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Out-of-pocket expenses of drug therapy may negatively affect adherence. We aimed to analyse 1-year discontinuation rates between cohorts initiating therapy with either generic simvastatin or non-generic atorvastatin.Statin-naìve initiators of atorvastatin and generic simvastatin in April-June 2003, and corresponding cohorts in 2005, were identified through the nationwide Finnish prescription register. Persistence with statin therapy was followed for 365 days, considering the treatment to have been discontinued when the tablet-free gap between two consecutive refills exceeded 90 days. Using multivariate-adjusted logistic regression, odds ratios (OR) for discontinuation associated with initiating with simvastatin vs. atorvastatin were estimated separately for each year.In the year 2003, 5838 persons initiated treatment with atorvastatin and 5644 with generic simvastatin. In the year 2005, the respective numbers were 5228 and 10 987. Soon after the introduction of generic substitution in 2003, there was no difference in the risk of discontinuation between the comparator groups [OR 0·97, 95% confidence interval (CI) 0·89-1·05]. Two years later, persons initiating with generic simvastatin were 20% less likely to discontinue statin therapy (OR 0·80; 95% CI 0·74-0·83). Among persons whose medicinal costs were almost completely reimbursed towards the end of the initiation year, the OR was 1·14 (95% CI 0·76-1·64, P = 0·033 for interaction).We found that lower out-of-pocket expenses associated with the initiating statin had a positive impact on persistence with therapy. The finding does not seem to apply to persons with minor copayments towards the end of the initiation year.

Sulphonylureas are widely used in the treatment of type 2 diabetes mellitus (T2DM). Based on laboratory findings, we determined the clinical significance of potential CYP2C9-mediated drug-drug interactions in hospitalized patients receiving glibenclamide, glimepiride or glipizide, all of which are metabolized by CYP2C9, together with a CYP2C9 inhibitor.An observational pharmaco-epidemiological database study was performed in a university hospital setting with 3884 patients with T2DM.Efficacy and safety of sulphonylurea therapy during the potential interaction (sulphonylurea treatment with a CYP2C9 inhibitor) vs. control periods (sulphonylurea treatment without a CYP2C9 inhibitor) were estimated using laboratory parameters.Almost 20% of patients were exposed to a potential drug-drug interaction with a CYP2C9 inhibitor during sulphonylurea treatment. More than 75% of the potential interactions occurred with trimethoprim, metronidazole and fluconazole. When all sulphonylureas were pooled and adjusted for age, gender, ward and sulphonylurea dose, mean and maximum fasting plasma glucose concentrations as well as maximum values of glycosylated haemoglobin were significantly lower during the interaction periods compared with control periods, whereas mean and minimum activities of alanine amino transferase and gamma-glutamyl transferase were higher. The minimum fasting plasma glucose values were more often below the target range in patients with potential interactions. The sulphonylurea dose did not differ significantly between patients who were or were not concomitantly treated with a potentially interacting drug.Concomitant use of a CYP2C9 inhibitor results in exaggerated pharmacodynamic effects of sulphonylureas and increases the risk of hypoglycaemia in T2DM patients receiving glibenclamide, glimepiride or glipizide.

To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers.The study was an open, partly randomized cross-over study including 23 volunteers receiving single doses of 3, 9 mg or 30 mg of finrozole as tablets or solution with 14 days between the administrations. The highest dose was given as tablets only. Serum concentrations of finrozole were determined using high performance liquid chromatography combined with mass spectrometry.The mean time to peak serum concentration ranged from 2.5 to 3.1, and 0.6-0.7 h after tablets and solution, respectively. The Cmax values increased as the dose increased. The calculated apparent mean elimination half-life (t(1/2,z)) was approximately 3 h after the solution, and approximately 8 h after the tablet. The AUC(0,infinity) after finrozole tablets increased proportionally from 3 mg to 9 mg and from 3 to 30 mg. The calculated relative mean bioavailabilities (AUC(0,infinity)-ratio) for the 3 mg and 9 mg doses of finrozole as tablets were 89% and 78%, respectively.The absorption of finrozole from the tablet formulation was relatively rapid, and the apparent elimination half-life was longer after the tablet than after the solution, probably reflecting overlap of the absorption with the elimination phase.

Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers.A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events.The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram.In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.

Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.

The effects of celiprolol on insulin sensitivity, glucose tolerance and serum lipids were compared to those of other antihypertensive drugs (beta- or Ca-blocker or ACE-inhibitor) in 23 dyslipidemic non-diabetic patients with controlled hypertension. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed before and 6 months after the study treatment. Six patients out of 23 were randomized to the control group where antihypertensive monotherapy was kept unchanged. Mean glucose disposal rate (M, mean +/- SEM) determined in the clamp test increased in the celiprolol group from 24.4 +/- 2.3 to 34.9 +/- 2.4 mumol/kg/min (p0.001). Insulin sensitivity improved during celiprolol treatment independent of the previous treatment. In the control group, M remained practically unchanged (21.6 +/- 3.7 mumol/kg/min). During 2 h OGTT, incremental glucose and insulin AUC decreased in the celiprolol group from 4.5 +/- 0.7 to 2.0 +/- 0.6 mM*h (p0.002) and from 113 +/- 16 to 72 +/- 10 mU/l*h (p0.005), respectively. There was also a small beneficial change in serum lipids in the celiprolol group: a reduction in serum total cholesterol (-4%), triglycerides (-11%) and LDL-cholesterol (-9%), and an increase in HDL-cholesterol (+6%) and HDL/LDL ratio (+15%). No significant change occurred in the control group. Fasting serum glucose and insulin did not change significantly in either group. In this study with a limited control group, celiprolol improved insulin sensitivity, glucose tolerance and serum lipid profiles of dyslipidemic hypertensive patients.

Plasma kinetics and beta-receptor blocking and -binding activity of timolol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.

The effect of chronic treatment with metformin (320 mg/kg/day) on plasma glucose and insulin as well as liver glycogen synthase activity and hepatic glycogen content was studied in obese hyperinsulinemic Zucker rats. Metformin significantly reduced both plasma glucose (by 10%) and insulin levels (by 39%) at fasting but had no effect on hepatic glycogen content or on the basal activity of liver glycogen synthase.

Cyclopentolate plasma levels were quantitated and heart rate and pupil size were monitored after ocular application of the drug to juveniles. In all, 12 children were given one 35-microliters eyedrop of either 1% cyclopentolate (n = 6) or placebo (n = 6) in randomized order in the lower cul-de-sac of one eye. A sensitive radioreceptor assay was used to determine the systemic drug absorption. With the exception of one child, detectable cyclopentolate concentrations were seen in plasma at as early as 3 min after the ocular drug application. There was a marked interindividual variation in peak plasma cyclopentolate concentrations ranging from undetectably low to 5.8 ng/ml (median, 2.9 ng/ml). In some children a second drug concentration peak was detected. Cyclopentolate increased the pupillary diameter from 4.8 +/- 1 mm before drug application to 8 +/- 0.9 mm at 30 min after administration, but the children's heart rate did not alter.

The activity of four liver enzymes participating in the xenobiotic metabolism was determined in male and female obese hyperinsulinemic Zucker rats. When compared to lean normoinsulinemic control animals the obese male rats had lower hepatic aryl hydrocarbon hydroxylase and the female animals lower 7-ethoxycoumarine O-deethylase and N-nitrosodimethylamine N-demethylase activities. The results contrast those reported in the literature for hypoinsulinemic streptozotocin diabetic rats.

The effects of the potent glucocorticoid type-II receptor (GR) antagonist, mifepristone, on corticosterone secretion and on expression of preprocorticotrophin-releasing factor (preproCRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and of pro-opiomelanocortin (POMC) mRNA in the pituitary gland were investigated in lean and obese Zucker rats. Treatment with mifepristone for 4 days (10 mg/kg orally twice daily) significantly (P < 0·05) stimulated corticosterone secretion in lean but not in obese rats. In lean rats the enhanced corticosterone secretion was associated with non-significant increments in the expression of preproCRF mRNA in the PVN and of POMC mRNA in the pituitary gland, while mifepristone significantly (P < 0·05) reduced the expression of preproCRF mRNA in the PVN of obese Zucker rats. It is concluded that antagonism of GR by mifepristone results in persistent activation of the adrenocortical axis in lean Zucker rats due to blockade of feedback inhibition by circulating corticosterone. In obese animals the abnormal response to mifepristone suggests that the neuroendocrine control of the HPA axis is altered in genetically determined obesity. Journal of Endocrinology (1992) 132, 425–431

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.

The proposed ADH-releasing capacity of chlorpropamide was tested after intravenous administration of the drug to nine healthy fasted volunteers. When compared with the placebo experiment, no evidence for increased ADH release was found. On the contrary, the AVP values measured after chlorpropamide injection were slightly lower during the first 2 h than after the saline injection. Serum chlorpropamide concentration was also measured. After a rapid distribution phase, a slow elimination phase followed. The calculated t 1/2 for distribution phase was 1.00 +/- 0.26 hrs (mean +/- s.e.m.).

A single chlorpropamide dose, when compared to placebo, reduced blood glucose in volunteers during fasting and glucagon stimulation without increase in pancreatic beta cell secretion. The finding suggests that extrapancreatic mechanisms may play a substantial role in the chlorpropamide action also after a single drug dose.

The activities of hepatic enzymes involved in glucose phosphorylation and NADPH production were studied in male and female obese Zucker rats (fa/fa) and lean control animals (Fa/-). The fa/fa animals were heavier and had higher serum insulin levels than the lean rats. The glucokinase activity and the total glucose phosphorylation capacity were also higher in the obese animals. The activity of glucokinase correlated significantly with serum insulin levels. The glucose-6-phosphate phosphohydrolase activity was unchanged or slightly lowered in the obese rats. The activity of malic enzyme was elevated in the obese animals.

The pharmacokinetics of chlorproamide was studied in eight healthy volunteers after intravenous and oral dosage. A long elimination half-life with considerable variations between subjects was recorded. The normalized areas under the curve were in close agreement between the subjects, suggesting that they had all absorbed the same magnitude of chlorpropamide. The AUCs after i.v. and p.o. administration did not differ significantly from each other. Thus, the differences in the bioavailability do not seem to be a critical factor in the previously reported large interindividual variations in chlorpropamide steady-state concentrations.

The value and reproducibility of the chlorpropamide-alcohol flush (CPAF) have been questioned, and objective measures of the test are required. Recording of facial skin temperature, measurement of chlorpropamide, ethanol and acetaldehyde concentrations have been proposed for this purpose. The present study was designed to evaluate the relative contributions of these variables in determining CPAF. Twenty-one Type 2 (non-insulin-dependent) diabetic patients (11 CPAF-positive and 10 CPAF-negative according to previous tests with standard amounts of alcohol and chlorpropamide) were investigated in a random fashion with either chlorpropamide or placebo given on three subsequent evenings before a two-step alcohol challenge with increasing body-weight-matched amounts of alcohol. Higher rises in facial skin temperature and heart rate, higher flush-score and higher acetaldehyde levels resulted from chlorpropamide therapy than followed placebo. After smaller alcohol challenges (with chlorpropamide pretreatment) there were positive intercorrelations between flush-score, rise in facial skin temperature, and plasma concentrations of chlorpropamide and blood acetaldehyde. The increased alcohol dose abolished most of these correlations and a minimum temperature rise of 1.8°C appeared in all but two subjects regardless of previous CPAF classification. During the current experimental conditions, the previously-classified CPAF-positive and CPAF-negative patients did not differ with respect to flush-score, rise in skin temperature, heart rate, blood acetaldehyde or ethanol concentrations, whereas they differed with respect to chlorpropamide concentrations. The present results support the view that CPAF is associated with elevated blood acetaldehyde levels due to inhibition of aldehyde dehydrogenase by chlorpropamide. Thus both alcohol and chlorpropamide concentrations are critical in determining the CPAF. Furthermore, body weight matching in applying the CPAF test is essential.

The effect of phenobarbital, a known inducer of drug-metabolizing enzymes, on hepatic glucose-metabolizing and NADPH-producing enzymes was evaluated in obese and lean female Zucker rats. Plasma glucose was slightly reduced and plasma insulin increased after one week of phenobarbital therapy. The induction clearly increased the activities of liver glucokinase in lean but not in obese animals. Hepatic glucose-6-phosphate phosphohydrolase activity, on the other hand, was reduced after phenobarbital, especially in obese rats. Thus phenobarbital affected the activities of hepatic enzymes modulating the intermediary metabolism in several ways: liver glucose phosphorylation was increased and glucose output reduced after enzyme induction in lean and obese Zucker rats, respectively. Phenobarbital also increased the activities of glucose-6-phosphate dehydrogenase and malic enzyme in lean animals indicating an increased NADPH generation.

The effect of an intravenous salbutamol dose (2 micrograms/kg or 8 micrograms/kg) on serum insulin and blood glucose was studied in 8 healthy volunteers after different glucose loads. Administration of glucose significantly increased circulating blood glucose and serum insulin concentrations before the salbutamol injection. The acute insulin releasing capacity of 2 micrograms/kg salbutamol was intensified and its blood glucose elevating effect was diminished by preceding glucose loading. Elevation of salbutamol dose from 2 to 8 micrograms/kg caused a 3.4 fold elevation of insulin secretion and an even more pronounced increase in blood glucose response.

Hypothalamic somatostatin concentration was determined in 6.5 to 9 months old male and female genetically obese fatty (fa/fa) and lean (Fa/-) Zucker rats. Similar somatostatin levels were found in fatty and lean animals in the hypothalamic regions previously known to contain the highest hormone levels (median eminence and arcuate, periventricular and ventromedial nuclei). The fatty animals were grossly obese and had a pronounced hyperinsulinemia.

The pharmacokinetics of and response to glipizide were studied in six insulin-independent diabetics by radioimmunoassay for glipizide and insulin. Blood glucose was also monitored. Beside control (off glipizide) the patients were studied when given 10 mg glipizide either as a single daily dose or divided into two doses. The peak drug concentration was reached on an average within 1.8-2.3 h. The AUCs did not differ between the two dosage regimens. The mean elimination half-life was 4.7 +/- 0.4 h, Vd 17.0 +/- 2.6 l, and the calculated total clearance 41.6 +/- 4.3 ml/min (mean +/- s.e.m.). In one patient a more than two-compartment pharmacokinetic model was obvious. The once or twice daily dosage regimens did not differ significantly in their ability to reduce blood glucose, but the overall efficacy of the therapy was poor in these patients. The maximal efficacy of a single 10-mg dose of glipizide to reduce blood glucose was maintained at the same level between 1.5 and 8 h despite the continued rapid falling of serum glipizide concentration over this period.