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Biomedical subjects

R Huupponen

Publications and source records attributed to R Huupponen.

At least 19 recordsLinked to original sources
PubMed2005

Adoption of celecoxib and rofecoxib: a nationwide database study.

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.

Age Factors↗
PubMed2004

Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers.

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.

Adult↗
PubMed2002

2-[(18)F]fluoro-2-deoxy-D-glucose combined with microdialysis can be used for the comparison of tissue glucose metabolism in obese and lean rats.

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.

Animals↗
PubMed2001

Human adipose tissue glucose uptake determined using [(18)F]-fluoro-deoxy-glucose ([(18)F]FDG) and PET in combination with microdialysis.

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.

Adipose Tissue↗
PubMed2001

Pharmacokinetics of finrozole (MPV-2213ad), a novel selective aromatase inhibitor, in healthy men.

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.

Administration, Oral↗
PubMed2001

Plasma concentration of topically applied betaxolol in elderly glaucoma patients.

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.

Absorption↗
PubMed2001

Effects of estrous cycle and steroid replacement on the expression of leptin and uncoupling proteins in adipose tissue in the rat.

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.

Adipose Tissue↗
PubMed2000

In vivo detection of vascular adhesion protein-1 in experimental inflammation.

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.

Amine Oxidase (Copper-Containing)↗
PubMed2000

Effects of chronic celiprolol treatment on brown fat, feeding, and drinking in fa/fa Zucker rats.

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.

Adipose Tissue, Brown↗
PubMed2000

Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure.

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.

Adrenergic beta-Antagonists↗
PubMed2000

Influence of hydroxychloroquine on the bioavailability of oral metoprolol.

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.

Adrenergic beta-Antagonists↗
PubMed2000

Acute inhibition of oestrogen biosynthesis does not affect serum leptin levels in young men.

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.

Adult↗
PubMed1999

Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure.

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.

Blood Pressure↗
PubMed1999

The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers.

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.

Adult↗
PubMed1999

A double-blind study of MPV-2213ad, a novel aromatase inhibitor, in healthy male subjects.

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.

Adult↗
PubMed1999

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition.

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.

Adult↗
PubMed1999

Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids.

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.

Administration, Oral↗