24-hour glycemic profile in type 2 diabetic patients treated with gliclazide modified release once daily.

OBJECTIVES: In type 2 diabetes, the primary and secondary prevention of long-term micro- and macrovascular complications requires a control of blood glucose levels 24 hours a day. The present study was undertaken to assess the effect of a new formulation of gliclazide administered once daily, gliclazide modified release, on plasma glucose levels over 24 hours. MATERIAL AND METHODS: In 21 type 2 diabetic patients previously treated by diet alone or oral antidiabetic agents, glycemic profile (8 am, 10 am, 12 am, 2 pm, 5 pm, 8 pm, 10 pm, 3 am and 8 am), overall glycemic control, acceptability, and compliance with treatment were assessed before and after a 10-week treatment with gliclazide modified release, (30-60 mg), given once daily at breakfast. RESULTS: The results indicate a significant decrease in plasma glucose levels at all points of the cycle. Mean plasma glucose levels over 24 hours and mean plasma glucose levels during the fasting and the postprandial periods were significantly improved after treatment. In previous drug-naive patients, decrease in HbA1C was observed (1.0 +/- 1.1%, P=0.022). The acceptability was good, with no hypoglycemic events, and a high compliance with treatment was also observed. CONCLUSION: We can therefore conclude that gliclazide modified release, given once daily at breakfast, is effective over 24 hours in reducing plasma glucose levels in type 2 diabetes. This once-daily administration should lead to an optimal patient compliance with treatment.

A review of the metabolism and pharmacokinetics of paroxetine in man.

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to the clinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokinetic parameters are not predictable from single-dose data. In many subjects, daily administration of 20-50 mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30 mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single dose. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events).

Endoscopic studies of nabumetone in patients with rheumatoid arthritis. A comparative endoscopic and histologic evaluation.

Gastric tolerance to 1 g of nabumetone administered in a single nightly dose was assessed in two trials in patients with rheumatoid arthritis. Gastroscopy and histology of mucosal biopsy specimens were performed before and after the end of treatment in both trials. Trial 1 was an open study that compared the effects of 1 g of nabumetone at night with those of naproxen (dose, 500 mg twice daily) and indomethacin (dose, 50 mg three times daily) in 41 hospitalized patients. After three weeks of treatment, nabumetone was significantly better tolerated than naproxen or indomethacin. Trial 2 was a randomized trial with 24 patients per group that compared 1 g of nabumetone given at night with 250 mg of naproxen given in the morning and 500 mg given at night for a period of three months. This single-blind study revealed that the number of patients with microscopic or macroscopic mucosal lesions was significantly smaller following intake of nabumetone. Concerning efficacy, as judged clinically by a rheumatologist, treatment with nabumetone was superior as well.

Reproducibility of and experiences with the BHK cell transformation assay.

Transformation of BHK 21 C 13 cells was investigated using the ability of transformed cells to reproduce in semi solid agar (anchorage independent growth). A number of modifications to previously published methods have been made, our assays were carried out on 16 compounds, including both carcinogens and non-carcinogens as judged by in vivo bioassay. Reproducibility of test results within the laboratory and with data derived from literature could be shown. Experiences concerning the optimal growth of transformed cells and the threshold level to differentiate between positive and negative results are discussed.

Transformation of BHK 21/CL 13 cells by various polycyclic aromatic hydrocarbons using the method of Styles.

Nine polycyclic aromatic hydrocarbons (PAHs) were investigated by the cell-transformation assay method of Styles. Benzo(a)pyrene [B(a)P], chrysene (CH), 3-methylcholanthrene (3-MC), benz(a)anthracene (BA), benzo(b)fluoranthene [B(b)F], and dibenz(a,h)anthracene (DBA) were tested, including liver homogenate, and showed dose-effect relationships and a more than 2-fold increase of transformation rates at LC50. Due to variations of the test method our results differed quantitatively from the data published by Purchase and Styles. Discrimination between the known carcinogens listed above and the noncarcinogens, phenanthrene (PA) and anthracene (AC), lacking a dose-effect relationship was, however, possible. Benzo(e)pyrene [B(e)P] was regarded as positive although producing only a 2-fold increase in the number of transformed colonies.

Studies on the detection of chemical carcinogens using a mammalian cell transformation assay. A correlated study of BHK cell transformation and bacterial mutagenicity.

Transformation of BHK 21/Cl 13 cells was used as a test system to detect the carcinogenic potential of Busulfan (Myleran). To correlate carcinogenicity of the compound with its mutagenic activity, bacterial mutagenicity was demonstrated in the Salmonella/microsome test.

Cell transformation of BHK 21 C 13 cells by various chemicals with and without S-9 mix.

Transformation of BHK 21 C 13 cells was evaluated by the ability of transformed cells to reproduce in semi solid agar (anchorage independent growth). The in vitro test system was carried out according to Styles with modifications. All compounds were tested with and without metabolic activation (S-9 mix). The results demonstrate the importance of a metabolizing system in this cell transformation assay.