Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders.

Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP-15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP-15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment.

Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557.

Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.

Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial.

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and beta-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

Practical aspects of measuring microalbuminuria in diabetic patients.

The importance of measuring microalbuminuria is well established; however, controversy still exists regarding the type of urine specimen to be used for detecting early renal impairment of diabetic patients. To evaluate practical aspects, albumin concentration and albumin/creatinine ratio of first void urine samples as well as urinary albumin excretion in timed specimens were determined by immunoturbidimetric method 3 times within 3 weeks in 192 adult diabetic patients (136 men, 56 women; Type 1/Type 2 diabetes: 90/102; age: 51.4+/-10.8 yr; duration of diabetes: 15.3+/-9.1 yr; body mass index: 27.9+/-4.6 kg/m2; HbA1c: 8.54+/-1.46%; actual blood pressure: 138+/-14/82+/-8 mmHg; serum creatinine: 94+/-20 pmol/l; x+/-SD). According to the urinary albumin excretion values one-third of patients (31.2%-30.7%-34.4%) were normoalbuminuric (<30 mg/24 hr), more than half of the patients (55.8%-57.3%-53.6%) proved to be microalbuminuric (30-300 mg/24 hr), while the remaining group of patients (13.0%-12.0%-12.0%) was macroalbuminuric (>300 mg/24 hr). Comparing the results of successive measurements, good correlation was found between the same laboratory values (urinary albumin excretion: kappa=0.64, kappa=0.67; urinary albumin concentration: kappa=0.60, kappa=0.62; albumin/creatinine ratio: kappa=0.54, kappa=0.61; first vs second and second vs third measurements, respectively). The percentage of patients being in the same range of albuminuria (ie normo-, micro- or macroalbuminuria) at successive measurements was 79.7-81.2% with urinary albumin excretion values, 77.1-77.6% with urinary albumin concentration and 74.5-78.6% with albumin/creatinine ratio. Good correlation was found between urinary albumin excretion and urinary albumin concentration (kappa=0.54; 0.54; 0.57) and nearly the same correlation was observed between urinary albumin excretion and albumin/creatinine ratio (kappa=0.49; 0.47; 0.54) at the three consecutive measurements (n=192). Using values of urinary albumin excretion for comparison at all measurements, 79.3% sensitivity and 69.5% specificity were found for urinary albumin concentration, whereas 74.6% sensitivity and 68.8% specificity were documented for albumin/creatinine ratio. Beside the standard measurement of urinary albumin excretion in timed urine samples, the use of the more convenient morning urinary spot collection could also provide useful results (urinary albumin concentration or albumin/creatinine ratio) for detecting early renal involvement in diabetic patients.

New possibilities in the diabetic diet.

Recent changes in diabetic diet have been reviewed with special regard to the role of obesity, eating habits, carbohydrate content, and the ratio of simple and complex carbohydrates in meals, glycaemic index and fibre content of diet. The lack of standard conditions for comparing the results of different examinations as well as the need for the decisive results of long-term studies have been pointed out. The recommended carbohydrate content of diabetic diet is 60%, fat content 30-35%. The previous complete elimination of simple naturally occurring carbohydrates from the diet is not recommended anymore, these may be consumed in a wider field. The observance of glycaemic index and the use of high-fibre diet are of high importance--even if not primary--especially in type II diabetic patient. In general it is recommended to maintain/obtain an ideal body weight and to introduce a simple diet--planned not only for diabetics.