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Healthy Male Subjects (healthy + male_subject)
Selected AbstractsSimultaneous determination of the flavonoid aglycones diosmetin and hesperetin in human plasma and urine by a validated GC/MS method: in vivo metabolic reduction of diosmetin to hesperetinBIOMEDICAL CHROMATOGRAPHY, Issue 2 2009Marios Spanakis Abstract Diosmetin and hesperetin are the aglycones of the flavonoid glycosides diosmin and hesperidin which occur naturally in citrus fruit. A GC/MS method for the simultaneous determination of diosmetin and hesperetin in human plasma and urine has been developed and validated. The method was linear in the 2,300 ng/mL concentration range for both diosmetin and hesperetin in plasma and urine (r >0.999). The precision of the method was better than 6.01 and 7.16% for diosmetin and hesperetin, respectively, and the accuracy was 96.76,100.40% and 95.00,105.50% for diosmetin and hesperetin, respectively. The lower limit of quantitation was found to be 2 ng/mL for both analytes in plasma and urine. Recovery of diosmetin, hesperetin and internal standard naringenin was greater than 82.5%. The method has been applied for the determination of diosmetin and hesperetin in plasma and urine samples obtained from a healthy male subject following a single oral 1000 mg dose of the flavonoid glycoside diosmin. The presence of hesperetin in plasma and urine samples indicates the metabolic reduction of diosmetin to its flavanone analogue hesperetin through reduction of the 2,3 double bond of the C-ring by the enzymes of bacteria of the intestinal microflora. Copyright © 2008 John Wiley & Sons, Ltd. [source] Endothelin attenuates endothelium-dependent platelet inhibition in manACTA PHYSIOLOGICA, Issue 4 2010R. E. Malmström Abstract Aim:, The vascular endothelium produces several substances, including nitric oxide (NO) and endothelin-1 (ET-1), which participate in the regulation of vascular tone in humans. Both these substances may exert other actions of importance for cardiovascular disease, e.g. effects on vascular smooth muscle cell proliferation and inflammation, and NO inhibits platelet function. Experiments were designed to investigate the effect of ET-1 on endothelium-dependent vasodilatation and attenuation of platelet activation. Methods:, In 25 healthy male subjects (25 ± 1 years), forearm blood flow was measured by venous occlusion plethysmography, and platelet activity was assessed by whole blood flow cytometry (platelet fibrinogen binding and P-selectin expression) in unstimulated and adenosine diphosphate (ADP)-stimulated samples during administration of ET-1, the endothelium-dependent vasodilator acetylcholine and the NO synthase inhibitor l -NMMA. Results:, Acetylcholine increased forearm blood flow and significantly inhibited platelet activation in both unstimulated and ADP-stimulated samples. In samples stimulated with 0.3 ,m ADP, fibrinogen binding decreased from 41 ± 4% to 31 ± 3% (P < 0.01, n = 11) after acetylcholine administration. The vasodilator response to acetylcholine was significantly impaired during infusions of ET-1 and l -NMMA. ET-1 did not affect platelet activity per se, whereas l -NMMA increased platelet P-selectin expression. Both ET-1 and l -NMMA attenuated the acetylcholine-induced inhibition of platelet activity. Conclusions:, Our study indicates that, further to inhibiting endothelium-dependent vasodilatation, ET-1 may also attenuate endothelium-dependent inhibition of platelet activation induced by acetylcholine. An enhanced ET-1 activity, as suggested in endothelial dysfunction, may affect endothelium-dependent platelet modulation and thereby have pathophysiological implications. [source] Reliability of orthostatic responses in healthy men aged between 65 and 75 yearsEXPERIMENTAL PHYSIOLOGY, Issue 4 2005Tim J. Gabbett The purpose of this study was to investigate the short-, medium- and long-term reproducibility of cardiovascular responses during 90° head-up tilt (HUT) in healthy older men. Twenty-eight healthy male subjects aged 69 (95% confidence intervals, 68,70) years participated in the study. Eight subjects underwent duplicate 90° HUT tests on consecutive days, while 20 subjects underwent four 90° HUT tests performed at baseline, and after 1 week, 1 month and 1 year. Following a 20-min supine resting period, each subject was rapidly tilted to the upright vertical position (90° HUT) and remained in that position for 15 min. Beat-by-beat recordings of mean (MAP), systolic (SBP) and diastolic (DBP) pressures were made via Finapres, while heart rate (HR) was monitored continuously from an electrocardiogram. No significant test,retest differences (P > 0.05) were observed for the changes in HR, MAP, SBP or DBP during 90° HUT. These measurements demonstrated high reproducibility (intraclass correlation coefficient, r= 0.91,0.99, P < 0.05). The supine resting and tilted HR, MAP, SBP and DBP over the 1-week, 1-month and 1-year period were not significantly different (P > 0.05) from baseline, and demonstrated high reproducibility (intraclass correlation coefficient, r= 0.82,0.98, P < 0.05). The results of this study demonstrate that in healthy older men, cardiovascular responses during orthostasis are highly reproducible, and this reproducibility is maintained over a 12-month period. These findings demonstrate that the 90° HUT test offers a reproducible method of monitoring longitudinal orthostatic responses in healthy older men. [source] A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulationHAEMOPHILIA, Issue 5 2007B. V. BYSTED Summary., Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven®) and a new rFVIIa formulation (VII25) stable at up to 25°C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 ,g kg,1, in a randomized order 2,3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89,0.96), within the predefined bioequivalence range (0.80,1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25°C. VII25's ,user-friendly' formulation removes the inconvenience of storing/transporting at 2,8°C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained. [source] Clinical trial: Inhibitory effect of revaprazan on gastric acid secretion in healthy male subjectsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2010Hyung-Keun Kim Abstract Background and Aim:, Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. Methods:, In a double-blind, three-way cross-over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24-h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics. Results:, Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose-dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (P < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups. Conclusions:, Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid-related disease. [source] Impact of formulation excipients on human intestinal transitJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2006Julia D. R. Schulze The accelerating effect of polyethylene glycol 400 on small intestinal transit has been previously reported. The aim of this study was to investigate the influence of other solubility-enhancing excipient, propylene glycol, D-,-tocopheryl-polyethylene glycol-1000 succinate (VitE-TPGS) and Capmul MCM, on human intestinal transit. A 5-g dose of each excipient was administered to seven healthy male subjects. Propylene glycol and VitE-TPGS were administered dissolved in 150 mL water. Capmul MCM was administered in the form of four 000 hard gelatin capsules to mask its taste and then given with 150 mL water. On a separate occasion, 150 mL water was administered as the control. Each formulation was radiolabelled with technetium-99 m to follow its transit using a gamma camera. The mean small intestinal transit times were 234, 207, 241 and 209 min for the control, propylene glycol, VitE-TPGS and Capmul MCM treatments, respectively. Although there were differences in the small intestinal transit times for the excipients investigated compared with the control, none of the results were statistically significant. Unlike polyethylene glycol 400 at the same dose of 5g, the excipients tested (propylene glycol, VitE-TPGS and Capmul MCM) had little or no impact on small intestinal transit. [source] The influence of lithium on the antidiuretic effect of desmopressinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2002Torbjörn Callréus ABSTRACT The objective of this study was to investigate the graded influence from lithium on the antidiuretic effects of desmopressin. Eight healthy male subjects participated in this open, randomised cross-over study with two periods comprising 6 days each. For each subject, one of the study days (6th day) was preceded by a period of lithium treatment. On the study days the subjects were orally water loaded to achieve a state of overhydration with a high urine flow rate. When a steady-state diuresis was achieved after approximately 2 h, 0.396 ,g of desmopressin was administered intravenously as a bolus injection. An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fitted to the urine osmolarity data. The effects of the independent variables, Uflow (baseline) (baseline urine flow rate), R0 (baseline osmolarity) and serum lithium concentration, on IC50 (concentration producing 50% of the maximum inhibition) could be expressed by multiple linear regression. In conclusion, we found that an indirect-response model can be a useful tool in investigating and describing the pharmacodynamic interaction between drugs, in this particular case, between lithium and desmopressin. [source] Pulsed radio-frequency electromagnetic fields: dose-dependent effects on sleep, the sleep EEG and cognitive performanceJOURNAL OF SLEEP RESEARCH, Issue 3 2007SABINE J. REGEL Summary To establish a dose,response relationship between the strength of electromagnetic fields (EMF) and previously reported effects on the brain, we investigated the influence of EMF exposure by varying the signal intensity in three experimental sessions. The head of 15 healthy male subjects was unilaterally exposed for 30 min prior to sleep to a pulse-modulated EMF (GSM handset like signal) with a 10 g-averaged peak spatial specific absorption rate of (1) 0.2 W kg,1, (2) 5 W kg,1, or (3) sham exposed in a double-blind, crossover design. During exposure, subjects performed two series of three computerized cognitive tasks, each presented in a fixed order [simple reaction time task, two-choice reaction time task (CRT), 1-, 2-, 3-back task]. Immediately after exposure, night-time sleep was polysomnographically recorded for 8 h. Sleep architecture was not affected by EMF exposure. Analysis of the sleep electroencephalogram (EEG) revealed a dose-dependent increase of power in the spindle frequency range in non-REM sleep. Reaction speed decelerated with increasing field intensity in the 1-back task, while accuracy in the CRT and N-back task were not affected in a dose-dependent manner. In summary, this study reveals first indications of a dose,response relationship between EMF field intensity and its effects on brain physiology as demonstrated by changes in the sleep EEG and in cognitive performance. [source] The pharmacodynamics and pharmacokinetics of S-tenatoprazole-Na 30 mg, 60 mg and 90 mg vs. esomeprazole 40 mg in healthy male subjectsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010R. H. HUNT Aliment Pharmacol Ther,31, 648,657 Summary Background, Racemic tenatoprazole 40 mg/day provides more prolonged acid suppression than esomeprazole 40 mg/day. Aim, To compare pharmacodynamic and pharmacokinetic profiles of tenatoprazole and esomeprazole. Methods, A single-centre, double-blind, double-dummy, randomized, 4-way, cross-over study was conducted in 32 healthy male subjects. S-tenatoprazole-Na 30, 60 or 90 mg, or esomeprazole 40 mg was administered once daily for 5 days with 10-day washout intervals. The 24-h intragastric pH was recorded at baseline and on day 5 of each period. Results, On day 5, median pH (5.34 ± 0.45 and 5.19 ± 0.52 vs. 4.76 ± 0.82, respectively, P < 0.002) and percentage time with pH > 4 (80 ± 11 and 77 ± 12, vs. 63 ± 11 respectively, P < 0.0001) for 24-h were higher with S-tenatoprazole-Na 90 mg and 60 mg than esomeprazole. In nocturnal periods, S-tenatoprazole-Na 90 mg, 60 mg and 30 mg were superior to esomeprazole with regard to median pH (5.14 ± 0.64, 4.94 ± 0.65, 4.65 ± 0.86 and 3.69 ± 1.18 respectively, P < 0.0001) and percentage time with pH > 4 (77 ± 12, 73 ± 17, 64 ± 17 and 46 ± 17 respectively, P < 0.0001). Proportion of subjects with nocturnal acid breakthrough with S-tenatoprazole-Na 90 mg, 60 mg and 30 mg was significantly less than with esomeprazole (54.8, 43.3, 56.7 and 90.3 respectively, P < 0.04). The proportion of subjects with >16 hrs with pH >4 was significantly higher with S-tenatoprazole-Na 90 mg and 60 mg than with esomeprazole (87.1%, 83.3% and 41.9% respectively, P < 0.02). Conclusions, S-tenatoprazole-Na produced significantly greater and more prolonged dose-dependent 24-h and nocturnal acid suppression than esomeprazole. S-tenatoprazole-Na may provide greater clinical efficacy compared with current PPIs for patients with ineffective once-daily therapy. [source] A cellular level approach to predicting resting energy expenditure: Evaluation of applicability in adolescents,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 4 2010ZiMian Wang We previously derived a cellular level approach for a whole-body resting energy expenditure (REE) prediction model by using organ and tissue mass measured by magnetic resonance imaging (MRI) combined with their individual cellularity and assumed stable-specific resting metabolic rates. Although this approach predicts REE well in both young and elderly adults, there were no studies in adolescents that specifically evaluated REE in relation to organ,tissue mass. It is unclear whether the approach can be applied to rapidly growing adolescents. The aim of the present study was to evaluate the applicability of the previous developed REE prediction model in adolescents, and to compare its applicability in young and elderly adults. Specifically, we tested the hypothesis that measured REE can be predicted from a combination of individual organ and tissue mass and their related cellularity. This was a 2-year longitudinal investigation. Twenty healthy male subjects with a mean age of 14.7 years had REE, organ and tissue mass, body cell mass, and fat-free mass (FFM) measured by indirect calorimetry, whole-body MRI, whole-body 40K counting and dual-energy X-ray absorptiometry, respectively. The predicted REE (REEp; mean ± SD, 1,487 ± 238 kcal/day) was correlated with the measured REE (REEm, 1,606 ± 237 kcal/day, r = 0.76, P < 0.001). The mean difference (118 ± 165 kcal/day) between REEm and REEp was significant (P = 0.0047), accounting for 7.3% of REEm for the entire group. The present study, the first of its type in adolescents, does not support the applicability of the organ,tissue-based REE prediction model during rapid adolescent growth. A modified general REE prediction model is thus suggested which may account for the higher REE/FFM ratio observed in adolescents. Am. J. Hum. Biol. 2010. © 2010 Wiley-Liss, Inc. [source] Consecutive monitoring of sleep disturbance for four nights at the top of Mt Fuji (3776 m)PSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 2 2005KOH MIZUNO phd Abstract, The purpose of the present study was to conduct consecutive monitoring of sleep from the second to the fifth night at altitude. Three healthy male subjects climbed the top of Mt Fuji (3776 m) and stayed there for 6 days. Polysomnographic recordings were performed during this period and control recordings were made at sea level 1 month after the mountaineering. Disturbed sleep characterized by an increased number of arousals and/or long wake time was observed to persist through the fifth night in all subjects. These results suggest that sleep disturbance might persist during initial days at altitude despite cumulating sleep pressure due to poor night's sleep. [source] Treatment with leuprolide acetate decreases the threshold of the ventilatory response to carbon dioxide in healthy malesTHE JOURNAL OF PHYSIOLOGY, Issue 2 2004Jason H. Mateika This investigation was designed to determine if suppression of testosterone alters the ventilatory response to carbon dioxide in the presence of high and low levels of oxygen. Eleven healthy male subjects completed a series of rebreathing trials during wakefulness, before and after treatment with a long-acting gonadotropin-releasing hormone agonist. Five subjects also completed studies during non-rapid eye movement (NREM) sleep. During wakefulness, subjects initially hyperventilated to reduce the partial pressure of carbon dioxide (PET,CO2) below 25 Torr. Subjects then rebreathed from a bag containing a normocapnic (42 Torr), low (50 Torr) or high oxygen (140 Torr) gas mixture. During each trial PET,CO2 increased while oxygen was maintained at a constant level. The threshold of the ventilatory response to carbon dioxide was considered to be the point at which minute ventilation began to rise in a linear fashion as PET,CO2 increased. The slope of the ventilatory response above the threshold was used as a measure of sensitivity to carbon dioxide. During NREM sleep, hypocapnia was induced via nasal mechanical ventilation. Several trials were completed until the cessation of mechanical ventilation resulted in a central apnoea which demarcated the threshold of the ventilatory response to carbon dioxide. In response to treatment with leuprolide acetate, the threshold measured in wakefulness decreased during carbon dioxide rebreathing in the presence of low (41.05 ± 0.77 versus 39.40 ± 0.83 Torr; P= 0.01) and high (46.32 ± 0.56 versus 44.78 ± 0.83 Torr; P= 0.01) oxygen levels. An increase in sensitivity (4.82 ± 0.61 versus 7.17 ± 1.20 l min,1 Torr,1; P= 0.02) was also observed during rebreathing in the presence of high but not low oxygen levels. The increase in sensitivity was accompanied by an increase in carbon dioxide production. The findings observed during NREM sleep were similar to those observed during wakefulness, since the PET,CO2 that demarcated the threshold was decreased after leuprolide treatment (42.1 ± 0.6 versus 39.6 ± 0.6 Torr; P= 0.002). Additionally, the decrease in PET,CO2 required to induce an apnoea was greater after treatment with leuprolide (2.56 ± 0.25 versus 4.06 ± 0.29 Torr; P= 0.004). We conclude that suppression of testosterone decreases the threshold of the ventilatory response to carbon dioxide during both wakefulness and sleep. [source] Elevation of anions in exercise-induced acidosis: a study by ion-exchange chromatography/mass spectrometryBIOMEDICAL CHROMATOGRAPHY, Issue 3 2008William McKinnon Abstract Acidosis is a major factor that determines the upper limit of exercise endurance. We have previously shown that anions usually associated with intermediary metabolism are elevated in critically ill patients with metabolic acidosis and contribute significantly to acidosis generation. This study was to determine whether volunteers with normal metabolism would exhibit similar elevations in anions associated with intermediate metabolism when exposed to a short-term physiological stress leading to a brief lactic acidosis. Physiological stress was induced on five healthy male subjects by means of a ramped exercise protocol. Blood was obtained immediately prior to and post-exercise, plasma ultrafiltrate was prepared and analysed immediately both by enzyme assay and liquid chromatography coupled to electrospray,mass spectrometry (LC/ESI-MS). Metabolic acidosis concomitant with a significant increase in blood lactate occurred in each subject, but in addition, anions normally associated with intermediate metabolism were significantly elevated after exercise. The contribution of these anions to generating an acidosis, and thus potentially limiting the extent of exercise, has never been acknowledged. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002Michael Lamson Abstract The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration,time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (±) values for the Cmax of lovastatin were 1.04±0.43, 2.03±0.65 and 4.03±3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC0,48 h of lovastatin were 14.6±7.8, 34.1 ±13.7, and 53.9±35.6 ng h/ml. The same tendency was also found for Cmax and AUC0,48 h values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the Cmax and AUC0,48 h values of lovastatin as well as lovastatin acid appeared to increase linearly. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of smoking on single dose pharmacokinetics of phenobarbitalBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2001A. Mirfazaelian Abstract In order to determine interaction of smoking with single dose pharmacokinetics of phenobarbital, a 60 mg tablet of the drug was given to 12 healthy male subjects in two groups (6 smokers and 6 non-smokers) in a double blind study. An HPLC method using UV detection was developed to assess phenobarbital in plasma of the subjects. Pharmacokinetic parameters were calculated and compared in the two groups. Pharmacokinetic parameters of the two groups were not significantly different in the two groups (p<0.05). The results show no considerable effect of cigarette smoking on phenobarbital pharmacokinetics, which is in agreement with enzyme studies performed previously. Copyright © 2001 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Kyoung Soo Lim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. , However, as yet few ,validated' or ,qualified' biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS , This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. , LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. AIMS LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects. METHODS A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15-0444 concentration,time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6,20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6,21.9 and 0.40,0.48 l h,1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen. [source] Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3ABRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Sandrine Turpault WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug,drug interactions in vivo. , This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions. WHAT THIS STUDY ADDS , This study describes a new cocktail containing five probe drugs that has never been published. , This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails. AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone. METHODS This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg,1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC. RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25. CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug,drug interactions in vivo. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim Stangier Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source] Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007Yifan Zhang What is already known about this subject ,,Gliclazide has been considered metabolized by CYP2C9. ,,Its modified release formulation, gliclazide MR, shows low pharmacokinetic variability in Whites but high variability in Chinese. What this study adds ,,The results of this study show that the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism. ,,CYP2C19 genetic polymorphism might be responsible for the high pharmacokinetic variability of gliclazide MR in Chinese. Aims To investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release (MR) in healthy Chinese subjects. Methods In a single-dose pharmacokinetic study, 24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose. In a multiple-dose pharmacokinetic study, 17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose. The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method. CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Results In the single-dose study, no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1, *1/*3 and *1/*13 subjects. In contrast, the AUC0,, of gliclazide was significantly increased by 3.4-fold [95% confidence interval (CI) 2.5, 4.7; P < 0.01] in CYP2C19 poor metabolizer (PM) subjects compared with CYP2C19*1 homozygotes. The half-life (t1/2) was prolonged from 15.1 to 44.5 h (P < 0.01). Similar differences were found in the multiple-dose study. The parameters of gliclazide AUCss, AUC0,, and Cmax were 3.4-fold (95% CI 2.9, 4.0), 4.5-fold (95% CI 3.8, 5.4) and 2.9-fold (95% CI 2.4, 3.4) increased (P < 0.01) in CYP2C19 PM subjects, respectively, compared with CYP2C19*1 homozygotes, and t1/2 was increased from 13.5 to 24.6 h (P < 0.01). Conclusions The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism. [source] Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionalityBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2002Donald J. Nichols Aims, To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods, Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results, The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36,47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19,38). Systemic exposure, as assessed by the mean area under the plasma concentration,time curve (AUC), was reduced by 11% (90% CI: 6,16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25,200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions, Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25,200 mg, systemic exposure increased in a slightly greater than dose-proportional manner. [source] GANGLION BLOCKADE DOES NOT PREVENT CORTISOL-INDUCED HYPERTENSION IN MANCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2005Paula M Williamson SUMMARY 1.,The aim of the present study was to assess the effect of ganglion blockade on blood pressure in cortisol treated human subjects. 2.,Four healthy male subjects were treated with cortisol 80 mg/day for a 5-day period. Ganglion blockade was achieved by intravenous trimethaphan. 3.,Ganglion blockade did not significantly alter blood pressure in the pretreatment phase or on the last day of cortisol treatment. 4.,Taken together with our previous observations that sympathetic activity is unaltered or reduced by cortisol, these results suggest that cortisol induced hypertension in humans is not a result of overactivity of the autonomic nervous system. [source] Concentration Of Egg White Lysozyme In The Serum Of Healthy Subjects After Oral AdministrationCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002Seiichi Hashida SUMMARY 1. While the egg white lysozyme preparation ER0068 (Neuzym®; Eisai, Tokyo, Japan) is widely used clinically, no studies have been performed on its pharmacokinetic properties at clinically relevant doses. In the present study, we used a highly sensitive two-site enzyme immunoassay in order to determine the pharmacokinetic properties of egg white lysozyme after oral administration of two doses within the clinical range, paying particular attention to the effects of food intake. 2. A total of 22 healthy male subjects aged 20,45 years participated in the study. All subjects had been screened for egg white allergy and non-specific lysozyme inhibitors in their serum. Subjects who received 90 mg ER0068 after an overnight fast reached a maximum serum concentration of 1700 pg/mL within 1 h, compared with non-detectable levels in untreated controls. In a second experiment, subjects received 30 and 90 mg ER0068 after an overnight fast and 90 mg in the non-fasted state and exhibited maximum serum levels of 37, 360 and 49 pg/mL, respectively. Egg white lysozyme concentrations in serum returned to undetectable levels after a maximum of 48 h. 3. We conclude that clinically relevant concentrations of egg white lysozyme are absorbed in significant amounts, despite its high molecular weight. However, food intake considerably reduces the amount of enzyme absorbed. [source] Cerebral oxygenation monitor during head-up and -down tilt using near-infrared spatially resolved spectroscopy,CLINICAL PHYSIOLOGY AND FUNCTIONAL IMAGING, Issue 4 2003Koichi Kurihara Summary Reflectance near-infrared spectroscopy (NIRS) has become a suitable and easily manageable method to monitor cerebral oxygenation changes in presyncopal and syncopal symptoms caused by postural changing or standing. A new clinical tissue oxygenation monitor has been recently developed which measures absolute tissue haemoglobin saturation (Tissue Oxygenation Index, TOI) utilizing spatially resolved spectroscopy (SRS). The present study examined the effects of postural changes on cerebral oxygenation as reflected in SRS-NIRS findings. Cerebral oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), and the TOI were recorded from both sides of the forehead in five healthy male subjects (age range, 28,40 years) during 90° head-up tilt (HUT) and ,6° head-down tilt (HDT). Three series of measurements were carried out on separate days. O2Hb was decreased during HUT. TOI was significantly lower in HUT than in the supine position (SUP). There was no significant change in TOI during HDT. A significant session effect was observed in the left forehead TOI during SUP, but not in the right. SRS-NIRS measurements confirmed sub-clinical alterations of cortical oxygenation during HUT. NIRS data from the left side of the forehead, which may vary with cognitive or emotional activation, were more variable than those from the right side. [source] | |||||||||||||||||||||||||