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Decrease in adiponectin level, a common feature in patients with type 2 diabetes mellitus, is considered to predict cardiovascular events. Elevated oxidized low-density lipoprotein (oxLDL), formed within the arterial wall, is commonly seen as part of the atherogenic profile. We investigated the association of adiponectin and oxLDL in 58 patients with type 2 diabetes mellitus and ischemic coronary artery disease. In addition to adiponectin, the serum lipid profile (including oxLDL), plasminogen activator inhibitor 1, high-sensitivity C-reactive protein, and whole-body glucose uptake determined by euglycemic-hyperinsulinemic clamp were evaluated. The average adiponectin level was 7.1 +/- 3.5 microg/mL and was higher in female than in male patients (P = .011). Adiponectin level correlated with whole-body glucose uptake (P = .037) and high-density lipoprotein (HDL) cholesterol concentration (P = .007) and was inversely associated with oxLDL (P = .005), triglycerides (P = .010), and plasminogen activator inhibitor 1 (P = .004). No association was found between adiponectin and high-sensitivity C-reactive protein or LDL cholesterol levels. In multiple linear regression analysis, adiponectin contributed to oxLDL concentration, whereas total cholesterol, LDL and HDL cholesterol, and triglycerides did not. In conclusion, our results suggest that low adiponectin concentration indicates increased oxidative state in the arterial wall, which further supports previous data on the role of adipose tissue in atherogenesis.

Objective: The trend towards polypharmacy is increasing among the elderly, and associated with this trend is an increased risk of adverse drug effects and drug-drug interactions. Our objective was to assess whether drug adverse effects reported by patients are in general agreement with those identified by a physician., Methods: We evaluated the medication of 404 randomly selected individuals aged 75 years or older by means of interviews carried out by trained nurses and examinations conducted by a physician. The medication used by these patients was recorded prior to the physician's examination and modified thereafter if considered appropriate. Adverse effects noted by the physician were compared to those self-reported by the patients., Results: Almost all of the patients (98.8%) were using at least one drug, and the mean total number of drugs used was 6.5. Adverse effects were self-reported by 11.4% of the patients, whereas the physician observed apparent adverse drug effects in 24.0% of the patients. No adverse effects were reported in 53.2% of the patients. There were only seven patients that had adverse effects that were both self-reported and identified by the physician, and only four of these patients reported the same adverse effect that had been identified by the physician., Conclusion: There was a great disparity between the adverse effects identified by the physician and those reported by the patients themselves. Based on our results, it would appear that elderly people tend to neglect adverse drug effects and may consider them to be an unavoidable part of normal ageing. Therefore, physicians should enquire about possible adverse effects even though elderly patients may not complain of any drug-related problems.

Objectives: To study the risk of serious upper gastrointestinal (GI) events associated with the concurrent use of selective serotonin re-uptake inhibitors (SSRIs) and different types of non-steroidal anti-inflammatory drugs (NSAIDs)., Methods: This was a nationwide, register-based matched case-control study on non-institutionalized residents of Finland during the period 2000-2004. Patient-cases with serious upper GI events (n=9191) were drawn from the Hospital Discharge Register, and individually matched controls (n=41,780) were drawn from the Population Register. Logistic regression was applied in the data analysis, and adjustments were made for various co-morbidities and the use of other drugs associated with the risk of serious upper GI event., Results: The adjusted odds ratio (AOR) of serious upper GI events for SSRI use compared to non-use of SSRIs or NSAIDs was 1.30 [95% confidence interval (95%CI: 1.13-1.50)], and the AOR for concurrent SSRI and NSAID use compared to the non-use of either drug was 4.19 (95%CI: 3.30-5.31). The AOR of upper GI events for the concurrent use of SSRIs with NSAIDs compared to patients using NSAIDs only was 1.57 (95%CI: 1.24-1.99). The respective AOR for traditional, non-selective NSAIDs was 1.77 (95%CI: 1.31-2.38), for semi-selective NSAIDs (nimesulide, nabumetone, meloxicam, and etodolac) 1.30 (95%CI: 0.76-2.24) and for COX-2 selective NSAIDs 1.33 (95%CI: 0.70-2.50)., Conclusions: The concurrent use of SSRIs and NSAIDs is associated with a moderate excess relative risk of a serious upper GI event when compared with NSAID use alone.

Aims: To evaluate the risk of first myocardial infarction (MI) associated with the use of various non-steroidal anti-inflammatory drugs (NSAIDs) in the general population., Methods and Results: We conducted a population-based matched case-control study over the years 2000-3 in outpatient residents of Finland. In the nationwide Hospital Discharge Register 33 309 persons with first time MI were identified. A total of 138 949 controls individually matched for age, gender, hospital catchment area, and index day were selected from the Population Register. For combined NSAIDs, the adjusted odds ratio for the risk of first MI with current use was 1.40 (95% CI, 1.33-1.48). The risk was similar for conventional (1.34; 1.26-1.43), semi-selective (etodolac, nabumetone, nimesulide, and meloxicam) (1.50; 1.32-1.71), and cyclo-oxygenase-2 (COX-2) selective NSAIDs (rofecoxib, celecoxib, valdecoxib, and etoricoxib) (1.31; 1.13-1.50). Age of current user did not consistently modify the risk. No NSAID was associated with an MI-protective effect. All durations from 1 to 180 days of conventional NSAIDs and from 31 to 90 days duration of COX-2 selective NSAIDs were associated with an elevated risk of MI., Conclusion: Current use of all NSAIDs is associated with a modest risk of first time MI.

Objective: To explore the separate and combined effects of simvastatin and a low-saturated diet rich in alpha-linolenic acid on serum fatty acids., Methods and Results: 120 hypercholesterolemic men were randomly allocated to a habitual diet or dietary treatment group and to receive, in random order, simvastatin 20 mg/d or placebo, each for 12 weeks, in a double-blind manner. Dietary treatment decreased proportions from total fatty acids of palmitic acid (C16:0) by 3.3% (P<0.05), stearic acid (C18:0) by 3.7% (P<0.05) and increased proportions of oleic acid (C18:1n-9) by 4.2% (P<0.01), and alpha-linolenic acid (C18:3n-3) by 29.8% (P<0.001). Simvastatin decreased proportions from total fatty acids of palmitic acid by 2.0% (P<0.01), linoleic acid (C18:2n-6) by 5.3% (P<0.001), and alpha-linolenic acid by 6.8% (P<0.05), and increased proportions of gamma-linolenic acid (C18:3n-6) by 11.1% (P<0.001), dihomo-gamma-linolenic acid (C20:3n-6) by 4.2% (P<0.01), arachidonic acid (C20:4n-6) by 14.2% (P<0.001), and the sum of long-chain polyunsaturated fatty acids (C20-22) by 9.0% (P<0.001). Simvastatin increased ratios of stearic to palmitic, gamma-linolenic to linoleic, and arachidonic to dihomo-gamma-linolenic acid by 7.6%, 17.0%, and 10.0% (P<0.001 for all), respectively, suggesting increased fatty acid elongase and Delta6- and Delta5-desaturase enzyme activities., Conclusions: Increased formation of long-chain polyunsaturated fatty acids and their metabolites may contribute a substantial part of the pleiotropic effects of simvastatin.

To evaluate the relative impact of abdominal obesity and newly diagnosed type 2 diabetes on insulin action in skeletal muscle and fat tissue, we studied 61 men with (n = 31) or without (n = 30) diabetes, subgrouped into abdominally obese or nonobese according to the waist circumference. Adipose tissue depots were quantified by magnetic resonance imaging, and regional glucose uptake was measured using 2-[(18)F]fluoro-2-deoxyglucose/positron emission tomography during euglycemic hyperinsulinemia. Across groups, glucose uptake per unit tissue weight was higher in visceral (20.5 +/- 1.4 micromol . min(-1) . kg(-1)) than in abdominal (9.8 +/- 0.9 micromol min(-1) . kg(-1), P < 0.001) or femoral (12.3 +/- 0.6 micromol . min(-1) . kg(-1), P < 0.001) subcutaneous tissue and approximately 40% lower than in skeletal muscle (33.1 +/- 2.5 micromol . min(-1) . kg(-1), P < 0.0001). Abdominal obesity was associated with a marked reduction in glucose uptake per unit tissue weight in all fat depots and in skeletal muscle (P < 0.001 for all regions). Recent type 2 diabetes per se had little additional effect. In both intra-abdominal adipose (r = -0.73, P < 0.0001) and skeletal muscle (r = -0.53, P < 0.0001) tissue, glucose uptake was reciprocally related to intra-abdominal fat mass in a curvilinear fashion. When regional glucose uptake was multiplied by tissue mass, total glucose uptake per fat depot was similar irrespective of abdominal obesity or type 2 diabetes, and its contribution to whole-body glucose uptake increased by approximately 40% in obese nondiabetic and nonobese diabetic men and was doubled in obese diabetic subjects. We conclude that 1) in abdominal obesity, insulin-stimulated glucose uptake rate is markedly reduced in skeletal muscle and in all fat depots; 2) in target tissues, this reduction is reciprocally (and nonlinearly) related to the amount of intra-abdominal fat; 3) mild, recent diabetes adds little insulin resistance to that caused by abdominal obesity; and 4) despite fat insulin resistance, an expanded fat mass (especially subcutaneous) provides a sink for glucose, resulting in a compensatory attenuation of insulin resistance at the whole-body level in men.

Objective: A number of drugs used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal (GI) haemorrhage. We studied the prescribing of NSAIDs with corticosteroids, oral anticoagulants or selective serotonin re-uptake inhibitors (SSRIs), as well as the use of gastroprotection among continuous and non-continuous users of NSAIDs in Finland., Methods: Concurrent use of various drugs was analysed in a nested case-control study in a population-based cohort of NSAID users in 2000 using data in the National Prescription Database., Results: Prescribing of any other drug with the potential to increase the risk of GI bleeding with NSAIDs was five times [5.2; 95% confidence interval (CI) 4.7-5.9] more common among continuous than non-continuous NSAID users, and the odds ratio for oral corticosteroids was 8.0 (95% CI 6.6-9.6). Of patients using continuous NSAIDs with oral corticosteroids, 73.3% had rheumatoid arthritis (RA). After excluding RA patients, the odds ratio remained high (4.5; 95% CI 3.3-6.1) and at the same level as for SSRIs (3.7; 3.1-4.4). Gastroprotective drugs were prescribed for 6.8% of the continuous users of NSAIDs alone, and for 20.4% of patients taking any of the studied drug combinations with NSAIDs. The continuous users of NSAIDs alone had gastroprotection 2.9 (2.5-3.3) times more often than other users of NSAIDs. With drug combinations (NSAID+corticosteroid, NSAID+SSRI, NSAID+anticoagulants), the use of gastroprotection did not differ from patients using lower amounts of NSAIDs., Conclusions: When prescribing NSAIDs, situations leading to habitual use should be avoided, potential complications due to clustering of risk factors recognised, and gastroprotection prescribed for patients with increased risk of GI haemorrhage.

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

Background and Objective: Cyclooxygenase 2-selective non-steroidal anti-inflammatory drugs (NSAIDs, coxibs) are recommended primarily for patients at high risk of gastrointestinal bleeding, most of them being elderly. Our objective was to describe and analyse patient- and physician-related factors affecting the adoption of celecoxib and rofecoxib 2 years after their launch in Finland., Methods: Retrospective analysis of the nationwide Prescription Register. Physicians who had issued at least 200 reimbursed prescriptions in 2002 (n = 12 033, 80% of working-age Finnish physicians) were involved in the analysis., Results and Discussion: Excluding patients with rheumatoid arthritis (RA), almost one-fifth (18%) of NSAIDs prescriptions were for coxibs. In patients with RA the share was 25%. The share of coxib prescriptions of all NSAIDs increased with age of the patient. Over one half (58%) of coxib prescriptions were issued for patients under 65 years of age. Specialists in physical and rehabilitation medicine were the fastest adopters of coxibs: one-third of their NSAID prescriptions in 2002 were for coxibs. Primary care physicians were the most conservative both in adopting and favouring coxibs., Conclusions: Coxibs have gained the status of standard prescription NSAIDs within a few years. Their use should be restricted to patients who could benefit most from the use. Routine prescribing of expensive new drugs increases the drug bill without additional health gain.

Objective: To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks., Methods: Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings., Results: The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration., Conclusions: Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.

Rationale: Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P(450) (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice., Objectives: The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs., Methods: Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration., Results: Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC ( P<0.001) and 20% increase in the elimination half-life ( P=0.0012) of 1-PP. Deramciclane did not potentiate the buspirone-induced increase in prolactin secretion. No significant differences were found in the psychomotoric testing or the subjective maximum sedation between the deramciclane phase and the placebo phase, either before or after buspirone administration. Of 16 subjects, 5 experienced dizziness during both study phases., Conclusion: Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramciclane and a single dose of buspirone.

Most western societies are enhancing rational pharmacotherapy to get best value for the constantly increasing expenditure on drugs. Government bodies and the medical profession took joint responsibility for the education programme for rational prescribing, launched in Finland at the end of the 1990s. The goals were to enhance critical thinking, and when appropriate, change prescribing behaviour. Various approaches that included evidence-based continuing medical education (CME), implementing clinical guidelines, delivering information, and providing prescribing feedback were used simultaneously. The commitment of the stakeholders and participants has been strong and the approaches have succeeded even though there is no clear outcome measure. The Government has recently decided to continue and widen the process, which started as a pilot programme, on a tight budget.

Objective: To describe characteristics of non-steroidal anti-inflammatory drugs (NSAIDs; Anatomical Therapeutic Chemical code M01A) users in Finland, with emphasis on intensity of use., Methods: Nationwide prescription database study over years 1997-2000 using a random sample of 500,000 persons. Low use was defined as 30 or fewer defined daily doses (DDDs) per year, moderate between 31 and 181 DDDs, and heavy 182 or more DDDs. Persons with rheumatoid arthritis (RA) were identified and analysed separately from non-RA patients., Results: The total NSAID consumption was 61.2 and reimbursed prescription NSAID use 31.2 DDD/1000 inhabitants per day in 2000. The annual prevalence of use varied between 17.1% and 18.8% throughout 1997-2000, and that of low, moderate and heavy use was 7.6%, 8.0% and 1.5%, respectively, in 2000. Females used more NSAIDs than men in all adult non-RA age groups, and of non-RA patients 58.4% were females. The share of females among the non-RA users increased with the intensity of use, as did the share of female patients 65 years or older. Among RA patients, the intensity of use was independent of age and gender, and 70% of RA patients were females. Of the heavy users in 2000, 27.7% ( n=2117) had continuously used 182 or more DDDs per year throughout the years 1997-2000. Non-RA users accounted for 78.4% of the annual heavy and 64.2% of the continuous heavy users., Conclusions: Exposure of patients to long-term use of NSAIDs and upper gastrointestinal bleeding should be reduced by regular analysis of patient's pain and consideration of other treatment options.

Objective: Hyperleptinemia, a hallmark of obesity, appears to be a risk factor for coronary artery disease. However, although leptin is a vasoactive hormone, no studies addressing leptin's effect on coronary perfusion have been performed. We examined the association between circulating leptin concentration and coronary vasoreactivity in young obese and nonobese males., Research Methods and Procedures: Myocardial blood flow was quantitated in 10 obese men (age 31 +/- 7 years, BMI 34 +/- 2 kg/m(2)) and 10 healthy matched nonobese men (age 33 +/- 8 years, BMI 24 +/- 2 kg/m(2)) using positron emission tomography and O-15-water. The measurements were performed basally and during adenosine infusion (140 micro g/kg per minute)., Results: Serum leptin was significantly higher in obese than nonobese subjects (10.3 +/- 5.6 vs. 4.3 +/- 2.5 ng/mL, p < 0.01). Basal myocardial blood flow was not significantly different between obese and nonobese subjects. Adenosine-stimulated flow was blunted in obese (3.2 +/- 0.6 mL/g per minute) when compared with nonobese subjects (4.0 +/- 1.1 mL/g per minute, p < 0.05). Serum leptin concentration was inversely associated with adenosine-stimulated flow in study subjects (r = -0.50, p < 0.05). This association was no longer observed after adjustment for obesity and/or hyperinsulinemia., Discussion: Hyperleptinemia and reduced coronary vasoreactivity occur concomitantly in young obese but otherwise healthy men. Moreover, the adenosine-stimulated myocardial flow is inversely related to prevailing concentration of serum leptin. Although this relationship appears to be explained by obesity and/or hyperinsulinemia, leptin might have a role in regulation of myocardial blood supply.

We evaluated the effects of rosiglitazone (4 mg b.i.d.) and metformin (1 g b.i.d.) monotherapy for 26 weeks on adipose tissue insulin-stimulated glucose uptake in patients (n = 41) with type 2 diabetes. Before and after the treatment, glucose uptake was measured using 2-[(18)F]fluoro-2-deoxyglucose and positron emission tomography and adipose tissue masses were quantified using magnetic resonance imaging. Rosiglitazone improved insulin-stimulated whole-body glucose uptake by 44% (P < 0.01 vs. placebo). Mean body weight was unchanged in the rosiglitazone group, while it decreased by 2.0 kg in the metformin group (P < 0.05 vs. placebo). In visceral adipose tissue, glucose uptake increased by 29% (from 17.8 +/- 2.0 to 23.0 +/- 2.6 micro mol x kg(-1) x min(-1), P < 0.05 vs. placebo) in the rosiglitazone group but to a lesser extent (17%) in the metformin group (from 16.2 +/- 1.5 to 18.9 +/- 1.7 micro mol x kg(-1) x min(-1), P < 0.05 vs. baseline). Because the visceral adipose tissue mass simultaneously decreased with both treatments (P < 0.05), no change was observed in total visceral glucose uptake per depot. Rosiglitazone significantly enhanced glucose uptake in the femoral subcutaneous area, either when expressed per tissue mass (from 10.8 +/- 1.2 to 17.1 +/- 1.7 micro mol x kg(-1) x min(-1), P < 0.01 vs. placebo) or per whole-fat depot (P < 0.05 vs. placebo). In conclusion, metformin treatment resulted in improvement of glycemic control without enhancement of peripheral insulin sensitivity. The improved insulin sensitivity of the nonabdominal subcutaneous adipose tissue during treatment with rosiglitazone partly explains the enhanced whole-body insulin sensitivity and underlies the central role of adipose tissue for action of peroxisome proliferator-activated receptor gamma agonist in vivo.

Background and Objective: Deramciclane is a new compound that has shown anxiolytic effects in animal experiments and in human studies. The aim of this study was to determine the pharmacokinetic parameters of deramciclane after intravenous and oral administration, and its oral bioavailability., Methods: Deramciclane 30 mg was given intravenously and orally as a tablet and as solution in an open, randomised, crossover three-period trial to 12 healthy male volunteers. Oral bioavailability of deramciclane and the pharmacokinetic parameters of deramciclane and N-desmethylderamciclane, the principal metabolite, were determined after intravenous and oral administration of the parent drug., Results: The first and second distribution half-lives (mean +/- SD) of deramciclane were 0.04 +/- 0.01 and 3.03 +/- 0.50h, respectively, and the half-life of the elimination phase was 26.6 +/- 5.5h. The clearance of deramciclane after an intravenous dose was 0.24 +/- 0.10 L/kg. The elimination phase half-life of N-desmethylderamciclane was 38.2 +/- 6.9h after intravenous and about 25 h after oral dosing of the parent compound. The mean oral bioavailability of deramciclane was 44% (range 27-58%) and 36% (23-50%) after administration of the oral solution and tablet, respectively. Deramciclane was well tolerated even after a 30 mg intravenous dose resulting in peak plasma concentrations 10 times higher than observed after its oral administration., Conclusions: After intravenous administration, the pharmacokinetics of deramciclane are adequately described by a three-compartment model. After oral administration its pharmacokinetics follow a two-compartment model with first-order absorption. The elimination phase half-life of the parent compound is similar after intravenous and oral administration, whereas the apparent half-life of N-desmethylderamciclane is longer after intravenous than after oral administration of the parent compound. The oral bioavailability of deramciclane is large and uniform enough to allow its clinical use as tablets.

To elucidate the role of adipose tissue glucose uptake in whole-body metabolism, sc and visceral adipose tissue glucose uptake and perfusion were measured in 10 nonobese and 10 age-matched obese men with positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose, and [(15)O]-labeled water during normoglycemic hyperinsulinemia. Whole-body and skeletal muscle glucose uptake rates per kilogram were lower in obese than in nonobese subjects (P < 0.01). Compared with nonobese, the obese subjects had 67% lower abdominal sc and 58% lower visceral adipose tissue glucose uptake per kilogram of fat. In both groups, insulin stimulated glucose uptake per kilogram fat was significantly higher in visceral fat depots than in sc regions (P < 0.01). Both sc and visceral adipose tissue blood flow expressed per kilogram and minute was impaired in the obese subjects, compared with the nonobese (P < 0.05). Fat masses measured with magnetic resonance images were higher in obese than in nonobese individuals. If regional glucose uptake rates were expressed as per total fat mass, total glucose uptake rates per depot were similar in obese and nonobese subjects and represented 4.1% of whole-body glucose uptake in obese and 2.6% in nonobese subjects (P < 0.02 between the groups). In conclusion, insulin-stimulated glucose uptake per kilogram fat is higher in visceral than in sc adipose tissue. Glucose uptake and blood flow in adipose tissue exhibit insulin resistance in obesity, but because of the larger fat mass, adipose tissue does not seem to contribute substantially to the reduced insulin stimulated whole-body glucose uptake in obesity.

Context: Limited information exists on the interaction between diet and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and the interaction's effect on serum lipid and lipoprotein levels, insulin sensitivity, and circulating antioxidant vitamin and provitamin levels., Objective: To evaluate the separate and combined effects of diet and simvastatin therapy on serum levels of lipids, lipoproteins, antioxidants, and insulin., Design, Setting, and Participants: Randomized, controlled crossover trial conducted from August 1997 to June 1998 in 120 previously untreated hypercholesterolemic men aged 35 to 64 years who were recruited from the community in Turku, southwestern Finland., Interventions: After a 4- to 6-week placebo run-in period, participants were randomly allocated to a habitual diet (n = 60) or dietary treatment group (n = 60), and each of these groups was further randomized in a double-blind crossover fashion to receive simvastatin (20 mg/d) or placebo, each for 12 weeks (n = 30 in each group). The main goals of the dietary treatment were to reduce energy intake from saturated plus trans-unsaturated fats to no more than 10% by replacing them partly with monounsaturated and polyunsaturated fats rich in omega-3 fatty acids and to increase intake of fruits, vegetables, and dietary fiber., Main Outcome Measures: Changes in levels of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol; triglycerides; apolipoprotein B; insulin; glucose; and antioxidants at week 12 of each treatment period, compared among the 4 groups., Results: Dietary treatment decreased levels of total cholesterol by 7.6% (P<.001), LDL cholesterol by 10.8% (P<.001), HDL cholesterol by 4.9% (P =.01), apolipoprotein B by 5.7% (P =.003), serum insulin by 14.0% (P =.02), and alpha-tocopherol by 3.5% (P =.04). Simvastatin decreased levels of total cholesterol by 20.8%, LDL cholesterol by 29.7%, triglycerides by 13.6%, apolipoprotein B by 22.4%, alpha-tocopherol by 16.2%, beta-carotene by 19.5%, and ubiquinol-10 by 22.0% (P<.001 for all) and increased levels of HDL cholesterol by 7.0% (P<.001) and serum insulin by 13.2% (P =.005). Glucose levels remained unchanged in all groups. The effects of dietary treatment and simvastatin were independent and additive., Conclusions: A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently potentiated the cholesterol-lowering effect of simvastatin, counteracted the fasting insulin-elevating effect of simvastatin, and, unlike simvastatin, did not decrease serum levels of beta-carotene and ubiquinol-10.

Aims: Direct assessment of tissue metabolism in vivo is important to understand the pathogenesis of obesity. Labelled glucose analogues are potential candidates to be used for this purpose. The aim of this study was to compare the kinetics and metabolism of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) in obese (fa/fa) and lean (Fa/?) Zucker rat tissues with microdialysis, and the measurement of uptake and phosphorylation with or without insulin bolus injection., Methods: Obese (n = 10) and lean (n = 11) anaesthetized rats underwent a microdialysis study after FDG-injection either with or without insulin stimulation. Microdialysis probes were inserted in the jugular vein, quadriceps muscle and liver. After 110 min, tissue [(18)F]-uptake and intracellular phosphorylation of FDG were studied in blood, liver, skeletal muscle, subcutaneous adipose tissue, intra-abdominal adipose tissue and hypothalamus., Results: When measured with microdialysis, insulin-enhanced FDG disappeared from the blood pool and interstitial space of skeletal muscle and liver more effectively in lean rather than in obese animals. Insulin-stimulated skeletal muscle and adipose tissue[(18)F]-uptake was impaired in obese Zucker rats compared with lean animals. Hypothalamic FDG uptake was six to sevenfold higher than in other measured tissues, but was attenuated in obese rats. In liver and in mesenteric fat, insulin-enhanced FDG phosphorylation in lean rats compared with obese animals., Conclusions: Positron-emitting glucose analogue FDG, combined with microdialysis and tissue analysis, is a feasible method in studying glucose metabolism at the cellular level in animal studies.

Aims/hypothesis: To determine the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [(18)F]-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) and glucose, for [(18)F]FDG in human adipose tissue., Methods: [(18)F]FDG-PET was combined with microdialysis. Seven non-obese (29 +/- 2 years of age, BMI 24 +/- 1 kg/m2) and seven obese (age 32 +/- 2 years of age, BMI 31 +/- 1 kg/m2) men were studied during euglycaemic hyperinsulinaemia (1 mU/kg. min-1 for 130 min). Abdominal adipose tissue [(18)F]FDG uptake (rGUFDG) and femoral muscle glucose uptake were measured using [(18)F]FDG-PET. Adipose tissue perfusion was measured using [15O]-labelled water and PET, and interstitial glucose concentration using microdialysis. Glucose uptake (by microdialysis, rGUMD) was calculated by multiplying glucose extraction by regional blood flow. The LC was determined as the ratio of rGUFDG to rGUMD., Results: Rates of adipose tissue glucose uptake (rGUMD) were 36 % higher in the non-obese than in the obese patients (11.8 +/- 1.7 vs 7.6 +/- 0.8 micromol/kg. min-1, p < 0.05, respectively) and a correlation between rGUMD and rGUFDG was found (r = 0.82, p < 0.01). The LC averaged 1.14 +/- 0.11, being similar in the obese and the non-obese subjects (1.01 +/- 0.15 vs 1.26 +/- 0.15, respectively, NS). Muscle glucose uptake was fourfold to fivefold higher than adipose tissue glucose uptake in both groups., Conclusion/interpretation: [(18)F]FDG-PET seems a feasible tool to investigate adipose tissue glucose metabolism in human beings. Direct measurements with [(18)F]FDG-PET and microdialysis suggest a LC value of 1.14 for [(18)F]FDG in human adipose tissue during insulin stimulation and the LC does not appear to be altered in insulin resistance. Furthermore, the obese patients show insulin resistance in both adipose tissue and skeletal muscle.

Aims: To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers., Methods: 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., Results: 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., Conclusions: 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.

Our aim was to study the concentration of betaxolol in plasma after its topical ocular use during the normal 12 hr dosing interval. Twenty microliters of betaxolol 0.5% solution were applied into both eyes of nine glaucoma patients, and the plasma concentrations of the drug were measured 12 hr thereafter using a radioreceptor assay. The same amount of betaxolol was then applied ocularly, and its concentration in plasma was measured at 5, 10, 15, 30 min and 1, 2, 4 and 8 hr thereafter. The mean (SD) concentration of betaxolol in plasma twelve hr after the first dose was 0.4 (0.2) ng/ml. After the second dose, the patients showed a biphasic concentration vs. time curve, the first peak occurring at 8 (4) min, and the second peak at 210 (132) min; the mean (SD) peak concentrations being 1.1 (0.3) and 2.0 (1.1) ng/ml, respectively. The area under the concentration vs. time curve showed a 4-fold variation among our patients. Topically applied betaxolol was rapidly absorbed into systemic circulation, and concentrations were detectable even at 12 hr. The interindividual variation in the systemic absorption of betaxolol was large.

Among other actions, leptin has been suggested to increase energy expenditure and to modulate the menstrual cycle. In fact, the main effect of leptin seems to be modulating the sympathetic nervous system and gonadotropin-releasing hormone pulsatility. We investigated whether changes in the plasma steroid concentrations during the estrous cycle and after ovariectomy and steroid replacement can modulate plasma leptin levels, adipose tissue leptin mRNA expression, and some of the candidates for mediating energy expenditure (uncoupling proteins (UCP) 1, 2, and 3 mRNA) in white and brown adipose tissue. Rats in estrous cycle or ovariectomized rats with or without estradiol or progesterone replacement therapy for 18 days were studied. Plasma leptin, insulin, estradiol and progesterone were measured with radioimmunoassays. Leptin mRNA expression was measured in subcutaneous, periovarian and mesenteric white adipose tissue and in interscapular brown adipose tissue. Expression of UCP 1, 2, and 3 mRNA in periovarian white and brown adipose tissue was analyzed. Plasma leptin levels were significantly decreased in the estrous (1.1 +/- 0.4 ng/ml) compared with the pro-estrous (1.7 +/- 0.4 ng/ml, F = 3.0, p = 0.046) phase of cycle. UCP1 mRNA levels in brown adipose tissue were more elevated during pro-estrus than during metestrus (F = 3.17, p = 0.039). Gene expressions of leptin, UCP2 or UCP3 mRNA did not change significantly during the cycle. In ovariectomized rats, estradiol and/or progesterone treatment had no effect on plasma leptin levels. Gene expression analysis of leptin and UCP1, 2 and 3 in adipose tissue was not affected by steroid replacement. In conclusion, the estrous cycle appears to have a minor effect on modulation of leptin and uncoupling proteins. Only plasma leptin levels and expression of UCP1 mRNA are modestly elevated during the estrous cycle in the rat. Since estrogen and/or progesterone substitution in ovariectomized rats does not affect circulating leptin concentration or expression of leptin and UCPs in adipose tissue, it is unlikely that steroids play a major role in their regulation.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Aims: Hydroxychloroquine (HCQ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo., Methods: Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM-MR) was also determined at baseline and after the ingestion of HCQ or placebo., Results: Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration-time curve (65 +/- 4.6%) and maximal plasma concentrations (72 +/- 6.9%) of metoprolol. While the DM-MR values were not significantly changed, the phenotypic classification of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration., Conclusions: HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator, except in an individual with limited CYP2D6 capacity.

Celiprolol is a novel beta-adrenoceptor blocking drug that displays clinically favorable effects on glucose and lipid metabolism. Because some other atypical beta-adrenoceptor blocking drugs have been described to act as agonists on beta(3)-adrenoceptors, we aimed to investigate the effects of celiprolol on brown fat and beta(3)-adrenoceptors. Chronic treatment of obese fa/fa Zucker rats with celiprolol (50 mg/kg/day orally for 20 days) increased GDP binding to brown fat mitochondria by 1.5-fold, whereas beta(3)-adrenoceptor agonist ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl )phenoxyacetamide, 3 mg/kg/day) increased the binding by 3.3-fold. Weight gain was reduced by 19% due to decreased water and food intakes in celiprolol-treated rats. Celiprolol did not activate lipolysis in rat adipocytes in vitro or stimulate human beta(3)-adrenoceptors expressed in Chinese hamster ovary cells as measured with Cytosensor microphysiometer. Therefore, celiprolol does not seem to activate brown fat via beta(3)-adrenoceptors.

Purpose: Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group)., Results: Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05)., Conclusions: Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating beta1- selective adrenoceptor antagonist, potentiates this effect.

Objective: Leptin plays an important role in the regulation of reproduction. To explore the contribution of oestradiol to serum leptin levels in men, we measured the concentrations of serum leptin and insulin after inhibition of oestrogen biosynthesis by selective blockade of the aromatase enzyme., Design: The study had a double-blind parallel group design., Methods: The aromatase inhibitor, MPV 2213ad, was given to eight healthy male volunteers as a single dose of 100mg. Eight men received placebo. Serum leptin and insulin were determined from blood samples collected at 0800h, 1600h and 2000h both on the actual test day (day 0) and on the previous day (day -1), and from single blood samples taken in the morning of days 1, 2, 4 and 7. Changes in serum leptin were correlated with those seen in serum oestradiol, testosterone, LH, FSH, cortisol and aldosterone, which were determined earlier., Results: After the aromatase inhibitor administration, mean serum oestradiol concentration was reduced by 74% from the baseline compared with a 19% reduction in the placebo group (P for difference <0.001), and returned to pre-treatment levels within four days. Despite marked changes in serum oestradiol and sustained elevations in serum testosterone, LH and FSH concentrations, serum leptin concentrations were similar in the group receiving the aromatase inhibitor and in the placebo group. We found a weak correlation between serum oestradiol and leptin, which could not be reproduced when the percentage changes in these variables were analysed., Conclusion: Marked short-term reduction in serum oestradiol concentration has no effect on serum leptin levels in young men.

The goal of this study was to examine the multiple-dose pharmacokinetics of selegiline and its metabolites desmethylselegiline, 1-methamphetamine, and 1-amphetamine after oral administration of selegiline HCl. Twelve healthy volunteers received 10 mg of selegiline HCl once daily for 8 days. The pharmacokinetic profiles of selegiline and the metabolites were examined from serum samples for 24 hours (i.e., the dosing interval, tau) on days 1, 4, and 8. The results indicated significant apparent accumulation of selegiline and desmethylselegiline during the 8-day period of selegiline administration. The AUC tau S of selegiline and desmethylselegiline were increased 2.7 fold (p < 0.001) and 1.5 fold (p < 0.001), respectively, from day 1 to day 8. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4-5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation. With both of the 1-amphetamine metabolites of selegiline, steady state was reached by day 4. We suggest that the most likely explanation for the apparent accumulation of selegiline and desmethylselegiline was the saturation of the MAO-B binding sites in tissues, although decreased first-pass metabolism of selegiline cannot be ruled out. The observed increase in selegiline and desmethylselegiline concentrations on multiple dosing is not likely to significantly increase the pharmacodynamic effect or adverse effects of selegiline compared with what has been found after a single 10-mg dose.

Unlabelled: 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., Subjects, Material and Methods: 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., Results: 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., Conclusions: 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.

The pharmacokinetics and tolerability of a new putative non-benzodiazepine type anxiolytic compound deramciclane was studied in two consecutive studies. An open dose-escalation design was used to study doses from 0.2 to 50 mg in 18 healthy male volunteers. In the second study doses from 50 to 150 mg were investigated in 14 healthy males in a double-blind, placebo-controlled, dose escalation study. Deramciclane was rapidly absorbed from the GI-tract and T(max) was 2-4 h. The elimination half-life increased from about 20 h to about 32 h with the increasing dose. Nevertheless, the AUC(0-infinity) values increased linearly within the studies over the dose ranges of 3-50 and 50-150 mg. However, the increase was more than the ratio of the dose over the total dose range of 3-150 mg. Therefore, non-linear pharmacokinetics of deramciclane at high doses cannot be excluded. N-desmethyl deramciclane, which is the active metabolite of deramciclane, was determined in plasma. C(max) was reached at about 6 h. The AUC(0-48 h) for the N-desmethyl metabolite was about one third of the AUC(0-infinity) of the parent compound and the ratio remained constant at each dose level. Deramciclane was safe, and was well tolerated at each dose level., (Copyright 1999 John Wiley & Sons, Ltd.)

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.

Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions., Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1-2 and 6-7, and twice daily on study days 3-5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1-2 and 6-7 were compared with each other., Results: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1-2 and 2.3 h on days 6-7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa., Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.

Objective: Novel aromatase inhibitors are developed with requirements of high potency and selectivity for the aromatase enzyme. The hormonal effects of a new, non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, were investigated in this study., Methods: The study was conducted as a double-blind, placebo controlled phase I study, where 32 healthy male volunteers were randomized to receive a single oral dose of either 0.3, 3 or 100 mg of MPV-2213ad or placebo. Serum concentrations of estradiol (E2), testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol and aldosterone were determined from samples taken 0, 4, 8 h and 12 h during the day of drug administration and 1, 2, 4 and 7 days after drug intake. The individual diurnal variation of circulating hormone concentrations was determined in all participants at 0, 4, 8 h and 12 h on the day before drug intake. Specimens for hematological and biochemical analyses were also collected., Results: A dose-dependent and statistically significant (P < 0.001) decrease in serum E2 concentrations was induced by MPV-2213ad. Lowest mean values were observed 8-12 h after drug administration and at 24 h the reductions were 10%, 34% and 69% from baseline in the 0.3-mg, 3-mg and 100-mg groups, compared with an 18% increase in the placebo group. Serum E2 concentrations returned to baseline within 4 days in all study subjects. A significant increase was observed in the serum concentrations of testosterone (P = 0.016), LH (P = 0.002) and FSH (P < 0.001) after administration of MPV-2213ad. Serum concentrations of cortisol and aldosterone were unaffected by MPV-2213ad. The drug was well tolerated., Conclusion: Single oral doses of MPV-2213ad, given to healthy male subjects, induced hormonal effects typical for a specific and selective inhibitor of the aromatase enzyme. Importantly, this study design with the determination of the diurnal rhythm in the levels of the corresponding hormones gives additional validity on the results.

Aims: The purpose of this study was to characterize the dose relationship of selegline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg., Methods: Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethlylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication., Results: The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels)., Conclusions: Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced T-demethylation of selegiline. The present results suggest that concomitant use of selegiline with exogenous female sex steroids should be avoided or the dosage of selegiline should be reduced in order to minimize the risks of selegiline related adverse drug reactions.

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; P < 0.001) 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.

Objective: Leptin is the hormonal product of the ob gene. It is expressed in adipocytes and participates in the regulation of food intake and metabolism. Since leptin also seems to signal metabolic information to the reproductive system, we studied the association between reproductive hormones and plasma leptin in normal-weight young women., Design: Eight young women with normal menstrual cycles (body mass index (BMI) 21.2 +/- 1.6 kg/m2) and eight young women using hormonal contraception (BMI 21.4 +/- 1.1 kg/m2) were studied. Furthermore, six women with normal menstrual cycles and no hormonal therapy (BMI 20.7 +/- 1.2 kg/m2) were studied around the time of the anticipated ovulation., Methods: Serum leptin, estradiol, progesterone and luteinizing hormone (LH) concentrations were measured with radioimmunoassays., Results: Serum leptin concentrations were similar at the beginning of the cycle, at the time of the anticipated ovulation and at the end of the menstrual cycle (10.2 +/- 7.1, 10.7 +/- 7.0 and 11.8 +/- 6.9 microg/l respectively). There was an association between leptin and LH concentrations (r= 0.37, P< 0.01) when values recorded during different time points during the cycle were plotted with each other. There was no change in serum leptin in samples taken at different times of the cyclic treatment with an oral contraceptive. There was no significant difference in mean serum leptin concentrations between women using oral contraceptives and women with no hormonal therapy., Conclusions: There is a link between serum leptin and LH concentrations during the menstrual cycle. Variations in circulating estrogen and/or progesterone concentrations have no major influence on circulating leptin in young female subjects.

Objective: The aim was to study the relationship between aqueous humour betaxolol concentration and intraocular pressure (IOP)., Methods: In this double-blind, randomized study, we administered betaxolol (a) or placebo (b) ocularly to 131 patients scheduled for cataract surgery. The patients were randomly divided into ten groups. In groups 1a and 1b, the drug was scheduled to be instilled 1-2 h, in groups 2a and 2b 12 h, in groups 3a and 3b 24 h, and in groups 4a and 4b 48 h before surgery. The pupil was dilated in all eyes prior to surgery. The IOP was measured with Perkins' applanation tonometer before the instillation of the drug and just before the peribulbar block. Twenty microlitres of 0.5% betaxolol or placebo solution was instilled into the eye. IOP was also measured before instillation of the drug and after 1 2 h in undilated eyes of 20 patients, whose contralateral eye was to be operated on, to rule out the effect of pupil dilation on IOP (groups 5a and 5b). Aqueous humour betaxolol concentrations were analysed using a radioreceptor assay., Results: Betaxolol did not decrease IOP significantly in eyes with pupillary dilation. Both betaxolol and placebo decreased IOP significantly in patients without pupillary dilation, the effect of betaxolol being slightly more pronounced. The betaxolol concentration in aqueous humour was 731 ng m-1 in group la, 2.4 h after drug instillation. Measurable concentrations of betaxolol were also detected in aqueous humour in group 4a 47.7 h after drug administration., Conclusion: No correlation between aqueous humour concentration of betaxolol and the effect on IOP was found in eyes where the pupil was dilated before surgery. A single betaxolol dose did not decrease IOP significantly in patients undergoing cataract surgery, but the IOP decreasing effect was, however, clearly seen in patients who did not receive mydriatic drugs. The routine use of topical betaxolol prior to cataract surgery to decrease IOP is not recommended.

Information on biological day-to-day variation is needed for detecting within-subject changes over time. In this study the daytime changes and the biological day-to-day variation of serum testosterone, follitropin, lutropin and oestradiol-17beta concentrations were investigated in 31 healthy males. To analyse daytime changes, blood specimens were taken at 0800 h, 1200 h, 1600 h and 2000 h during one day (n=31) and two days (n=8). The day-to-day variation was analysed from blood specimens collected at 0800 h on days 1 and 2 (n=31) and additionally on days 3, 4, 6 and 9 (n=8). The evaluation of the day-to-day variation was based on calculations of the within-subject (CVA+I) and between-subject (CV(G)) coefficients of variation. When the within-subject day-to-day variances were not too heterogeneous, they were used for the calculation of 95 % reference change limits. Serum testosterone and oestradiol-17beta concentrations showed a significant daytime variation; testosterone had higher serum concentrations at 0800 and 1200 h. A peak in the serum concentration of oestradiol-17beta occurred at 1200 h with a decrease towards the evening. There were no clear daytime changes in the serum concentrations of follitropin or lutropin. For different analytes the reference change limits were: serum testosterone +/- 32.0 %, serum follitropin +/- 24.1 % and serum oestradiol-17beta +/- 38.3 %. The reference change limit was not calculated for serum lutropin, as a high degree of heterogeneity and individuality was found. The interpretation of the results of hormone measurements requires recognition of the biological daytime and day-to-day changes of hormones. The reference change limits determine what changes are significant when monitoring the patient.

The expressions of uncoupling proteins 2 and 3 (UCP2; UCP3) mRNA were studied in obese (fa/fa) Zucker rats treated with two weight gain reducing agents for three weeks. The specific beta 3-adrenoceptor agonist BRL 35135 (0.5 mg/kg/day orally) increased the expression of UCP3 mRNA by 3.8-fold (P < 0.0001; two-way ANOVA) and that of UCP1 mRNA by 2.6-fold (P = 0.014) in brown adipose tissue, but had no effect on expression of UCP3 mRNA in white fat or in the soleus muscle, or on UCP2 mRNA expression in brown or white fat. The antihyperglycemic metformin (300 mg/kg/day orally) had no effect on expressions of UCP1, UCP2 or UCP3 in any tissue studied. Concentrations of plasma insulin were significantly correlated with the levels of white fat UCP2 mRNA (in the control group: r = 0.89, P = 0.0015) and UCP3 mRNA (in the control group: r = 0.80, P = 0.009) suggesting that insulin may play a role in the control of UCP2 and UCP3 mRNA expressions in white adipose tissue.

Selective beta3-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The aim of this study was to investigate how changes in energy balance affect energy intake and interaction of peripheral metabolic feedback signals with central neuroendocrine mechanisms participating in the control of body energy balance. Expression of preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus and preprocorticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus were measured by in situ hybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl)phenoxyacetamide, 3 mg kg(-1) day(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expression of leptin mRNA in epididymal fat and serum levels of leptin were analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. Treatment with ZD7114 significantly reduced weight gain and activated brown adipose tissue thermogenesis, but had no effect on food intake. Expressions of preproNPY or preproCRF mRNAs were similarly not changed by treatment with ZD7114. Furthermore, ZD7114 had no effect on plasma insulin or leptin and the expression of leptin mRNA in epididymal fat. However, statistically significant correlations were found between preproNPY and preproCRF mRNA expressions and brown fat thermogenic activity and plasma insulin levels in the ZD7114 treated rats, but not in the control rats. It is concluded that treatment with ZD7114 markedly activated brown fat thermogenesis, but did not affect neuropeptide Y (NPY) and CRF gene expression per se. However, the correlation analyses suggest that ZD7114 may modulate feedback connections of brown adipose tissue thermogenesis and plasma insulin with the hypothalamic neuroendocrine mechanisms integrating body energy balance.

Aims: A novel non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, was entered into an open dose-escalation study. The objective of this study was to investigate the tolerability and efficiency of this new compound with assessment of the hormonal effects after study drug administration., Methods: MPV-2213ad was given to 39 healthy male volunteers. Single increasing oral doses of 0.003, 0.03, 0.3, 3, 9, 30 and 100 mg were given to three subjects at each dose level, after which ten subjects received the 300 mg dose and eight subjects the highest 600 mg dose of MPV-2213ad., Results: Serum oestradiol levels were suppressed by 58-65% when MPV-2213ad was given at doses between 0.3 and 30 mg. A reduction in serum oestradiol levels by 83% from baseline was achieved with the 300 mg dose. No additional decrease was seen with the highest dose. The suppression lasted longer with higher doses of MPV-2213ad. After the 300 and 600 mg doses serum oestradiol returned to baseline within 4 days. Marked increases in serum concentrations of testosterone, androstenedione, 17-OH-progesterone, LH and FSH were also observed at doses between 100 and 600 mg of MPV-2213ad. The drug was well-tolerated and the adverse events were mild or moderate including hot flushes, mild vertigo, nausea, acne and gastrointestinal discomfort., Conclusions: MPV-2213ad has a potent, dose-dependent inhibitory effect on serum oestradiol. It was selective for the aromatase enzyme with no signs of adreno-cortical suppression or haematological or biochemical toxicity.

The effects of a vasodilating beta-blocker, celiprolol, on insulin sensitivity and cardiovascular risk factors were compared with those of another beta1-selective adrenoceptor blocker, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. A randomized 21-month crossover trial was carried out with 25 patients with dyslipidemia receiving antihypertensive monotherapy. The study consisted of a 3-month active run-in period and two treatment periods, during which the patients received celiprolol (200-400 mg daily) or the control drug for 12 and 6 months in a crossover manner. A hyperinsulinemic euglycemic clamp and an oral glucose tolerance test (OGTT) were performed every 6 months. According to the clamp tests, the insulin-sensitivity index increased on average by 32% (p < 0.0001) during celiprolol treatment compared with that with the other antihypertensive agents, including ACE inhibitors. In OGTT, area under the incremental glucose curve decreased by 36% (p = 0.002) during celiprolol treatment, whereas insulin secretion diminished on average by 26% (p = 0.006). The mean decrease in fasting serum triglycerides was 11% (NS), whereas the high-density lipoprotein to low-density lipoprotein (HDL/LDL) ratio increased by 15% (p = 0.012). The results suggest that celiprolol improves insulin sensitivity of hypertensive patients with dyslipidemia in long-term therapy.

We have evaluated the risk for pharmacokinetic and/or pharmacodynamic interactions of concomitantly administered selegiline, a selective monoamine oxidase type B inhibitor, and citalopram, a widely used selective serotonin uptake inhibitor antidepressant. Two parallel groups of healthy volunteers received 20 mg of citalopram (n = 12) or placebo (n = 6) once daily for 10 days in a randomized, double-blind fashion, followed by concomitant selegiline 10 mg once daily for 4 days. The safety of this drug combination was assessed by measurements of blood pressure, heart rate, body temperature, and inquiries for adverse events. Blood samples were taken for the analysis of serum concentrations of both study drugs and their metabolites and plasma prolactin, adrenaline, noradrenaline, and 3,4-dihydroxyphenylglycol (DHPG); urinary excretion of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were assessed. After a 5-week washout, the 12 subjects who took citalopram in the first part of the study received 10 mg of selegiline once daily for 4 days to compare the pharmacokinetics of selegiline with and without concomitant citalopram. The safety analysis showed no significant differences in vital signs or the frequency of adverse events between the study groups. Plasma prolactin concentrations were increased by 40% after 10 days' treatment with citalopram (p = 0.03); this was not potentiated by concomitantly administered selegiline. The comparison of plasma concentrations of noradrenaline, adrenaline, and DHPG and the amount of serotonin and 5-HIAA excreted into urine between the study groups indicated no signs of subclinical pharmacodynamic interaction between selegiline and citalopram. The relative bioavailability of selegiline was slightly reduced (by 29%; p = 0.008) when citalopram was coadministered compared with selegiline alone. However, no indication of a pharmacokinetic interaction was found in the analysis of serum concentrations of the three main metabolites of selegiline. The pharmacokinetics of citalopram remained unaffected by concomitant selegiline. The present results indicate lack of clinically relevant pharmacodynamic or pharmacokinetic interactions between selegiline and citalopram.

The effects of a beta 3-adrenoceptor agonist on insulin-induced changes in lipid metabolism were studied in obese male Zucker (fa/fa) rats during euglycaemic clamp. Rats were treated with BRL 35135 (R*, R*-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)-ethyl-amino]-propyl] phenoxyacetate hydrobromide) (0.5 mg/kg per day in drinking water) for three weeks before an euglycaemic hyperinsulinaemic clamp was performed. Insulin infusion lowered serum non-esterified fatty acids and plasma glycerol more efficiently in BRL 35135-treated than in control rats although plasma insulin remained significantly lower in the BRL 35135-treated than in the control rats during the clamp. In conclusion, chronic treatment with BRL 35135 potentiates the effect of insulin on lipid metabolism.

Cyclosporine binds with cyclophilin, an abundant protein found in almost all tissues, and the resulting complex interacts with calcineurin diminishing T-cell activation. Cyclophilin can be regarded as a cellular "receptor" for cyclosporine. Measuring cyclosporine binding to cyclophilin may offer a link between pharmacokinetics and pharmacodynamics that could improve monitoring of cyclosporine therapy. The authors investigated the feasibility of the cyclophilin binding assay and compared the results with a standard specific monoclonal radioimmunoassay in 100 blood samples taken for therapeutic drug monitoring. The results obtained with these methods were related closely with each other (r = 0.96; p < 0.001) but the mean (+/-SEM) concentrations were approximately two-fold higher in cyclophilin binding assay than in radioimmunoassay (520.4 +/- 49.9 ng/ml versus 257.7 +/- 28.6 ng/ml, respectively, p < 0.001). The shapes of the cyclosporine concentration versus time curves in two patients after a liver and heart transplantation, respectively, were similar after both methods but cyclophilin binding assay gave higher values than radioimmunoassay. Before firm conclusions on the clinical value of cyclophilin binding assay can be made, comparative studies in patients linking cyclosporine concentrations measured with cyclophilin binding assay and standard methods to the therapeutic outcome are needed.

MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.

The role of gonadotropins, androgens, and insulin in the regulation of circulating leptin levels is obscure. In order to clarify the relationships of these parameters we studied serum leptin levels in 19 healthy control subjects and in 35 hyperandrogenic and hyperinsulinemic patients with polycystic ovary syndrome (PCOS). Serum leptin concentrations did not differ significantly between PCOS patients and control subjects. When PCOS and control groups were analyzed together by univariate analysis, serum leptin was positively correlated with body mass index (BMI), body weight, serum insulin, serum triglyceride, and serum free testosterone concentrations. Serum leptin was inversely correlated with serum sex hormone binding globulin (SHBG) concentrations. There were no significant correlations between serum leptin and testosterone, androstenedione, or gonadotropin concentrations. Serum insulin, triglyceride, and free testosterone concentrations were positively correlated, and serum SHBG was negatively correlated with BMI. However, when BMI on one hand and serum insulin, triglyceride, free testosterone, or SHBG on other hand were used as independent variables in the partial correlation analysis with leptin, BMI turned out to be the variable primarily responsible for all of the correlations with leptin. In conclusion, the concept that circulating leptin levels would be different in PCOS patients than in regularly menstruating control subjects is not supported by our data.

The effects of chronic alcohol intake and carbachol stimulation on pancreatic muscarinic receptor binding and insulin concentrations were studied in the rat pancreas. There was a strong correlation between the number of muscarinic receptors and the concentration of insulin in the pancreas. The concentration of insulin decreased in the pancreas after long-term ethanol exposure and increased after carbachol stimulation. These results indicate that the secretion of insulin is mediated via the muscarinic receptor pathway, and that the changes in the number of muscarinic receptors may have a role in insulin deficiency after long-term alcohol consumption.