OBJECTIVE -The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial.RESULTS -Significant decreases (P Ͻ 0.001) in mean HbA 1c (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (Ϫ0.73 and Ϫ0.74%) were not significantly different from the change in the immediate-release metformin group (Ϫ0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (Ϫ1.06%; mean difference [2,000 mg extended-release metformin Ϫ immediate-release metformin]: Ϫ0.36 [98.4% CI Ϫ0.65 to Ϫ0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS -Once-or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment. Diabetes Care 29:759 -764, 2006M etformin hydrochloride has been widely used as an effective and generally well-tolerated glucoselowering agent for Ͼ40 years and is the most frequently prescribed first-line therapy for patients with type 2 diabetes (1). Metformin typically reduces basal and postprandial hyperglycemia by ϳ25% in Ͼ90% of patients when given alone or with other therapies during a program of managed care (2). In the U.K. Prospective Diabetes Study, intensive glucose control with metformin appeared to reduce the risk of diabetes-related end points in overweight patients and was associated with less weight gain and fewer hypoglycemic attacks than insulin (3).The objective of this study was to evaluate the efficacy, tolerability, and safety of a novel extended-release oral formulation of metformin compared with conventional immediate-release metformin during 24 weeks of double-blind treatment. When administered with food, the extended-release metformin tablet gradually releases drug over 8 h into the upper gastrointestinal tract (4), where metformin is primarily absorbed (5). Prolonged release of metformin from extended-release metformin tablets has been demonstrated in pharmacokinetic studies (6,7). Extended-release metformin showed slightly lower maximum concentrations, longer times to maxi...

The concentration (C) dependent part of the ESR line width (AH) of a paramagnetic solute in a diamagnetic solvent arises from intermolecular interactions between paramagnetic molecules, and these interactions are strongly modulated by the translational motions of these molecules. Thus (dAH/dC) depends upon the diffusion constant (D), and measurements of (dAH/dC) can be used to determine D. Although this method of measuring D may not be the most favored one for bulk media, it could be one of the few methods applicable to the study of diffusion within bilayers. We have evaluated this procedure for measuring D by studying (dA/f/dC) in a number of bulk solvents over a very wide range of (T/77) where T is the temperature and t; is the solvent viscosity.At low viscosity, the spin-exchange interactions dominate, and dAff/dC is linear in D or in (T/rj). At moderate viscosities dAH/dC varies little with (T/rj) because the dipolar interaction which varies as D-1 competes with the spin-exchange interaction. In fact, (dAH/dC) remains relatively constant over quite a wide range of (T/n), but at very low T/t] the (dAR/dC) values evidence an upsweep with decreasing (T/tj). The low (T/rt) resultsare not yet understood, but it is clear that (dAR/dC) gives useful diffusion data at low viscosities (high T/jj) only.

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The key aspects of the pharmacokinetics of transdermal delivery systems including time lag, steady-state plasma levels and decline phase are illustrated in this review. The 7 currently marketed transdermal systems [nitroglycerin (glyceryl trinitrate), estradiol, clonidine, fentanyl, nicotine, scopolamine (hyoscine) and estradiol/norethisterone acetate] are discussed, as are systems in development. Single-dose absolute bioavailability studies characterise the period of onset, the steady-state plateau and the declining phase, and typify transdermal delivery. More complex temporal profiles result from interactions with enhancers or removal of the system before steady-state conditions are achieved. Clinically these systems are used to achieve multiple peak serum estradiol concentrations after application of transdermal estradiol, and an initial peak systemic concentration of testosterone after application of transdermal testosterone. Multiple-dose, dose proportionality and skin site bioequivalence studies are needed for the full pharmacokinetic characterisation of a transdermal delivery system. The relationship of system design to variability is discussed. Although the data are limited, population factors, cutaneous metabolism and tolerance all appear to influence the disposition of drugs administered transdermally. For example, the route of delivery influences which nitroglycerin metabolite predominates. Furthermore, as a result of tolerance to nitrates, a transdermal delivery system must be removed for 8 to 12 hours for optimal effect. Therefore, transdermal delivery systems, designed on the basis of pharmacokinetic principles and concentration-effect relationships, have the potential to provide optimal therapy for the treatment of some conditions.