(s)
Disulfuros/farmacología , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Melanocitos/efectos de los fármacos , Melanoma Experimental/patología , Pravastatina/farmacología , Pirroles/farmacología , Animales , Apoptosis/efectos de los fármacos , Atorvastatina , Línea Celular Tumoral/efectos de los fármacos , Disulfuros/antagonistas & inhibidores , Disulfuros/farmacocinética , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Citometría de Flujo , Ácidos Heptanoicos/antagonistas & inhibidores , Ácidos Heptanoicos/farmacocinética , Ácido Mevalónico/farmacología , Ratones , Fosfatos de Poliisoprenilo/farmacología , Pravastatina/antagonistas & inhibidores , Pravastatina/farmacocinética , Pirroles/antagonistas & inhibidores , Pirroles/farmacocinética , Sulfóxidos , Terpenos/metabolismoRESUMEN
The statins or HMG-CoA reductase inhibitors are considered one of the most effective classes of drugs for reducing LDL and total cholesterol. Although, statin treatment has beneficial effects in the prevention of cardiovascular disease, considerable inter-individual variation exists in response to statin therapy, as well as in the incidence of adverse effects. Genetic factors contribute to patients' inter-variability in the lipid-lowering response to statins,drug-interactions and the occurrence of muscle damage havebeen reported. However, studies investigating aspects of pharmacokinetics, pharmacodynamics and disease-related genes have found no association that could impact on the decisions to treat with statins. Improved strategies that assess the simultaneous influence of multiple relevant susceptibility factors on disease risk (eg, diet, lifestyle and gene effects) are required. Data from pharmacogenetics studies investigating the association between gene variation and drug response and/or susceptibility to adverse effects are promising and are expected to impact on the clinical treatment of hypercholesterolemia.
Asunto(s)
Variación Genética , Ácidos Heptanoicos/efectos adversos , Ácidos Heptanoicos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Hipercolesterolemia/genética , Enfermedades Musculares/genética , Pirroles/efectos adversos , Pirroles/farmacocinética , Animales , Atorvastatina , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Colesterol/genética , Colesterol/metabolismo , Ácidos Heptanoicos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Enfermedades Musculares/inducido químicamente , Pirroles/uso terapéutico , Factores de RiesgoRESUMEN
A fast, sensitive and specific method is presented for the quantification of RSD921 in human plasma by liquid chromatography coupled with tandem mass spectrometry using tri-deuterated RSD921 (3d-RSD921) as an internal standard. A single-step liquid/liquid extraction was performed with diethyl ether/hexane (80 : 20, v/v) using 0.5 ml of plasma. The plasma calibration curves were linear from 0.1 to 20 ng ml(-1) (r > 0.999). Between-run precision, based on the percent relative deviation for replicate (n = 40) quality controls, was < or =7.27% (0.5 ng ml(-1)), < or =7.39% (5.0 ng ml(-1)), and < or =5.06% (20.0 ng ml(-1)). Between-run accuracies, based on the relative error, were +/-2.59%, +/-1.23% and +/-1.64% respectively. The method was developed to evaluate the pharmacokinetic profile after 15 min of intravenous stepwise-ascending infusion dose of RSD921 in 18 healthy volunteers. A dissociation study of protonated RSD921 and 3d-RSD921 by collision-induced dissociation using in-source fragmentation and tandem mass spectrometry is also presented.