OBJECTIVETo characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units·mL 21 (Gla-300), compared with insulin glargine 100 units·mL 21 (Gla-100) at steady state in people with type 1 diabetes. RESEARCH DESIGN AND METHODSA randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steadystate study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units·kg 21 (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units·kg 21 Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units·kg 21 of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h. RESULTSAt steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (£105 mg·dL 21 ) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100. CONCLUSIONSGla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.Although insulin analog-based products do not exactly replicate dynamic natural portal insulin release, their insulin concentration (INS) profiles closely mimic those of interprandial endogenous insulin levels. However, meeting glycemic goals with oncedaily injections of these agents, while minimizing the frequency of hypoglycemia and
In this study, lixisenatide at a dose of 20 μg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.
AimsTo characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM).MethodsA total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability.ResultsThe cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15–21] and 33.4% (95% CI 28–41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.ConclusionsGla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.
We studied whether inhibition of angiotensin converting enzyme stimulates the formation of nitric oxide and prostacyclin in cultured human and bovine endothelial cells by an enhanced accumulation of endothelium-derived bradykinin. Nitric oxide formation was assessed in terms of intracellular cyclic GMP accumulation, prostacyclin release by a specific radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat dose-and time-dependently increased the formation of nitric oxide and prostacyclin. These increases, peaking within 10 minutes, were maintained for at least 60 minutes. 1 Although the primary action of these agents is the inhibition of systemic and local formation of angiotensin II, a number of experimental and clinical data suggest that other dilator mechanisms may be involved in the hypotensive effect of ACE inhibitors. 2 -3 Since ACE is identical to the kininase II of the kallikrein-kinin system that inactivates bradykinin by liberating the C-terminal dipeptide phenylalanyl-arginine, 4 it has been suspected that a significant part of the blood pressure-lowering effect of ACE inhibitors in vivo is
Insulin glulisine injection [3(B)-Lys, 29(B)-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin. The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption. Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg. The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075-0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general. The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly -- but consistently -- greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and...
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