RESUMEN
The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.
Asunto(s)
Bezafibrato/administración & dosificación , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/administración & dosificación , Niacina/administración & dosificación , Animales , Colesterol/sangre , Quimioterapia Combinada , Masculino , Ratas , Ratas Endogámicas Lew , Triglicéridos/sangreRESUMEN
PURPOSE: To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other "gastrointestinal (GI) drugs." Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. METHODS: The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. RESULTS: In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. CONCLUSIONS: The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
Asunto(s)
Bezafibrato/farmacología , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Lípidos/sangre , Animales , Bezafibrato/administración & dosificación , Bezafibrato/farmacocinética , Colesterol/sangre , Colesterol en la Dieta/administración & dosificación , HDL-Colesterol/sangre , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Duodeno , Inhibidores Enzimáticos/farmacología , Hiperlipidemias/sangre , Hipolipemiantes/administración & dosificación , Hipolipemiantes/farmacocinética , Lipasa/antagonistas & inhibidores , Lipoproteínas HDL/sangre , Masculino , Polietilenglicoles/farmacología , Ratas , Ratas Endogámicas Lew , Tensoactivos/farmacologíaRESUMEN
The stability of benactyzine in a multicomponent injectable antidote formulation in deuterium oxide was studied in the presence of various concentrations of trimedoxime bromide. Benactyzine was found to be more stable in the absence of trimedoxime bromide and its degradation rate accelerated linearly with increasing concentrations of trimedoxime bromide. The main reasons for the accelerated decomposition rate of benactyzine were found to be the nucleophilic effect of the bromide ion and the oxime moiety. For each trimedoxime concentration studied, t90 for benactyzine at 25 degrees C was calculated and was found to be 5.3-1.5 years within the concentrations range of 0-120 mg/ml. Rate constants and activation energies for benactyzine degradation were determined for each of the concentrations studied.
Asunto(s)
Benactizina/química , Reactivadores de la Colinesterasa/química , Antagonistas Muscarínicos/química , Trimedoxima/química , Soluciones FarmacéuticasRESUMEN
The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia-Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg(-1)). Continuous administration of niacin into the duodenum at 1.66 mg h(-1) (total dose 40 mg kg(-1) day(-1)) for up to 7 days (Model A) or at 2.22 mg h(-1) over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15-25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg(-1)) has a greater lipid-lowering effect than a higher dose (200 mg kg(-1)) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.