Half-life (t1/2) is the oldest but least well understood pharmacokinetic parameter, because most definitions are related to hypothetical 1-compartment body models that don’t describe most drugs in humans. Alternatively, terminal half-life (t1/2,z) is utilized as the single defining t1/2 for most drugs. However, accumulation at steady state may be markedly over predicted utilizing t1/2, z. An apparent multiple dosing half-life (t1/2, app) was determined from peak and trough steady-state ratios and found to be significantly less than reported terminal t1/2s for eight orally dosed drugs with t1/2,z values longer than one day. We define a new parameter, “operational multiple dosing half-life” (t1/2, op), as equal to the dosing interval at steady-state where the maximum concentration at steady-state is twice the maximum concentration found for the first dose. We demonstrate for diazepam that the well-accepted concept that t1/2,z representing the great majority of the AUC will govern accumulation can be incorrect. Using oral diazepam, we demonstrate that t1/2, op is remarkably sensitive to the absorption t1/2, even when this absorption t1/2 is much less than t1/2,z, and describe the relevance of this in designing extended release dosage forms. The t1/2, op is compared with previously proposed half-lives for predicting accumulation.

Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.

Context: Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50-60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment. Objective: The main aim of this review is to summarize metformin HCl-loaded micro-and nanoparticulate drug delivery systems. Method: The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro-and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed. Conclusion: Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.

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Treatment of disseminatedTrichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for the treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (g/ml) were determined according to Clinical and Laboratory Standards Institute microdilution method M27-A3 at 24 and 48 h using two endpoints, MIC-2 and MIC-0 (the lowest concentrations that inhibited ϳ50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFCs; g/ml) were determined by seeding 100 l of all clear MIC wells (using an inoculum of 10 4 CFU/ml) onto Sabouraud dextrose agar. Time-kill curves were assayed against four clinical T. asahii isolates and the T. asahii ATCC 201110 strain. The MIC-2 (ϳ50% reduction in turbidity compared to the growth control well)/MIC-0 (complete inhibition of growth)/MFC values that inhibited 90% of isolates at 48 h were, respectively, 8/32/64 g/ml for fluconazole, 1/2/8 g/ml for itraconazole, 0.12/0.5/2 g/ml for voriconazole, 0.5/2/4 g/ml for posaconazole, and 0.25/1/4 g/ml for isavuconazole. The MIC-0 endpoints yielded more consistent MIC results, which remained mostly unchanged when extending the incubation to 48 h (98 to 100% agreement with 24-h values) and are easier to interpret. Based on the time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis revealed that killing rates are dose and antifungal dependent. The lowest concentration at which killing activity begins was for voriconazole, and the highest was for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole, followed by itraconazole ϳ posaconazole ϳ isavuconazole > fluconazole.

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The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit(®)RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288 nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH = 6.8) ranged from 92 to 100% in 12 h. These results suggest that Eudragit(®)RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.

No abstract