Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1

Aims/hypothesis The aim of this study was to determine the effect of several antidiabetic agents on insulin-stimulated glycogen synthesis, as well as on mRNA expression.Methods Cultured primary human skeletal myotubes obtained from six healthy subjects were treated for 4 or 8 days without or with glucose (25 mmol/l), insulin (400 pmol/l), rosiglitazone (10 mol/l), metformin (20 mol/l) or the AMP-activated kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) (200 mol/l). After this, insulin-stimulated glycogen synthesis was determined. mRNA levels of the glucose transporters GLUT1 and GLUT4, the peroxisomal proliferator activator receptor gamma (PPAR gamma) co-activator 1 (PGC1) and the myocyte-specific enhancer factors (MEF2), MEF2A, MEF2C and MEF2D were determined using real-time PCR analysis after 8 days exposure to the various antidiabetic agents.Results Insulin-stimulated glycogen synthesis was significantly increased in cultured human myotubes treated with insulin, rosiglitazone or metformin for 8 days, compared with non-treated cells. Furthermore, an 8-day exposure of myotubes to 25 mmol/l glucose impaired insulin-stimulated glycogen synthesis. In contrast, treatment with AICAR was without effect on insulin-mediated glycogen synthesis. Exposure to insulin, rosiglitazone or metformin increased mRNA expression of PGC1 and GLUT4, while AICAR or 25 mmol/l glucose treatment increased GLUT1 mRNA expression. Metformin also increased mRNA expression of the MEF2 isoforms.Conclusions/interpretation Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents. These data show that chronic treatment of human myotubes with insulin, metformin or rosiglitazone has a direct positive effect on insulin action and mRNA expression.     

Myelodysplastic syndrome at a large tertiary care community hospital: analysis according to the international prognostic scoring system

The outcome of patients diagnosed myelodysplastic syndromes (MDS) between 1990 and 1997 from William Beaumont Hospital (WBH) was analyzed according to the International Prognostic Scoring System (IPSS) risk categorization. A retrospective study of 195 MDS patients wa s performed. Seventy-nine patients with MDS, in whom a karyotype was obtained and with an adequate follow-up were included in the final analysis. Cases of proliferative CMML (WBC > 12x10(9)/l) were excluded from the study. The overall median survival was 3.1 years, and median survival stratified by IPSS was 3.4, 4.1 and 0.5 years for the INT-1, INT-2 and high risk group and not yet reached for the low risk group. The overall survival by IPSS subcategorization were 6.88, 5.29, 5.30 and 2.12 years for the low, INT-1, INT-2, and high risk groups respectively. Cytogenetics were significant in predicting the overall survival. The IPSS score stratified patients into risk categories for development of AML. The risk of development into AML was 8, 8, 33 and 54% for the low, INT-1, INT-2 and high risk groups, respectively. We conclude that IPSS score can be useful in predicting survival and AML evolution in some MDS patients.     

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet

AIM/HYPOTHESIS: We examined insulin signal transduction at the level of insulin receptor substrates (IRS) 1 and 2, phosphatidylinositol (PI) 3-kinase and glucose transport in isolated subcutaneous adipocytes from obese and lean women. METHODS: Glucose transport and insulin signalling were investigated in isolated adipocytes from six obese women (BMI 36-43 kg/m(2)) (before and after 11 days of very low calorie diet) and from six lean women (BMI 22-26 kg/m(2)). RESULTS: Insulin sensitivity of glucose transport was reduced in adipocytes from obese women (p<0.05), with further reductions in basal and maximal insulin-stimulated glucose transport after a very low calorie diet (p<0.05). In obese women, IRS-1 associated PI 3-kinase activity was markedly impaired (p<0.05), whereas, IRS-2 associated PI 3-kinase activity was normal. IRS-1 associated PI 3-kinase activity remained blunted after a very low calorie diet, whereas IRS-2 associated PI 3-kinase activity was increased. GLUT4 protein was reduced by 37% in obese versus lean subjects (p<0.05), and decreased further after a very low calorie diet (from 19+/-4 to 14+/-4 arbitrary units; p<0.05). CONCLUSION/INTERPRETATION: IRS-1 signalling to PI 3-kinase is a site of insulin resistance in adipocytes from obese women, whereas insulin action on IRS-2 is normal. Thus, IRS-1 and IRS-2 undergo differential regulation in adipocytes from obese insulin resistant subjects. Finally, a very low calorie diet is associated with a further impairment in glucose transport in adipose tissue. The defect in glucose transport after a very low calorie diet occurs independent of further defects in insulin signalling at the level of the PI 3-kinase.     

Heart rate variability in long-term risk assessment in middle-aged women with coronary heart disease: The Stockholm Female Coronary Risk Study

OBJECTIVES: Low heart rate variability (HRV) is associated with poor prognosis after acute coronary events in men. In women, the prognostic impact is not well documented. The objective of this study was to assess the long-term predictive power of HRV on mortality amongst middle-aged women with coronary heart disease (CHD). DESIGN, SETTINGS AND SUBJECTS: Consecutive women below 65 years hospitalized for an acute coronary syndrome during a 3-year period in Stockholm were examined for cardiovascular prognostic factors including HRV, and followed for a median of 9 years. An ambulatory 24-h electrocardiograph was recorded during normal activities, 3-6 months after hospitalization. SDNN index (mean of the standard deviations of all normal to normal intervals for all 5-min segments of the entire recording) and the following frequency domain parameters were assessed: total power, high-frequency (HF) power, low-frequency (LF) power, very-low frequency (VLF) power and LF/HF ratio. Using Cox proportional hazards regression, the hazard ratios (HR) for each 25% decrease of the HRV parameters were assessed. RESULTS: After controlling for the independent, significant predictors of mortality amongst the clinical variables, the following HRV parameters were found to be significant predictors of all-cause mortality: SDNN index [HR 1.56, 95% confidence intervals (CI) 1.19-2.05], total power (HR 1.21, 95% CI 1.08-1.35), VLF power (HR 1.22, 95% CI 1.09-1.36), LF power (HR 1.18 95%, CI 1.07-1.30) and HF power (HR 1.18, 95% CI 1.05-1.33). The results were essentially the same when cardiovascular mortality was used as end-points. The HRV parameters were stronger predictors of mortality in the first 5 years following the index event. CONCLUSION: Low HRV is a predictor of long-term mortality amongst middle-aged women with CHD when measured 3-6 months after hospitalization for an acute coronary syndrome, even after controlling for established clinical prognostic markers.     

The safety and persistence of non-vitamin-K-antagonist oral anticoagulants in atrial fibrillation patients treated in a well structured atrial fibrillation clinic

Aims To examine the long-term persistence and safety of the non-vitamin-K-antagonist oral anticoagulants (NOACs) dabigatran (D), rivaroxaban (R) and apixaban (A) in patients with non-valvular atrial fibrillation (AF) treated in the framework of a well structured, nurse-based AF unit for initiation and follow-up of NOAC.

Methods Retrospective clinical data were collected for 766 consequent patients from a single cardiology outpatient clinic incorporating the AF unit.

Results The follow-up time, median (q1-q3), was 367 days (183–493) for D patients (n?=?233), 432 days (255–546) for R patients (n?=?282) and 348 days (267–419) for A patients (n?=?251). No significant differences were found between the three groups with regard to age, sex, renal function, or CHA₂DS₂-VASc score. For all bleeding events the incidence rates per 100 patient-years of follow-up (95% confidence interval [CI], p-value) were reported more often for treatment with R (17.2, 12.7–22.8) than for D (7.0, 4.0–11.3, p?=?0.001) and A (8.7, 5.2–13.6, p?=?0.013). The differences remained significant after adjustment for clinically relevant variables. Discontinuation rates (n?=?167) were lower for A (11.5, 7.5–16.8) than for D (30, 23.4–37.9, p?<?0.001) and R (23.9, 18.6–30.1, p?=?0.001), and were mainly attributed to drug-specific side effects and bleedings. The majority of discontinued patients (n?=?142, 85%) proceeded with other types of oral anticoagulants.

Limitation The main limitation of the study is the small patient population with a short follow-up time.

Conclusion In a retrospective study at a single AF clinic, NOACs showed significantly different bleeding rates and varied discontinuation rates when compared to each other, related mainly to agent-specific side effects and bleedings. The majority of patients that discontinued proceeded with other types of oral anticoagulant.     

Clinical importance of risk factors and exercise testing for prediction of significant coronary artery stenosis in women recovering from unstable coronary artery disease: the Stockholm Female Coronary Risk Study

BACKGROUND: The objectives of this study were to investigate the relation between coronary risk factors, exercise testing parameters, and the presence of angiographically significant coronary artery disease (CAD) (> or =50% luminal stenosis) in female patients previously hospitalized for an acute CAD event. METHODS AND RESULTS: All women younger than age 66 years in the greater Stockholm area in Sweden who were hospitalized for acute coronary syndromes during a 3-year period were recruited. Besides collection of clinical parameters, coronary angiography and a symptom-limited exercise test were performed in 228 patients 3 to 6 months after the index hospitalization. The mean age was 56 +/- 7 years. Angiographically nonsignificant CAD (stenosis <50%) was verified in 37% of the patients; significant CAD was found in 63%. The clinical parameters that showed the strongest relation with the presence of significant CAD after adjusting for age were history of myocardial infarction (odds ratio [OR] 4.91, 95% confidence interval [CI] 2.35 to 7.49), history of diabetes mellitus (OR 3.83, 95% CI 1.63 to 14.31), serum high-density lipoprotein cholesterol <1.4 mmol/L (OR 2.11, 95% CI 1. 20 to 3.72), and waist-to-hip ratio >0.85 (OR 1.78, 95% CI 1.02 to 3. 10). A low exercise capacity and associated low change of rate-pressure product from rest to peak exercise were the only exercise testing parameters that were significantly related to angiographically verified significant CAD (<90% of the predicted maximal work capacity adjusted for age and weight, OR 1.91, 95% CI 1. 04 to 3.50). CONCLUSIONS: In female patients recovering from unstable CAD, exercise capacity was the only exercise testing parameter of value in the prediction of significant CAD. The consideration of certain clinical characteristics and coronary risk factors offer better or complementary information when deciding on further coronary assessment.