The aim of this study was to investigate the effect of orally administered ketoconazole and voriconazole on the pharmacokinetics of carvedilol and its metabolites in rats. Fifteen healthy male Sprague–Dawley (SD) rats were randomly divided into three groups: A group (30?mg/kg ketoconazole), B group (30?mg/kg voriconazole) and C group (control group). A single dose of carvedilol was administered orally 30?min after administration of ketoconazole and voriconazole. Carvedilol and its metabolites plasma levels were measured by ultra-high performance liquid chromatography-mass spectrometry method (UPLC–MS/MS), and pharmacokinetic parameters were calculated by DAS 3.0 software. The co-administrated with ketoconazole could significantly increase the maximal plasma concentration (Cmax) and area under the curve (AUC) of carvedilol (p?0.01). And the Cmax of its three metabolites 4′-hydroxyphenyl carvedilol (4′-HPC), 5′-hydroxyphenyl carvedilol (5′-HPC) and o-desmethyl carvedilol (o-DMC) decreased drastically by 39.4% (p?0.01), 45.0% (p?0.01) and 40.8% (p?0.05), respectively. Following co-administered with voriconazole, Tmax of carvedilol and o-DMC increased, and the Cmax of 5′-HPC decreased by 27.7% (p?0.05), while other drugs pharmacokinetic parameters performed no significant differences. Therefore, in clinical, when carvedilol was co-administrated with ketoconazole, dose adjustment of carvedilol should be taken into account. 相似文献
Isoniazid is a rare overdose that causes seizures and there is limited evidence to guide treatment. We report a 20‐year‐old female migrant who presented with recurrent seizures after ingesting 25 g of isoniazid. She was treated with activated charcoal, repeated doses of midazolam for the seizures, and given multiple doses of pyridoxine (14 mg), limited by availability. She was admitted to intensive care, and 5.5 hours post‐ingestion, she was commenced on continuous veno‐venous hemodiafiltration (CVVHDF). She was extubated after 24 hours and CVVHDF was ceased 6 hours later (30 hours post‐overdose). Her renal function remained normal and her initial lactate was the highest at 2.3. She made a full recovery. Five plasma samples were collected before, during, and after CVVHDF, and isoniazid was quantified with liquid chromatography‐tandem mass spectrometry. A pharmacokinetic analysis of time‐isoniazid concentration data was fitted to a two‐compartment model with first‐order input (with fixed ka) with the effect of CVVHDF modeled as a time‐dependent covariate. This suggested that there was initially good clearance with CVVHDF (4 times endogenous clearance), which rapidly declined within hours. 相似文献
Purpose: Salvianolic acid B micro-porous osmotic pump controlled release pellets (SalB-CRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed.Method: Extrusion-spheronization was used to prepare the starter cores containing SalB/MCC/Kollidon®CL-SF/Flowlac®100 of 30:40:15:15 [w/w, The formulation composition of SalB immediate-release pellets (SalB-IRPs)] and complexed with lactose. The pellets were subsequently coated with Surelease aqueous dispersion to achieve controlled-release properties. Furthermore, a single-dose pharmacokinetics study was carried out in New Zealand White (NZW) rabbits.Results: In the starter cores, the lactose content was 25% based on the SalB-IRPs constituent. The optimal coating polymer ratio of Surelease aqueous dispersion and polyvinyl alcohol–polyethylene glycol (PVA–PEG) graft copolymer (EC/PVA–PEG) was found to be 70:30 (w/w, %) with a coating weight of 5%. The prepared SalB-CRPs had similar in vitro release under three different pH release mediums. A good IVIVC was characterized by a high coefficient of determination (r?=?0.9801). The in vivo study indicated that the maximum plasma concentration (Cmax) of SalB-CRPs was decreased, peak concentration time (Tmax) and mean residence time (MRT) were all prolonged, as that of SalB-IRPs. In addition, the area under concentration–time curve from 0 to 24?h (AUC0–24?h) and 0 to infinity (AUC0–∞) were significantly higher, compared with those of SalB-IRPs.Conclusion: Collectively, these results manifested that SalB-CRPs were likely to be a more suitable formulation in treating cardiovascular disease with improved in vivo retention, decreased plasma drug concentration fluctuation. 相似文献
Objective: For better treatment of circadian cardiovascular events, a novel Propranolol hydrochloride (PNH) delayed-release osmotic pump capsule was developed.
Methods: The capsule body was designed of asymmetric membrane and the capsule cap was made impermeable. The physical characteristics of capsule body walls and membrane permeability were compared among different coating solutions.
Results: The formulation with the glycerin and diethyl phthalate (DEP) ratio of 5:4 appeared to be the best. The lag time and subsequent drug release were investigated through assembling the capsule body with capsule caps of different length. WSR N-10 was chosen as the suspending for its moderate expanding capacity. The influence of factors (WSR N-10 content, NaCl content and capsule cap length) on the responses (lag time and drug release rate) was evaluated using central composite design-response surface methodology. A second-order polynomial equation was fitted to the data and actual response values were in good accordance with the predicted ones. The optimized formulation displayed complete drug delivery, zero-order release rate with 4-h lag time. The results of in vivo pharmacokinetics in beagle dogs clearly suggested the controlled and sustained release of PNH from the system and that the relative bioavailability of this preparation was about 1.023 comparing the marketed preparation.
Conclusions: These results indicate that by the adjustment of capsule cap length, PNH could be developed as a novel pulsatile and controlled drug delivery system. 相似文献