Dry/wet cycling reduces spore germination and viability in six peatland bryophytes.

Dry/wet cycling driven by water level fluctuation in wetlands may strongly influence the destiny of seeds. However, how dry/wet cycling affects spore survival and germinability in peatland bryophytes is poorly understood. Six peatland bryophytes, three hummock- and three hollow-dwelling Sphagnum species, were chosen as study species. We tested the effects of dry (60% air RH)/wet (waterlogging) cycle frequency (once per 12, 8 or 4 days for low, medium or high, respectively) and ratio (3:1, 1:1 or 1:3 dry:wet time per cycle) on spore germinability, viability, dormancy percentage and protonema development. Dry/wet cycling significantly reduced spore germination percentage and viability and slowed protonema development in all Sphagnum species, being more pronounced with higher dry/wet cycling frequencies. The hummock species S. capillifolium and S. fuscum had higher spore germination percentage after the continuous dry treatment, while the hollow species S. angustifolium, S. squarrosum and S. subsecundum showed the opposite response, compared to the continuously wet treatment. Except for S. squarrosum, spore viability was higher after the dry than after the wet treatment. Spore viability and dormancy percentage were higher after a dry/wet ratio of 1:3 than after ratios of 3:1 and 1:1. Our study shows that both germinability and viability of bryophyte spores are reduced by dry/wet cycling (especially when frequent) in peatlands. This emphasizes the need to ensure constant water levels and low frequencies of water level fluctuation, which are relevant in connection with wetland restoration, to promote Sphagnum spore survival and establishment in peatlands after disturbances.

The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure.

OBJECTIVE: Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure. MATERIALS: Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III. METHODS: A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2. RESULTS: There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively. CONCLUSIONS: The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.

The Obstructive Lung Disease in Northern Sweden (OLIN) longitudinal paediatric study I--the first 10 years.

BACKGROUND: Prospective studies of asthma and allergic conditions based on the general population are scarce. AIM: To summarize the methods and main results from a prospective study among school children. METHODS: In 1996, a cohort of 3525 children aged 7/8 years in Northern Sweden were invited to a questionnaire survey using an expanded ISAAC protocol, and 97% participated. The cohort has been followed up yearly with high participation rate. Skin prick tests were conducted 1996, 2000 and 2006/2007. Allergens in dust from homes and schools have been analyzed. Sub samples have participated in interviews, lung function tests, bronchial hyper reactivity test, and analyses of IgE and IgG antibodies in serum. RESULTS: The prevalence of asthma was 6% at age 7-8 years and increased by age. The incidence of physician-diagnosed asthma after the age of 7-8 years was around 1/100/year. The prevalence of positive skin prick test increased from 21% at age 7-8 to 30% at age 11-12 years. Remission of allergic sensitization was rare, while asthma remission was 5% yearly. The main risk factor for asthma and allergic sensitization increased in importance with increasing age. Allergic and non-allergic asthma had different risk factor pattern. Environmental risk factors decreased in impact after the age of 7. Avoidance of pets at home did not protect from asthma or allergic sensitization. CONCLUSION: The study includes important sources of data for further longitudinal analyses that will contribute to the understanding of the development and the nature of asthma and allergic sensitization.

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure.

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.

Postoperative stroke in a child with cerebral palsy heterozygous for factor V Leiden.

A 5-year-old with spastic quadraparetic cerebral palsy suffered multiple strokes after extensive orthopedic surgery. Coagulation testing was undertaken to determine whether a familial thrombophilia was present. The patient was found to be heterozygous for factor V Leiden. Factor V Leiden may be a risk factor for central nervous system events in special-needs children, particularly when common medical conditions create additional procoagulant risks.

Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5-mononitrate in healthy subjects.

OBJECTIVE: The new calcium sensitiser levosimendan also possesses vasodilatory effects due to potassium-channel opening. The aim of the present study was to assess the possible haemodynamic interactions between levosimendan and isosorbide-5-mononitrate in young healthy men. METHODS: The study was crossover, placebo controlled, double blind, randomised, and it comprised of four study days with one medication--levosimendan, isosorbide-5-mononitrate, levosimendan plus isosorbide-5-mononitrate or placebo--given on each. Levosimendan was administered i.v. as an initial bolus dose of 12 microg/kg over 10 min, followed by a continuous infusion of 0.2 microg/kg/min for a total time of 2 h. Isosorbide-5-mononitrate (20 mg) was given orally as a single dose. Leg blood flow and venous capacity (venous occlusion plethysmography), cardiac output (impedance cardiography), skin blood flow (laser-Doppler flowmetry), blood pressure and heart rate were recorded at baseline, and 20 min, 1 h, 2 h, 4 h and 6 h after the start of the infusion. An orthostatic test was performed at baseline and at 2 h 15 min. Twelve healthy, male subjects were included. Their mean age was 24 years (range 20-34 years). RESULTS: Levosimendan increased leg blood flow by 32%, and no additive effect of the combination of levosimendan and isosorbide-5-mononitrate was observed. The effects of levosimendan on heart rate and blood pressure were minimal and in close conformity with previous studies. In general, there were no additive effects of the combination compared with each drug alone at rest. The only additive effect was seen in the orthostatic response. Heart rate increased by 40 beats min(-1) with the combination (95% confidence interval compared with placebo 11-24 beats min(-1)), by 30 beats min(-1) with levosimendan (2-15 beats min(-1)), by 28 beats min(-1) with isosorbide-5-mononitrate (1-15 beats min(-1)), and by 22 beats min(-1) with placebo. Furthermore, three subjects were unable to stand upright for the stipulated time with the combination, and the orthostatic test had to be discontinued prematurely. There were no changes in the conduction intervals in the electrocardiogram on any of the treatments. The combination had no influence on the occurrence of headache compared with isosorbide-5-mononitrate alone. CONCLUSION: No major additive haemodynamic effects of the combination of levosimendan and isosorbide-5-mononitrate compared with each drug alone could be observed at rest. However, during an orthostatic test, the circulatory response was significantly potentiated with the combination, and three of the subjects were unable to stand upright for the stipulated time.

Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function.

Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.

High-throughput and ultra-high-throughput screening: solution- and cell-based approaches.

The trend towards assay miniaturization for high-throughput and ultra-high-throughput screening continues to spur development of homogeneous, fluorescence-based assays in higher density, smaller volume microplate formats. Recently, first-generation microfluidic devices have been designed for performing continuous-flow biochemical and cell-based assays. These devices provide orders-of-magnitude reduction in reagent consumption, and offer the potential for implementing high-throughput screening in formats that integrate up-front compound handling with unique assay functionality.

Experimental evidence for a persistent spore bank in Sphagnum.

Spore capsules of four Sphagnum species were buried at different depths in peat on a bog. Spore viability was determined after 0, 1, 2 and 3 yr. Viability generally declined with time, but viable spores were still found at all depths after 3 yr. The light-coloured spores of S. balticum and S. tenellum retained their viability better than the darker spores of S. fuscum and S. lindbergii. Survival was highest under wet but aerobic conditions, but was also high under humid or periodically desiccated conditions. By contrast, most spores stored under wet, anaerobic conditions died within 2-3 yr. These results, and predictions from them, are not consistent with earlier results for spores of long-lived and dominant bryophytes, or for seeds of phanerogams of undisturbed wetlands and forests. There was no correlation between spore size and longevity across species, but the small spores from small capsules of S. balticum and S. tenellum generally showed higher viability than those from the medium-sized and large capsules of the same species. This suggests a positive intraspecific relationship between longevity and dispersal distance. There was an indication of conditional dormancy, controlled by weather, in Sphagnum spores. The experiments indicate that Sphagnum spores can form a long-term persistent spore bank under suitable conditions, with a half-life of between 1 and 20 yr (mean across species of 2.6 and 5.0 yr at two depths studied), and with potential values in individual spore capsules of several decades, or even of centuries. Sphagnum spores kept refrigerated showed 15-35% viable spores after 13 yr. The capacity to form a persistent spore bank that can be activated whenever favourable conditions occur might help explain the wide geographical distribution of many Sphagnum species in the boreal and temperate zones, where they have managed to colonize almost every suitable patch of acidic, nutrient-poor wetland.

Microchip-based systems for target validation and HTS.

Microarray and microfluidic device technologies for performing genetic and biochemical analyses are revolutionizing biological research. These technologies are now being applied to gene expression profiling and to primary screening for target validation and lead discovery in the pharmaceutical industry. In this article, we briefly review microchip technology and discuss future development trends.

Separation of linoleic acid oxidation products by micellar electrokinetic capillary chromatography and nonaqueous capillary electrophoresis.

In this work the suitability of micellar electrokinetic capillary chromatography (MEKC) and nonaqueous capillary electrophoresis (CE) to the analysis of the primary oxidation products of linoleic acid was studied with uncoated fused-silica capillaries. The primary autoxidation products of linoleic acid are the four hydroperoxide isomers 13-hydroperoxy-cis-9, trans-11-octadecadienoic acid, 13-hydroperoxy-trans-9, trans-11-octadecadienoic acid, 9-hydroperoxy-trans-10,cis-12-octadecadienoic acid, 9-hydroperoxy-trans-10, trans-12-octadecadienoic acid. Addition of a surfactant such as sodium dodecyl sulfate (SDS) or sodium cholate (SC) into the running buffer (20-30 mM 3-(cyclohexylamino)-1-propanesulfonic acid (CAPS) or ammonium acetate, pH 9.5-11) was required to enhance the water solubility of the sample and selectivity of the separation. MEKC proved to be a promising new technique for the separation of the primary oxidation products of lipids giving results comparable to high performance liquid chromatography (HPLC). Partial separation of hydroperoxide isomers was also achieved using nonaqueous CE with methanol-acetonitrile-sodium cholate as running buffer.

Subattomole-Sensitivity Microchip Nanoelectrospray Source with Time-of-Flight Mass Spectrometry Detection.

A microfabricated microfluidic device coupled with a nanospray tip for electrospray ionization of dilute solutions is described. The device has been interfaced with a time-of-flight mass spectrometer and evaluated for sensitive, high-speed detection of peptides and proteins. The electrospray voltage was applied through the microchip to the nanospray capillary that was attached at the end of a microfabricated channel. Fluid delivery rates were 20-30 nL min(-)(1) through the hybridized structure without any pressure assistance. On-line microchip electrophoresis has been demonstrated and the effect of the capillary-chip junction on band broadening examined. Full mass spectra are acquired within 10-20 ms at 50-100 spectra s(-)(1) storage rates. Detection of subattomole levels of sample from a 100 nM solution is demonstrated for infusion experiments.

Aerobic endurance exercise or circuit-type resistance training for individuals with impaired glucose tolerance?

The role of physical activity in the prevention of non-insulin-dependent diabetes mellitus (NIDDM) is of utmost importance. The aim of the present study was to evaluate the metabolic effects of aerobic endurance exercise and circuit-type resistance training in subjects with impaired glucose tolerance (IGT). Twenty-two individuals participated in the study. Fourteen subjects were enrolled in the aerobic endurance exercise part of the study; seven exercised regularly for six months, while seven served as controls. Maximal aerobic capacity (VO2max) was measured and insulin sensitivity and insulin secretion were assessed by a frequently sampled intravenous glucose tolerance test (FSIVGTT). Eight subjects participated in a circuit-type resistance training program for three months. Insulin sensitivity and substrate oxidation were then assessed using the euglycemic insulin clamp technique combined with indirect calorimetry. The aerobic endurance exercise program caused in increase in VO2max (21.6 +/- 1.9 to 25.4 +/- 2.4 ml/kg.min; p < 0.05) and HDL-cholesterol (1.14 +/- 0.06 to 1.23 +/- 0.08 mmol/l; p < 0.05), but no change in insulin sensitivity nor insulin secretion occurred. However, comparing the changes between the intervention and control group, the differences disappeared. Circuit-type resistance training increased insulin sensitivity (glucose disposal) by 23% (p < 0.05), primarily due to a 27% increase in non-oxidative glucose metabolism. Both circuit-type resistance training and aerobic endurance exercise seem to have beneficial effects in subjects with impaired glucose tolerance. However, by improving insulin sensitivity, circuit-type resistance training may postpone the manifestations of NIDDM in these high-risk individuals and should therefore be included in an exercise program for IGT subjects.

The effect of prolonged doxycycline therapy on Chlamydia pneumoniae serological markers, coronary heart disease risk factors and forearm basal nitric oxide production.

Chronic Chlamydia pneumoniae infection, characterized by elevated levels of C. pneumoniae IgG and IgA antibodies and immunocomplexes, is associated with myocardial infarction and angiographically verified coronary heart disease. C. pneumoniae organisms have also been found in coronary atheromas, but not in healthy vessels. We investigated the effect of 4 months' doxycycline therapy on serological markers of C. pneumoniae infection and coronary risk factors. Thirty-four non-smoking men, aged 57.9 (+/- 5.2) years, who had mild hypertension or moderate hypercholesterolaemia and a previous coronary bypass, were randomly assigned to receive doxycycline or matching placebo for 4 months. Acetylsalicylic acid and beta-blocker were the only other medications allowed. Patients were examined physically and by laboratory tests; their basal nitric oxide production was determined by blood flow responses to intra-arterial monomethyl-L-arginine at baseline and at 2 and 4 months. The tests were also taken at 6 months after medication. At entry, the demographic, clinical, blood flow and laboratory measurements were similar in both groups, with the exception of fibrinogen and triglyceride levels, which were higher in the placebo group. No significant changes were found in any of the parameters during the treatment. Thus extended doxycycline therapy did not affect C. pneumoniae antibodies or coronary heart disease risk factors. We conclude that doxycycline monotherapy may not be sufficient to eradicate chronic C. pneumoniae infection.

Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals.

BACKGROUND: Levosimendan is a new calcium sensitizer, acting calcium-dependently on cardiac troponin C. In the present study pharmacokinetic-pharmacodynamic interrelations of levosimendan were assessed. SUBJECTS AND METHODS: Ten healthy subjects (22-27 years) were given single doses of 2 mg of levosimendan in 4 different formulations: intravenous (i.v.), conventional tablet (CT), conventional capsule (CC), and slow-release tablet (SR) on different days. Systolic time intervals and impedance cardiography were recorded up to 4 hours post drug. Plasma concentrations of levosimendan and its metabolite OR-1855 were analyzed using HPLC. Hysteresis loops were constructed by connecting the effect-concentration points in time order. In addition, pharmacokinetic-pharmacodynamic modelling was performed with the i.v. data. RESULTS: The i.v. administration, giving a maximal levosimendan concentration of 180 ng x ml(-1), increased heart rate by 8 beats min(-1) and cardiac output by 18%. It shortened heart rate corrected electromechanical systole QS2i by 23 ms, indicating a fairly strong positive inotropic effect. The conventional oral formulations (giving maximal drug concentrations of about 70-80 ng x ml(-1)) increased heart rate by 4-5 beats min(-1) and cardiac output by 5-8%, while QS2i shortened by 9-13 ms. The SR formulation resulted in low drug concentrations and generally weaker effects than the other formulations. The bioavailability of CT and CC was 83 and 87%, while that of SR was only 31%. QS2i showed counter-clockwise hysteresis after all formulations (p < 0.01). The mean equilibration half-time (ln(2)/k(e0)) after i.v. administration was 9.6 min. Only after SR, OR-1855 was detected in appreciable amounts in plasma, the highest value being 2.2 ng x ml(-1) which occurred 24 hours after drug intake. CONCLUSION: In conclusion, the pharmacokinetic-dynamic behavior of the inotropy index QS2i indicates an equilibration delay of levosimendan, which most probably reflects the time the drug requires to distribute from plasma to its cardiac site of action. The deviant kinetic-dynamic profile of the oral slow-release formulation suggests a different absorption pattern of levosimendan from this formulation.

Management of common pediatric fractures.

Pediatric fractures are seen commonly in emergency departments. Pediatricians are usually the first physicians to assess injured children. Pediatricians should be comfortable in evaluating the fracture and interpreting radiographs prior to consulting an orthopedist. An understanding of the differences between pediatric and adult bone makes the assessment of children and their radiographs easier. Musculoskeletal injuries, fractures, and sprains are common, most of which require minimal care. Growth plate injuries, however, pose a risk for permanent deformity and must be managed with care.

Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers.

OBJECTIVE: To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise. BACKGROUND: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. DESIGN AND METHODS: This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. RESULTS: Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. CONCLUSION: The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG.

Assessment of cardiac performance: short- and medium-term variability of impedance cardiography at rest and during dynamic exercise.

Short- and medium-term variability of impedance cardiography at rest and during exercise at a heart rate of 155-160 beats/min were assessed in 12 healthy men aged 21-28 years. Two consecutive measurements within 1 min were performed 4 times at 2-hour intervals on 2 days 14 days apart. Ejection fraction was the most reproducible of all impedance cardiography parameters, the CV ranging from 3.3-5.9%. The short-term reproducibility of cardiac output and stroke volume at rest was good, the between-repeats coefficient of variation (CV) being 4-6%. The reproducibility weakened with longer time span (between-day CV being about 12%) and higher heart rates (exercise). However, even the between-day reproducibility at rest was as good as that of heart rate. Between-day CV during exercise were about 20%.

COMT inhibition by entacapone does not affect growth hormone or prolactin secretion in healthy volunteers.

We studied the effects of entacapone, a novel inhibitor of the enzyme catechol-O-methyltransferase (COMT), on spontaneous and levodopa (LD) modulated secretion of growth hormone (GH) and prolactin (PRL) in 12 healthy male volunteers. The study had a double-blind, cross-over design with two experimental settings. In the first setting the subjects received a single oral dose of 400 mg of entacapone or matching placebo in a randomized order. In the second setting, a single oral dose of 300 mg of LD and 75 mg of carbidopa was administered concomitantly with either 400 mg of entacapone or matching placebo in a randomized order. Entacapone had no effect on resting levels of GH, but PRL concentrations in plasma were slightly lower after entacapone than after placebo. As expected, LD/carbidopa increased the concentration of GH and decreased that of PRL. The effects of LD were not influenced by concomitant administration of entacapone. Compared with the administration of LD/carbidopa together with placebo, concomitant administration of entacapone increased the AUC of LD by 29% and reduced the AUC of 3-O-methyldopa (a metabolite of LD produced by COMT) by 69%. Entacapone appears not to enhance the effects of LD on hypothalamic-pituitary function, although the LD dose used may have been bigger than optimal for detection of a small modulatory influence.