Insulin absorption: a major factor in apparent insulin resistance and the control of type 2 diabetes mellitus.

Our experience over many years from 2 diabetes clinics with large patient populations indicated that, apparently, excessive doses of intermediate-acting insulin preparations (150-300 U of NPH insulin), alone or in combination with rapid-acting insulin, generally did not result in acceptable control of fasting blood glucose. We hypothesized that insulin resistance at the tissue level and the known variability of insulin absorption were not satisfactory explanations. To deal with the ambiguities of available data on insulin absorption, we elected to measure insulin bioavailability via a different approach. Thirteen publications provided plasma insulin concentrations after the subcutaneous administration of defined doses of insulin. These data were then analyzed by noncompartmental analysis and by standard pharmacokinetic methods. Analyses required only knowledge of the areas under the plasma insulin curve and the metabolic clearance rate of insulin. Both of these are parameters measurable with considerable accuracy. Quantitative pharmacokinetic analysis of published insulin absorption curves for insulin administered subcutaneously revealed mean absorption levels for regular and lispro insulin of 70 to 80%, 30% or less for NPH insulin, and 30 to 40% for lente insulin. In conclusion, poor absorption of intermediate-acting insulin preparations, or combinations of intermediate- and rapid-acting insulin preparations, explains the difficulty in lowering blood glucose in patients with type 2 diabetes mellitus who have had long-standing disease, are insulin resistant, and have a flat insulin response to a glucose load.

Defining and assessing adherence to oral antipsychotics: a review of the literature.

The definition and assessment of adherence vary considerably across studies. Increasing consensus regarding these issues is necessary to improve our understanding of adherence and the development of more effective treatments. We review the adherence literature over the past 3 decades to explore the definitions and assessment of adherence to oral antipsychotics in schizophrenia patients. A total of 161 articles were identified through MEDLINE and PsycINFO searches. The most common method used to assess adherence was the report of the patient. Subjective and indirect methods including self-report, provider report, significant other report, and chart review were the only methods used to assess adherence in over 77% (124/161) of studies reviewed. Direct or objective measures including pill count, blood or urine analysis, electronic monitoring, and electronic refill records were used in less than 23% (37/161) of studies. Even in studies utilizing the same methodology to assess adherence, definitions of an adherent subject varied broadly from agreeing to take any medication to taking at least 90% of medication as prescribed. We make suggestions for consensus development, including the use of recommended terminology for different subject samples, the increased use of objective or direct measures, and the inclusion in all studies of an estimate of the percentage of medication taken as prescribed in an effort to increase comparability among studies. The suggestions are designed to advance the field with respect to both understanding predictors of adherence and developing interventions to improve adherence to oral antipsychotic medications.

Kinetic and cardiovascular comparison of immediate-release isradipine and sustained-release isradipine among non-treatment-seeking, cocaine-dependent individuals.

The authors sought to determine whether sustained-release (SR) isradipine provided comparable systemic availability to that of immediate-release (IR) isradipine in non-treatment-seeking, cocaine-dependent individuals. This information could be used to design a rational dosage regimen for additional isradipine clinical trials in the treatment of stimulant dependence and related neurovascular disorders. Eight male volunteers who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for cocaine dependence participated in a randomized, double-blind, crossover study. Subjects received a 15-mg dose of an IR isradipine formulation and a 30-mg dose of an SR isradipine formulation, separated by a 2-day interval. Vital signs and blood sampling for isradipine serum levels were performed before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, and 24 h after each isradipine dose administration. Neither the 15-mg dose of IR isradipine nor the 30-mg dose of SR isradipine produced significant adverse effects on cardiovascular parameters, but the IR formulation was more likely to produce marked short-term decreases in pressor response. Significant intersubject variability in serum concentrations and pharmacokinetic parameters occurred for both formulations. The relative bioavailability of the SR formulation was 55.5% of that of the IR formulation. Both formulations cumulatively may deliver about the same amount of drug, but IR isradipine achieves a higher peak concentration than SR isradipine. The more favorable cardiovascular profile of SR isradipine would, however, make it more appropriate as an investigational medication for the treatment of stimulant dependence and related neurovascular disorders.