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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.

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.

Debrisoquine hydroxylation was assessed in 54 type I and in 42 type II diabetic patients. The distribution of metabolic ratio debrisoquine/4-hydroxydebrisoquine (MR) in urine of the patients was compared with a MR-distribution of 176 healthy subjects, and the correlation of glucose balance parameters with the MR was investigated. One poor metabolizer of debrisoquine was found among type I diabetics but no poor metabolizers were found among type II diabetics. Despite the low frequency of the poor metabolizers, the prevalences of debrisoquine hydroxylation phenotypes did not differ from that in healthy volunteers in either diabetic group. No correlation was found between MR and fasting blood glucose or blood glycosylated hemoglobin A1c, whereas a negative correlation was evident between age and the excretion of 4-hydroxydebrisoquine in urine. In summary, debrisoquine hydroxylation is essentially unaltered in type I and type II diabetes mellitus, and no relationship exists between debrisoquine hydroxylation and glucose balance.

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 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 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.

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.