RESUMO
Com mudanças na expectativa de vida, comorbidades edisponibilidade de novos fármacos, aumentou a ocorrênciade interações medicamentosas por mecanismos farmacocinéticose farmacodinâmicos. Para a biotransformação dosmedicamentos, os organismos desenvolveram sistemas enzimáticoscapazes de metabolizar e excretar esses produtos.Os polimorfismos genéticos dessas enzimas condicionamsua eficiência em metabolizar determinados medicamentos.A conjugação com moléculas solúveis em água, adicionadasao medicamento, facilitam sua excreção. Os transportadoresdesempenham importante papel no influxo, efluxo e na excreçãode medicamentos através dos sistemas biliar e urinário.O tratamento de doenças cardiovasculares frequentementeenvolve uso de múltiplos fármacos, principalmente nos pacientesidosos e portadores de comorbidades. Nesse sentido, éimportante o conhecimento dessas interações medicamentosas,frequentemente responsáveis pelos insucessos terapêuticos epela ocorrência de efeitos adversos...
With changes in life expectancy, co-morbidities and theavailability of new drugs, the occurrence of drug interactionsby pharmacokinetic and pharmacodynamic mechanisms hasincreased. For the bio-transformations of medications theorganisms have developed enzymatic systems able to metabolizeand excrete these products. The genetic polymorphisms ofthese enzymes affect their efficiency in metabolizing certaindrugs. The combination with water-soluble molecules addedto the medication facilitates the excretion. Transporters playan important role in the inflow, outflow and the excretion ofmedications through the biliary and urinary systems. Thetreatment of cardiovascular diseases often involves the useof multiple drugs especially in elderly patients and patientswith co-morbidities. In this sense, it is very important theknowledge about these drugs interactions which are oftenresponsible for the therapeutic failure and for the occurrenceof adverse effects...
Assuntos
Humanos , Feminino , Idoso , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Interações Medicamentosas/fisiologia , Cetoconazol/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Membrana Celular/metabolismo , Polimorfismo Genético/genéticaRESUMO
In this work we described the development of a new solid oral formulation of ketoconazole, a broad-spectrum antifungal agent that belongs to the class II of Biopharmaceutics Classification System (BCS). The ketoconazole raw material supplier was selected to present a best flow and compactation. In addition we used direct compression and superdisintegrants associated to polyols to enhance the dissolution of the ketoconazole tablets. The dissolution was evaluated based in level C in vivo/in vitro correlation established. The best formulation was obtained with croscarmellose/maltose association that in the accelerated stability assays presented no differences on quality specifications and no drug-excipients interaction by DSC analyses. In this work it was possible to confirm the use of sugar-based excipients as suitable dissolution enhancers in pharmaceutical technology and real processes conditions.
Assuntos
Antifúngicos/farmacocinética , Excipientes/química , Cetoconazol/farmacocinética , Carboximetilcelulose Sódica/química , Estabilidade de Medicamentos , Dureza , Humanos , Maltose/química , Solubilidade , Comprimidos/análise , Equivalência TerapêuticaRESUMO
BACKGROUND: Loratadine is a long-acting antihistamine with selective peripheral histamine H(1)-receptor antagonistic activity and fewer sedative effects compared with conventional antihistamines, and is widely used in Mexico. Although several generic formulations of loratadine are available in Mexico, based on a literature search, information concerning the bioavailability of each formulation in the Mexican population is not available. OBJECTIVE: The aim of this study was to compare the bioavailability and tolerability of 2 oral formulations of loratadine 20 mg (two 10-mg tablets) used in Mexico: Sensibit (test formulation; Laboratorios Liomont S.A. de C.V., Mexico City, Mexico) and Clarityne (reference formulation; Schering-Plough S.A. de C.V., Mexico City, Mexico) in healthy volunteers. METHODS: This open-label, randomized, 2-period crossover study was conducted at Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico. Eligible subjects were healthy male Mexican volunteers aged > or=18 years. Subjects were randomly assigned to receive a single 20-mg dose (two 10-mg tablets) of the test or reference formulation, followed by a 2-week washout period, followed by the same dose of the alternate formulation. A 400-mg dose of ketoconazole (2 doses in 24 hours) was administered to each subject before the administration of each formulation, and a 200-mg dose of ketoconazole was given together with each formulation (ie, a total of 600 mg of ketoconazole was administered). Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(maX), AUC(0-t), and AUC(0-infinity), blood samples were drawn at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 5, 8, 12, 16, and 22 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of C(maX) and AUC were within the predetermined equivalence range of 80% to 125%. Tolerability was assessed by monitoring vital signs and subject interview regarding the potential presence of adverse events (AEs). RESULTS: Thirty-two subjects were enrolled in the study (mean age, 22 years [range, 18-28 years]; mean weight, 68.9 kg [range, 58-79 kg]; mean height, 170.8 cm [range, 158-183 cm]). Sixteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of CmaX, AUC(0-t), and AUC(0-infinity) were 81.43% to 106.01%, 83.12% to 100.23%, and 84.06% to 101.10% (all, P < 0.05), meeting the predetermined criteria for bioequivalence. Similar results were found for data without a logarithmic transformation. No AEs were reported throughout the study. CONCLUSIONS: In this small study in healthy Mexican volunteers, a single, 20-mg dose of the test formulation of loratadine was found to be bioequivalent to that of the reference formulation based on the rate and extent of absorption when concomitantly administered with ketoconazole. Both formulations were well tolerated.
Assuntos
Antifúngicos/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Hipersensibilidade/sangue , Cetoconazol/farmacocinética , Loratadina/farmacocinética , Administração Oral , Adolescente , Adulto , Antifúngicos/administração & dosagem , Disponibilidade Biológica , Estudos Cross-Over , Interações Medicamentosas , Quimioterapia Combinada , Seguimentos , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Humanos , Hipersensibilidade/tratamento farmacológico , Cetoconazol/administração & dosagem , Loratadina/administração & dosagem , Masculino , México , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
A randomized, crossover study was conducted in 24 healthy female volunteers to compare the bioavailability of two brands of ketoconazole (200 mg) tablets; Onofin-K (Farmacéuticos Rayere S.A., Mexico) as the test and Nizoral (Janssen-Cilag, Mexico) as the reference products. The study was performed at the Clinical Pharmacology Research Center of the Hospital General de Mexico in Mexico City. Two tablets (400 mg) were administered as a single dose with 250 ml of water after a 12 h overnight fast on two treatment days separated by a 1 week washout period. After dosing, serial blood samples were collected for a period of 12 h. Plasma harvested was analysed for ketoconazole by a modified and validated HPLC method with UV detection in the range 400-14000 ng/ml, using 200 microl of plasma in a full-run time of 2.5 min. The pharmacokinetic parameters AUC(0-t), AUC(0-alpha), Cmax, Tmax and t(1/2) were determined from plasma concentrations of both formulations and the results discussed. AUC(0-t), AUC(0-alpha) and Cmax were tested for bioequivalence after log transformation of data, and no significant differences were found either in 90% classic confidence interval or in the Anderson and Hauck test (p < 0.05). Based on statistical analysis, it is concluded that Onofin-K is bioequivalent to Nizoral.
Assuntos
Cetoconazol/sangue , Cetoconazol/farmacocinética , Adolescente , Adulto , Análise de Variância , Química Farmacêutica , Intervalos de Confiança , Estudos Cross-Over , Feminino , Humanos , México , Pessoa de Meia-Idade , Comprimidos com Revestimento Entérico , Equivalência TerapêuticaAssuntos
Humanos , Dermatologia , Interações Medicamentosas , Biotransformação , Farmacocinética , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Anfotericina B/efeitos adversos , Anfotericina B/farmacocinética , Eritromicina/efeitos adversos , Eritromicina/farmacocinética , Corticosteroides/efeitos adversos , Corticosteroides/metabolismo , Griseofulvina/efeitos adversos , Griseofulvina/farmacocinética , Cetoconazol/efeitos adversos , Cetoconazol/farmacocinéticaAssuntos
Humanos , Interações Medicamentosas , Dermatologia , Farmacocinética , Biotransformação , Cetoconazol/farmacocinética , Cetoconazol/efeitos adversos , Griseofulvina/efeitos adversos , Griseofulvina/farmacocinética , Anfotericina B/farmacocinética , Anfotericina B/efeitos adversos , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Eritromicina/efeitos adversos , Eritromicina/farmacocinética , Corticosteroides/efeitos adversos , Corticosteroides/metabolismoRESUMO
Patients and methods: Thirty four patients with more than one year after the transplantation, with stable renal function and receiving triple immunosuppression were studied. Conventional cyclosporine was changed to the microemulsion form maintaining the same daily dose. Drug serum levels, serum creatinine and blood pressure were measured within two to eight months after the conversion. Doses of microemulsion cyclosporine were adjusted to achieve serum levels of 150 ñ 40 ng/ml. Results: Microemulsion cyclosporine induced a slight initial increase in blood cyclosporine levels. Afterwards, levels were more stable than with conventional cyclosporine (165-185 and 145-210 ng/ml respectively) and the dispersion of values were lower (standard deviations of 70 and 100 ng/ml respectively). Twenty three patients did not require dose adjustments, in four it was reduced and in five it was increased. There were no changes in serum creatinine or blood pressure after the conversion. Conslusion: More stable serum levels without adverse reactions were obtained with microemulsion cyclosporine. Doses of cyclos porine need not to be changed during the conversion
Assuntos
Humanos , Masculino , Feminino , Transplante de Rim/reabilitação , Ciclosporina/farmacocinética , Cetoconazol/farmacocinética , Azatioprina/administração & dosagem , Prednisona/administração & dosagem , Nitrendipino/administração & dosagem , Seguimentos , Terapia de Imunossupressão/métodosRESUMO
Se evaluó un micrométodo para la realización de pruebas de sensibilidad de levaduras frente a antifúngicos, basado en el macrométodo en medio líquido estandarizado por el National Committee for Clinical Laboratory Standards (NCCLS) Subcommittee on Antifungal Susceptibility Testing. En este trabajo se compararon ambos métodos utilizando 6 cepas de referencia de diferente sensibilidad a los siguientes antifúngicos, anfotericina B (AMB), flucitosina (5FC), fluconazol (FCZ), itraconazol (ITZ), ketoconazol (KTZ) y miconazol (MCZ). Se observaron variaciones de sólo 1 ó 2 diluciones entre los resultados de las concentraciones inhibitorias mínimas (CIM) obtenidas con las dos técnicas. Asimismo, se compararon las lecturas visuales de CIM por micrométodo con las mediciones turbidimétricas del crecimiento en distintas concentraciones de antifúngicos frente a 47 aislamientos de Candida albicans. Existió una correlación significativa (p<0.001) entre CIM visual y la inhibición del 80 por ciento de crecimiento determinada por turbidimetría con AMB, 5FC, FCZ, ITZ y MCZ; en cambio no hubo correlación alguna para KTZ (p=1.00)
Assuntos
Antifúngicos/uso terapêutico , Anfotericina B/farmacocinética , Fluconazol/farmacocinética , Flucitosina/farmacocinética , Itraconazol/farmacocinética , Cetoconazol/farmacocinética , Miconazol/farmacocinética , Testes de Sensibilidade Microbiana , Leveduras/efeitos dos fármacos , ArgentinaRESUMO
Se evaluó un micrométodo para la realización de pruebas de sensibilidad de levaduras frente a antifúngicos, basado en el macrométodo en medio líquido estandarizado por el National Committee for Clinical Laboratory Standards (NCCLS) Subcommittee on Antifungal Susceptibility Testing. En este trabajo se compararon ambos métodos utilizando 6 cepas de referencia de diferente sensibilidad a los siguientes antifúngicos, anfotericina B (AMB), flucitosina (5FC), fluconazol (FCZ), itraconazol (ITZ), ketoconazol (KTZ) y miconazol (MCZ). Se observaron variaciones de sólo 1 ó 2 diluciones entre los resultados de las concentraciones inhibitorias mínimas (CIM) obtenidas con las dos técnicas. Asimismo, se compararon las lecturas visuales de CIM por micrométodo con las mediciones turbidimétricas del crecimiento en distintas concentraciones de antifúngicos frente a 47 aislamientos de Candida albicans. Existió una correlación significativa (p<0.001) entre CIM visual y la inhibición del 80 por ciento de crecimiento determinada por turbidimetría con AMB, 5FC, FCZ, ITZ y MCZ; en cambio no hubo correlación alguna para KTZ (p=1.00) (AU)
Assuntos
Testes de Sensibilidade Microbiana/métodos , Antifúngicos/uso terapêutico , Anfotericina B/farmacocinética , Flucitosina/farmacocinética , Fluconazol/farmacocinética , Cetoconazol/farmacocinética , Miconazol/farmacocinética , Itraconazol/farmacocinética , Leveduras/efeitos dos fármacos , ArgentinaRESUMO
Se estudia la degradación del ketoconazol en condiciones aceleradas de degradación y su compatibilidad química en los excipientes más comunes empleados en la formulación de formas farmacéuticas tópicas. Se obtiene como resultado que el principio activo es compatible con los excipientes considerados a excepción del polietilenglicol 400, así como que es resistente a la degradación en las condiciones expuestas