Healthy Japanese Male Volunteers Research Articles

Elevated RANTES level is associated with metabolic syndrome and correlated with activated platelets associated markers in healthy younger men.

The objective of this study was to clarify the relationship of regulated on activation normal T cell expressed and secreted (RANTES) levels with metabolic syndrome (MS) and activated platelets-associated markers. We conducted a cross-sectional study of 210 healthy Japanese male volunteers (mean age 41 years old) who did not take any medications and were free of cardiovascular or cerebrovascular disease. The RANTES is correlated with age, diastolic blood pressure, and fast glucose by multivariate analysis using the cardiovascular risk factors (R (2) = .396, P < .001). The plasma RANTES level is significantly associated with MS after adjusting for age (P = .040). Once plasma interleukin 6, an activator of platelets, and plasma platelet-derived microparticles, a marker for activated platelets, are put into the equation, plasma RANTES level is significantly correlated with the activated platelet-associated markers (R (2) = .396, P < .001). These suggest the possible role of elevated RANTES in the forerunner of atherosclerosis in healthy younger men.

Evaluation of Assay Sensitivity and the Concentration-Effect Relationship of Moxifloxacin in a QT/QTc Study in Japan

To investigate the potential for a QT/QTc study in Japan, a randomized, single-blind, crossover study was conducted using moxifloxacin in 64 healthy Japanese male volunteers. A 12-lead Holter electrocardiogram was used to test a relatively small population at each of 4 incorporated clinical research units to confirm the assay sensitivity and efficiency. Moxifloxacin (400 mg) significantly prolonged QT intervals, as previously reported, with small variations in this study. In addition, the placebo-adjusted mean QTcF changes from predose baseline showed that the lower bounds of the 1-sided 95% confidence interval exceeded 5 milliseconds at all of the clinical research units. The data also indicated statistically significant concentration-QT relationships in 3 of the 4 research units by separate analysis. These findings and the small amount of variability in this study suggest the feasibility of conducting a high-quality QT/QTc study in Japan.

The Inhibition by Levocetirizine and Fexofenadine of the Histamine-induced Wheal and Flare Response in Healthy Caucasian and Japanese Volunteers

This randomized, double-blind, placebo-controlled crossover study compared inhibition by one 5 mg dose of levocetirizine with two 60 mg doses of fexofenadine separated by 12 h of histamine-induced wheal and flare responses in 9 Caucasian and 9 Japanese healthy male volunteers. Levocetirizine was more inhibitory than fexofenadine on wheal, flare and pruritus (p < 0.005). Variability, evaluated from the standard deviation of inhibition, ranged from 14% to 23.2% for levocetirizine and 65.4% to 112.4% for fexofenadine. Levocetirizine had a faster onset of action (30-90 min versus 2 h), shorter time to maximum effect (3-4 versus 3-6 h) and longer duration of action (at least 24 h versus ~12 h) than fexofenadine. The plasma levels of levocetirizine rose more quickly, reached higher levels, were more consistent and decreased slower than those of fexofenadine. There were no clinically significant ethnic differences in responsiveness to the drugs.

Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Objectives: To evaluate the influence of meals on the pharmacokinetics of omeprazole and rabeprazole and to investigate these PPIs with reference to CYP2C19 genotypes in healthy Japanese men. Methods: This was a randomized, open label, four-way crossover study. Twelve healthy Japanese male volunteers received a single oral dose of either 20 mg omeprazole or 10 mg rabeprazole, in the fasted state and after a standardized breakfast. Results: Between the administration of omeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC, Tmax, and half-life. Between the administration of rabeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC and half-life, whereas the Tmax of rabeprazole after breakfast was significantly delayed (2.8 ± 1.0 vs 5.3 ± 1.8 h, respectively; p = 0.006). PMs demonstrated the highest Cmax and AUC after drug intake under the fasting state and after breakfast, and homo EMs showed a significantly delayed Tmax. Conclusion: When a single dose of either PPI was administered, the pharmacokinetics of omeprazole was not affected by the meal, whereas the Tmax of rabeprazole after the meal was significantly delayed.

Bioavailability of intravenous fosphenytoin sodium in healthy Japanese volunteers.

To compare and evaluate the bioavailability for intravenous fosphenytoin sodium with that of intravenous phenytoin sodium in Japanese subjects. In study 1, healthy Japanese male volunteers received a 30-min infusion of 375 mg fosphenytoin sodium or an equimolar dose of 250 mg phenytoin by a double-blind, crossover method. In study 2, other healthy Japanese male volunteers received a 30-min or 10-min infusion of 563 mg fosphenytoin sodium, followed by a dose of 750 mg after 2 weeks in an unblinded manner. Comparing with 250 mg phenytoin sodium, 375 mg fosphenytoin sodium exhibited lower total plasma phenytoin C max, whereas the geometric mean ratio of the AUC of total and free phenyotoin for fosphenytoin sodium at a dose of 375 mg was very similar to phenytoin sodium at a equimolar dose of 250 mg (AUC0–t ratio: 0.98 and 1.02, respectively). Therefore, fosphenytoin is almost completely converted to phenytoin in subjects. Fosphenytoin sodium was rapidly converted to phenytoin at doses of 375, 563, and 750 mg. The maximum concentration (C max) of total plasma phenytoin increased in a dose-dependent manner. The area under the plasma concentration–time curve (AUC) increased slightly more than proportionally with the administered dose, and clearance (CL) decreased with increasing dose. Pain and other infusion-site reactions were reported by all 12 subjects with phenytoin sodium, whereas very few symptoms were observed with fosphenytoin sodium. In conclusion, fosphenytoin sodium is considered to be a useful substitute for phenytoin sodium with almost no associated injection-site reactions.

Evaluation of the bioequivalence of a fixed-dose combination tablet of pioglitazone–metformin versus commercial tablets in healthy Japanese male volunteers

SUMMARY In chronic asymptomatic diseases such as Type 2 diabetes mellitus (T2DM) poor adherence to therapy is a common problem. Simplification of treatment regimens using fixed-dose combination formulations has the potential to improve patient compliance. In this randomized, crossover, single-dose study we evaluated the bioequivalence of a new fixed-dose combination of pioglitazone–metformin (30/500 mg) and commercial tablets (pioglitazone 30 mg plus metformin 2 × 250 mg) in 84 healthy Japanese male volunteers in a fasted state. The plasma concentration–time curves for unchanged pioglitazone and unchanged metformin were almost identical for the two formulations. The 90% confidence intervals for the ratios of maximum observed concentration (Cmax) and area under the plasma concentration–time curve from time 0 to 72 h (AUC0–72) for unchanged pioglitazone, and for Cmax and AUC0–48 of unchanged metformin, were within the 0.80–1.25 range, which meets the criterion for test-to-reference bioequivalence between th...

A comparison of the central nervous system effects of alcohol at pseudo-steady state in Caucasian and expatriate Japanese healthy male volunteers

In general, Japanese and Caucasians differ in their response to alcohol. To investigate these differences the alcohol clamping method can be used. This strictly controlled infusion regimen provides a reliable tool to study contrasts in central nervous system (CNS) effects and/or alcohol disposition. In this study, twelve Japanese and twelve Caucasian healthy volunteers received two concentrations of intravenous alcohol or placebo using the alcohol clamp. Infusion rates during the steady state phase were used to compare alcohol clearance between the subgroups. Central nervous system (CNS) effects were frequently measured throughout the clamp. On average, significantly lower amounts of alcohol were needed to maintain similar stable concentrations in the Japanese group. However, these differences disappeared when values were corrected for lean body mass. The most pronounced pharmacodynamic differences between the groups were observed on body sway and on the visual analogue scale for subjective alcohol effects, mainly at the highest dose level. The alcohol clamp seems a useful method to compare differences in alcohol metabolism between groups. Some CNS effects of alcohol differed clearly between Japanese and Caucasians, but others did not, even though alcohol levels were stable and similar between the two groups.

Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution

This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6% hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500ml 6% HES 130/0.4 (Voluven 6%; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30min. Plasma concentration of 6% HES 130/0.4 was highest at end of infusion (5.53±0.55mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14±0.16l/h, 1.12±0.26h, and 9.98±2.38h, respectively, and the volume of distribution was 4.76±0.64l. Mean area under the concentration-time curve was 26.7±3.75mg/mlh. The total amount of HES excreted into urine was 59.4% of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5±0.4g/dl at baseline to 13.8±0.4g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. Single administration of a 500ml solution of 6% HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24h after drug administration, accounting for 96% of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups.

Pharmacokinetics, Pharmacodynamics and Safety of Tolvaptan, A Novel, Oral, Selective Nonpeptide AVP V2-receptor Antagonist: Results of Single- and Multiple-Dose Studies in Healthy Japanese Male Volunteers

Single- and multiple-dose studies were conducted to assess the pharmacokinetics, pharmacodynamics and safety of tolvaptan in healthy Japanese subjects. All studies were single-center, randomized, placebo-controlled, single-blind or double-blind. In an ascending single-dose study, subjects were given a single oral dose of 15-120 mg tolvaptan or placebo. In multiple-dose studies, subjects were given 30, 60, 90 or 120 mg tolvaptan or placebo once daily for 7 days. After a single dose of 15-120 mg tolvaptan, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from zero to time t (AUC(t)) increased dose-dependently, and increases in AUC(t) were dose-proportional. Increases in 24-hour cumulative urine volume were dose- and AUC(24hr)-dependent. Urine excretion rates reached a maximum within 2-4 h after dosing. The maximal urine excretion rates increased dose-dependently, and appeared to reach a plateau at doses ≥ 60 mg. A decrease in urine osmolality and an increase in free water clearance indicated an aquaretic effect of tolvaptan. Serum sodium concentrations were increased by tolvaptan and were higher than that with placebo, even 24 h after dosing, while serum potassium concentrations were unchanged. No tolvaptan accumulation was found after multiple dosing for 7 days. Although 24-hour cumulative urine volume following multiple dosing slightly decreased, a sustained diuretic effect was observed throughout the dosing period. The most common adverse event was mild thirst. Single and multiple oral doses of tolvaptan exhibited dose-dependent aquaretic effects. Tolvaptan was well tolerated at all doses tested.

Absence of Adverse Effects of Oseltamivir on Sleep: A Double-Blind, Randomized Study in Healthy Volunteers in Japan

Influenza-associated neuropsychiatric symptoms include parasomnias such as sleepwalking which is a common sleep disturbance in childhood. Oseltamivir is a widely used antiviral drug for influenza. Recently, sleepwalking-like events have been reported in patients with influenza receiving oseltamivir. We investigated whether oseltamivir itself has effects on sleep. In this crossover study, healthy Japanese male volunteers were randomized into two treatment groups, each of which comprised two double-blind 4-day treatment periods. In the first period, group A received 75 mg oseltamivir (evening dose) on day 3, followed by 75 mg b.i.d. on day 4, and placebo in the second period. Group B received the same treatments, but in reverse order. Polysomnographic assessments were performed on all four nights of each treatment period. Pharmacokinetics were assessed during a 2-day open-label phase beginning on day 12. Thirty-one volunteers aged 20-24 years were enrolled. No volunteer had electroencephalographic abnormalities, and no abnormal behaviour was observed. Sleep parameters measured over the whole night and during early- and late sleep periods (first and last thirds of the night) were very similar for oseltamivir and placebo, although the amount of stage 2 sleep in the middle sleep period was slightly greater with oseltamivir. Pharmacokinetics for oseltamivir phosphate in groups A and B were very similar, but for oseltamivir carboxylate, AUC and C(max) values were higher in group B, probably because this group received oseltamivir on the evening of day 11. Oseltamivir was well tolerated. Oseltamivir did not produce clinically relevant changes on nocturnal polysomnographic variables in young Japanese men.

Effects of Food on the Pharmacokinetics of Edoxaban, an Oral Direct Factor Xa Inhibitor, in Healthy Volunteers

The primary objective of this study was to assess the effect of a standard high-fat meal on the single-dose (60 mg) pharmacokinetics (PK) of edoxaban in healthy Japanese and Caucasian male volunteers matched by body mass index. This was an open-label, randomized, 2-period crossover study. All 32 enrolled volunteers completed the study per protocol. Both serial blood and urine samples were collected, and edoxaban concentrations were analyzed by a validated liquid chromatography/tandem mass spectrometry method. Activated partial thromboplastin and prothrombin times were obtained as measures of pharmacodynamic effect. The point estimates of the geometric mean ratios (fed/fasted) for AUC(0-t), AUC(0-∞), and C(max) demonstrated modest increases ranging from 6% to 22% across PK parameters for both race cohorts. The disposition was similar in both Japanese and Caucasian matched volunteers with slightly higher AUC values (ranging from 7%-9%) in Caucasians. There were no serious adverse events during the study. All drug-related adverse events were mild and self-limited, and none were bleeding related. Both Japanese and Caucasian volunteers demonstrated a modest but clinically insignificant food effect. It was concluded that edoxaban can be administered without regard to food.

Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers.

The pharmacokinetic profile of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a new nootropic agent, was studied in healthy Japanese male volunteers. Nefiracetam was administered orally at doses of 10-200 mg in the single-dose studies, and at doses of 200 mg three times a day for seven days in the multiple-dose study. An HPLC method was used to determine the concentrations of nefiracetam in serum, urine and faecal samples. Linear kinetic behaviour was obtained after single oral administration. Serum concentrations of nefiracetam reached maximum values (Cmax) within 2 h for all dosage groups, and declined monophasically after Cmax with half-lives of 3-5 h. The area under the concentration-time curve (AUC infinity) and Cmax were linearly related to the dose. The apparent clearance (CL) values were 94.4-140.3 mL min-1. Urinary excretion of nefiracetam was independent of the administered dose, and less than 10% of the dose was recovered in urine as the unchanged form within 24 h after administration. Renal clearance (CLR) did not change significantly as dose increased from 10 to 1200 mg. Faecal excretion of nefiracetam was less than 0.1% of the dose up to 24 h after a 300 mg oral dose. Food intake delayed the absorption of nefiracetam but did not significantly modify its pharmacokinetics. No clinically significant accumulation of nefiracetam in the body was observed during and after multiple doses.

Comparison of sagging at the cheek and lower eyelid between male and female faces

Facial sagging is a well-known morphological feature associated with aging and reduced dermal elasticity. Its morphological characteristics and mechanism have been studied in females, but it is unclear whether or not there is a gender difference. The aim of this study was to clarify the morphological characteristics of sagging and the mechanism of sagging formation in male faces as compared with female faces, focusing on changes in dermal elasticity. Faces of 98 healthy Japanese male volunteers, in their 20s-60s, were photographed at an angle of 45°. Upper and lower cheek sagging severity was evaluated by using photograph-based grading criteria. In addition, new photograph-based grading criteria of sagging severity at the lower eyelid were established and used. Dermal elasticity was measured using a non-invasive, in vivo suction skin elasticity meter, Cutometer(®). Furthermore, photographs of 108 healthy Japanese female volunteers in their 20s-60s were used to compare the difference in the morphological characteristics of sagging between males and females. Male facial sagging was prominent at the lower eyelid, upper cheek and lower cheek. Sagging severity in the upper and lower cheek was almost the same between males and females at all ages, whereas sagging at the lower eyelid in males was significantly more severe than that in females after middle age. Although dermal extensibility (U(f)) was not related to age, total deformation recovery (U(a)), -(amount of deformation) -(U(f)-U(a)), overall elasticity of the skin including creep and creep recovery (U(a)/U(f)), net elasticity excluding viscoelastic creep (U(r)/U(e)), ratio of elastic recovery to total deformation (U(r)/U(f)) and -(ratio of viscoelastic to elastic distention) -(U(v)/U(e)) were all significantly negatively related to age in both men and women. Furthermore, as in female faces, male facial sagging was significantly negatively related to dermal elasticity parameters, such as -(U(f)-U(a)), U(a)/U(f), U(r)/U(e) and U(r)/U(f). These results indicate that the morphology and areas of sagging in male faces are similar to those in females in the cheek, but sagging at the lower eyelid is more severe in males after middle age. Furthermore, the dermal elasticity of male facial skin decreased with age similar to that of females, and may therefore be associated with the sagging formation in male faces.

Multiple doses of pegylated long-acting growth hormone are well tolerated in healthy male volunteers and possess a potential once-weekly treatment profile

Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long-acting rhGH preparation (NNC126-0083). Randomized, double-blinded, placebo-controlled, multiple-dose, dose-escalating (0·02, 0·04, 0·08 and 0·16 mg protein/kg), sequential dose group trial. Forty adult Japanese healthy male volunteers (aged 20-45; body mass index: 18·0-27·0 kg/m(2)). Five groups (n = 8) were randomized to receive multiple doses of NNC126-0083 (n = 6) or placebo (n = 2). Primary outcome was safety, and tolerability of multiple doses of NNC126-0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3)] were taken after multiple ascending doses. NNC126-0083 was well tolerated and not associated with any local injection-site reactions or lipoatrophy. Following administration, NNC126-0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady-state PK was achieved after the third dosing. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0·16 mg protein/kg). A strong dose-dependent pharmacodynamic response in circulating concentrations of both IGF-I and IGFBP-3 compared with placebo (P < 0·0001) was observed during the administration of all doses. Multiple administration of NNC126-0083 in healthy male volunteers indicates that NNC126-0083 has the potential for an efficacious, well-tolerated, once-weekly rhGH compound in the treatment of GH deficiency.

Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20-32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration (C (max)) and area under the concentration-time curve (AUC(0-96)) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C (max) was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC(0-96) was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (>14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25-5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.

Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male japanese subjects

Background: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. Objective: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. Methods: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. Results: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C max) increased in a manner that was less than dose proportional. T max ranged from 1.50 to 6.00 hours, and elimination t ½ ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V d (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t ½ ranged from ∼10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (∼1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was ≥80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. Conclusions: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.

Pharmacokinetics and safety of single and multiple doses of Asacol tablets in Japanese healthy volunteers

The pharmacokinetics and safety of Asacol (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn's disease, were studied in Japanese healthy male volunteers. Drug plasma concentrations and urinary and fecal excretions after a single dose (400-4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated. All adverse events were "not serious." The peak plasma concentration (C max) was reached at 12.3-18.0 hours after a single dose, and the C max and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The C max and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects. Asacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.

An open-label, single-dose, parallel-group, dose-increasing study comparing the pharmacokinetics and tolerability of pilsicainide hydrochloride in healthy Korean and Japanese male subjects

Background: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias. Objective: The objective of this study was to compare the pharmacokinetics and tolerability of pilsicainide in healthy Korean and Japanese male volunteers to satisfy regulatory requirements for marketing pilsicainide in the Republic of Korea. Methods: This was an open-label, single-dose, parallel-group, dose-increasing study. It was simultaneously conducted in healthy Korean and Japanese volunteers from September 2005 through May 2006; pilsicainide was approved for use in the Republic of Korea in 2007. Subjects for the 100-mg group were enrolled after the performance of tolerability evaluations in the 50-mg dose group. Serial blood and urine samples were collected up to 24 hours after dosing, and drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Tolerability was evaluated by monitoring adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiograms (ECGs). Results: Sixteen healthy Korean male subjects (mean [SD] age, 24.5 [4.2] years; weight, 71.8 [5.5] kg; height, 176.6 [6.3] cm) and 16 healthy male Japanese subjects (age, 24.7 [4.9] years; weight, 60.2 [4.4] kg; height, 171.9 [6.4] cm) were enrolled in the study. Values for AUC and C max of pilsicainide increased proportionally with dose escalation in all subjects. Pilsicainide reached C max 0.5 to 1.5 hours after dosing in both the Korean and Japanese subjects. The mean (SD) dose-normalized values for C max for the Korean and Japanese subjects were 9.4 (1.9) and 9.2 (1.6) ng/mL/mg, respectively. The mean (SD) dose-normalized values for AUC 0-∞ were 56.0 (8.0) ng · h/mL/mg in the Korean subjects and 53.8 (8.1) ng · h/mL/mg in the Japanese subjects. None of these findings were statistically significant. A total of 9 AEs occurred in 7 of the 16 Korean subjects; they included dizziness, feeling of being hot, somnolence, and atrioventricular block. All of the AEs were mild in severity and were considered possibly related to pilsicainide. Two of the 16 Japanese subjects had a total of 4 AEs. All of the AEs occurred in the subjects treated with 50 mg. Of the 2 subjects with AEs, 1 subject had a decrease in blood pressure, a sense of discomfort, and PR-interval prolongation on ECG, while the other developed a premature ventricular contraction (PVC). The PR-interval prolongation and PVC were determined to be possibly related to pilsicainide, and these were mild in severity. The other AEs (ie, decreased blood pressure, sense of discomfort) were moderate in severity. Conclusions: The results of this study suggest that the pharmacokinetic profile of pilsicainide was not significantly different between these healthy Korean and Japanese male volunteers. A single dose (50 or 100 mg) of pilsicainide was well tolerated in both ethnic groups.

In vivo evaluation of the protective capacity of sunscreen by monitoring urocanic acid isomer in the stratum corneum using Raman spectroscopy

Urocanic acid (UCA) is a major ultraviolet (UV) ray-absorbing component in the epidermis, and it isomerizes from the trans to the cis form upon exposure to UV radiation. Continuous measurement of UCA isomers in the skin at the same area is not available using conventional methods. This study aimed to evaluate the protective capacity of sunscreen by non-invasively monitoring the trans-UCA (t-UCA) amount in the stratum corneum (SC) by confocal Raman spectroscopy. In vivo Raman spectra of the skin at the cheek or volar forearm were obtained from 27 healthy Japanese volunteers of different ages (age range, 22-53 years) throughout a whole year using confocal Raman spectroscopy. Eighteen healthy male Japanese volunteers (age range, 25-52 years) were enrolled for the evaluation of the protective capacity of sunscreen. The concentration depth profile of t-UCA relative to keratin was calculated from the Raman spectra in the 400-2200 cm(-1) region. Then, the integrated amount within the depth of 0-12 mum was calculated, which represented the total amount of t-UCA in the SC. The integrated amount of t-UCA in the cheek skin was significantly lower than that in the volar forearm skin throughout a year. The amount of it in the volar forearm skin was significantly the lowest in summer, but not in the cheek skin. The amount of t-UCA decreased immediately after UV exposure even below 1 minimal erythema dose, remained low for 1 week, and gradually increased up to the initial level about 2 weeks after UV exposure. The decrease in the t-UCA amount was hindered by the application of sunscreen on the skin surface. There were no statistical differences in response to UV exposure between the erythema-positive and erythema-negative groups. The monitoring of the amount of t-UCA in the SC by confocal Raman spectroscopy is a good method to assess the efficacy of sun protective substances.

Sagittal alignment of the lower extremity while standing in Japanese male

There is little information available regarding the sagittal mechanical axis of the lower extremity of normal subjects under weight-bearing conditions. The purpose of this study was to determine the sagittal alignment of the lower extremity under such conditions. Anteroposterior and lateral radiographs were taken of the 20 lower extremities of 10 healthy male Japanese volunteers (mean age, 27 years) while standing. The coronal mechanical axis passed through 33.9% medial to the proximal tibial articulating surface. The sagittal mechanical axis passed through 38.0% anterior to the distal femoral condyle and 27.9% anterior to the proximal tibial articulating surface, and also passed 5.2 mm anterior to the intercondylar notch. Our study therefore showed that the coronal and sagittal mechanical axes of the lower extremity do not always pass through the center of the knee. This has important implications for alignment in surgery of lower extremities such as total knee arthroplasty and osteotomy.