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Pyoderma gangrenosum is an uncommon ulcerative cutaneous lesion manifesting as rapidly progressing single or multiple skin ulcers. Permanent stoma in inflammatory bowel disease patients remains an independent risk of pyoderma gangrenosum. In the current report, we describe a case of pyoderma gangrenosum in a post-colostomy ulcerative colitis patient with chronic hepatitis B. Pyoderma gangrenosum began seemingly as peristomal dermatitis that rapidly developed into painful ulcerations with subsequent appearance of sterile pustules and ulcerations in the left lower leg. The patient significantly improved after active management with prednisolone, antiviral therapy with entecavir, and wound dressings. Our case suggests that physicians and surgeons should have a high index of suspicion of pyoderma gangrenosum in post-colostomy ulcerative colitis patients who develop peristomal dermatitis.

Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Objective To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Methods Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. Results In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Conclusions Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

BACKGROUND There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS Patients with obesity (BMI, 35-50 kg/m2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 - 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY3-36 , and GIP), insulin and glucagon. RESULTS Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P

PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China’s registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2–4, the incidence of febrile neutropenia, and the safety. A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3–4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan–Meier analysis (n = 49, P = 0.153). PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

OBJECTIVE The kidney plays a key role in both the metabolism and excretion of vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of vildagliptin. METHODS A total of 96 subjects were enrolled, and each subject received vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. RESULTS Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the Cmax of vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. CONCLUSIONS These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.

Objective To assess the effects of meal timing on the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin in Japanese patients with Type 2 diabetes. Methods In this open-label, single-center crossover study, 12 Japanese patients with Type 2 diabetes were randomized to twice-daily vildagliptin 50 mg, administered 30 min before or immediately before breakfast and dinner for 7 days. After a 7-day washout period, patients received the other regimen. Blood samples were collected for the determination of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1) and glucose. Results Vildagliptin absorption appeared slower when administered 30 min before rather than immediately before meals (tmax absolute range: 1.00 - 2.00 h vs. 0.33 - 1.58 h). Vildagliptin Cmax and AUC0-8 h were essentially the same irrespective of meal timing (geometric mean ratio: Cmax 1.08 (90% CI; 0.92 - 1.26); AUC0-8 h 0.97 (90% CI; 0.91 - 1.05)). Meal timing did not affect pharmacodynamics; complete DPP-4 inhibition (> 90%) was sustained for 8 h post-dose, and plasma active glucagon-like peptide-1 levels increased 2 - 3-fold from baseline. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPPG) reductions from baseline did not differ significantly with meal timing (30 min before vs. immediately before: FPG, -8.9 vs. -5.8 mg/dl; adjusted AUE0-4 h, -67.0 vs. -51.0 mg×h/dl). Vildagliptin was well tolerated. Conclusions Dosing 30 min or immediately before meals did not affect vildagliptin pharmacokinetics or pharmacodynamics in Japanese patients with Type 2 diabetes.

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

Context: Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extra-pancreatic mechanisms. Objective: We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism. Design: Randomized, double blind, crossover study. Setting: Academic clinical research center. Patients: Twenty patients with type 2 diabetes, body mass index between 28 and 40 kg/m2. Intervention: Seven days treatment with the selective DPP-4 inhibitor vildagliptin or placebo. Standardized test meal on day seven. Main Outcome Measures: Venous DPP-4 activity, catecholamines, free fatty acids, glycerol, glucose, (pro)insulin; dialysate glucose, lactate, pyruvate, glycerol. Results: Fasting and postprandial venous insulin, glucose, glycerol, triglycerides and free fatty acid concentrations were not different with vildagliptin and with placebo. Vildagliptin augmented the postprandial increase in plasma norepinephrine. Furthermore, vildagliptine increased dialysate glycerol and lactate concentrations in adipose tissue while suppressing dialysate lactate and pyruvate concentration in skeletal muscle. The respiratory quotient increased with meal ingestion but was consistently lower with vildagliptin. Conclusions: Our study is the first to suggest that DPP-4 inhibition augments postprandial lipid mobilization and oxidation. The response may be explained by sympathetic activation rather than a direct effect on metabolic status.

Background: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic β-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes. Methods: Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15). Results: Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and C max during combination treatment were small (≤ 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE 0-5h reduced by 12% (p = 0.005) and AUE 0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE 0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE 0.5-5.5h reduced by 11% (p - 0.029) and AUE 0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia. Conclusions: Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.

We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin [9-39] in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin [9-39]. The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUCISR) and glucose (total AUCglucose) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUCISR/AUCglucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUCISR/AUCglucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 ± 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing alpha- and beta-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects.This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose.Exposure to vildagliptin (AUC(0-infinity) and C(max)) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC(0-infinity), 0.80 (0.60, 1.06), p = 0.192; C(max), 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [-8% for AUC(0-infinity), geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; -23% for C(max), geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C(max) was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC(0-infinity) was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC(0-infinity) and C(max) were increased by 29-84% and 24-63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment.There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.

Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers. This was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed. Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating ‘flip-flop’ kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h). Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.

Vildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.To assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10 mg, 25 mg and 100 mg twice daily following oral administration in patients with type 2 diabetes.Thirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10 mg, 25 mg and 100 mg as well as placebo twice daily for 28 days.Vildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p0.001] and glucose-dependent insulinotropic peptide (GIP) [p0.001] were increased whereas postprandial glucagon was significantly reduced at the 25 mg (p = 0.006) and 100mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25 mg dosing regimen and by 2.5 mmol/L with the 100 mg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.Vildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

Little is known about electroconvulsive therapy (ECT) use in Asian inpatients with schizophrenia. This study examined trends of ECT use for schizophrenia patients in Asia between 2001 and 2009 and its independent demographic and clinical correlates.Data on 6761 hospitalized schizophrenia patients (2001 = 2399, 2004 = 2136, and 2009 = 2226) in nine Asian countries and territories were collected by either chart review or interviews during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs and ECT use were recorded using a standardized protocol and data-collection procedure.The frequency of ECT was 3.3% in the whole sample; rising from 1.8% in 2001 to 3.3% in 2004 and 4.9% in 2009 (P 0.0001). However, this increased trend was driven solely by increased ECT use in China (P 0.0001), and the inclusion of India in the 2009 survey. There were wide inter-country variations: 2001, 0% (Hong Kong, Korea) to 5.9% (China); 2004, 0% (Singapore) to 11.1% (China); 2009, 0% (Hong Kong) to 13.8% (India) and 15.2% (China). Multiple logistic regression analysis of the whole sample revealed that patients receiving ECT were less likely in the 35-64-year age group, had shorter length of current hospitalization and fewer negative symptoms, and were more likely to receive second-generation antipsychotic medications compared to those who were not treated with ECT (R(2) = 0.264, P 0.001).ECT use for schizophrenia has increased over the past decade in China, being low/relatively stable in other Asian countries/regions. Reasons for substantial variations in ECT frequency in Asia require further study.

Little is known about the pattern of QT interval (QTc) prolongation in Asian patients with schizophrenia. This study examined trends of QTc prolongation in schizophrenia inpatients in six Asian countries and territories between 2004 and 2008/2009 and its independent demographic and clinical correlates.Data on 3482 hospitalized schizophrenia patients (2004 = 1826 and 2008/2009 = 1656) in six Asian countries and territories were collected by either chart review or interviews during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs, and QTc interval were recorded using a standardized protocol and data collection procedure.The frequency of QTc prolongation (456 ms) was 2.4% in the whole sample, decreasing from 3.1% in 2004 to 1.6% in 2008/2009 (p = 0.004) with wide intercountry variations. However, this decreased trend was driven by decreased QTc prolongation detected in China and Hong Kong (both p-values0.05). Multiple logistic regression analysis of the whole sample revealed that patients having more likely to have an illness lasting longer than 5 years and received antipsychotics classified as list-1 drugs according to the Arizona Centre for Education and Research on Therapeutics. Compared with 2004, patients in 2008/2009 were less likely to have QTc prolongation. Thioridazine caused QTc prolongation most frequently (odds ratio (OR) 4.4; 95% confidence interval (CI) 1.2-15.2), followed by sulpiride (OR 2.4; 95% CI 1.3-4.5), clozapine (OR 2.4; 95% CI 1.4-4.2), and chlorpromazine (OR 1.9; 95% CI 1.07-3.5).Frequency of QTc prolongation was low in Asian patients with schizophrenia. QTc prolongation in schizophrenia decreased in China and Hong Kong between 2004 and 2008/2009 but increased in Taiwan over the same period, remaining low in the other countries.

Research in prescription pattern of antidepressants in Asia is lacking. This study aims to compare the antidepressants prescription pattern in Asia in 2003-2004 and 2013.The Research in East Asia Psychotropic Prescription Pattern on Antidepressants (REAP-AD) had worked collaboratively in 2003-2004 (REAP-AD 2003/2004) and 2013 (REAP-AD 2013) to study the prescription pattern of antidepressants in Asia. The REAP-AD 2013 study was conducted in China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand using a unified research protocol and questionnaire.Forty psychiatric centers participated in REAP-AD 2013 and a total of 2,319 patients receive antidepressants were analyzed. In 2013, 39.6% of the antidepressant prescriptions were for diagnoses other thandepressive disorder compared with 38.4% in REAP-AD 2003/2004. Out of all the antidepressants listed in the Anatomical Therapeutic Chemical Classification index by the World Health Organization Collaborating Center for Drug Statistics Methodology (Oslo), only 38% antidepressants were prescribed in participating centers in 2013 compared with 46% in REAP-AD 2003/2004. The selective serotonin reuptake inhibitors were the most common antidepressant prescribed in the participating centers, which was similar to the 2003-2004 survey. Prescription of newer generation antidepressants had increased in 2013 survey; on the contrary, prescription of tricyclic antidepressants had reduced.This study has contributed significantly in relation to the changing patterns of antidepressant use in all the participating Asian centers in the last 10 years. The findings are important in shaping optimal antidepressant prescription and future policy making.

Objective To systematically investigate the reproducibility and reliability of a newly developed, less invasive approach of estimating blood volume (BV), using indocyanine green (ICG) measured with pulse-spectrophotometry. Design Prospective, clinical study. Setting Surgical unit at a university hospital. Patients Twenty-two patients undergoing general anesthesia for elective surgery and seven healthy volunteers. Interventions Catheters were inserted into the forearm veins of healthy volunteers for the administration of ICG and blood sampling for the measurement of hemoglobin concentration. Measurements and Main Results The distribution volumes of ICG in seven healthy volunteers were estimated repetitively following three or four consecutive intravenous administrations at 30-min intervals. A low intrasubject coefficient of variation of 3.94 +/- 2.03 (SEM) % and a reasonable intersubject coefficient of variation of 13.3 +/- 5.52% (in mL/kg) for the BV measurements were obtained. In addition, ICG was administered to 22 patients, first under general anesthesia by a bolus, and then by a bolus with a constant-rate infusion. The ICG blood concentration was noninvasively measured with pulse-spectrophotometry. The blood concentration time courses following both bolus and constant-rate infusion were well fitted by the one-compartment model, indicating that the distribution equilibrium of ICG is instantaneous. The distribution volumes estimated following bolus injection correlate closely with the distribution volume estimated based on constant-rate infusion administration (r2 = .90). Conclusions The BV estimation with a bolus injection of ICG and pulse-spectrophotometry is reliable, as reflected by the reproducible BVs estimated in the same subject. The integrated pulse-spectrophotometry monitoring system offers a less invasive and useful tool for bedside estimation of BV. (Crit Care Med 1998; 26:1446-1451)

This study was to assess differences in the symptom profile of depressive illness across various countries/territories in Asia. The study was a part of the Research on Asia Psychotropic Prescription project. The participating countries/territories include China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand.The pattern of depressive symptoms in 1,400 subjects with depressive disorder from 42 psychiatric centers in 10 Asian countries/territories was assessed. We collected information on socio-demographic and clinical characteristics with a standardized protocol and data collection procedure.The most common presentations of depressive symptoms were persistent sadness, loss of interest, and insomnia. Similar findings were found regardless of the region, country, or its income level. Patients with depressive disorder from high-income countries presented significantly more with vegetative symptom cluster (P 0.05), while those from the upper middle-income countries had significantly more with both mood (P 0.001) and cognitive symptom clusters (P 0.01). In lower middle-income countries, patients with depressive symptoms had significantly less mood symptom cluster (P 0.001) but significantly more cognitive symptom cluster (P 0.05).This study demonstrates that in Asia, despite variations in the initial symptom reported by the patients, across different countries/territories, core depressive symptoms remain the same. Variations have been found in presentation of depressive symptoms with regards to the level of income of countries. Physical or vegetative symptoms were reported more by centers in higher income countries, while depressive cognition and suicidal thoughts/acts were more frequently reported from lower income countries.

Background QT interval prolongation is associated with an increased risk of potentially fatal ventricular tachycardias, including torsade de pointes. Regulatory guidance recommends the "thorough QT/QTc" (TQT) study as the gold standard for assessing the propensity of novel nonantiarrhythmic drugs to delay cardiac repolarization. An opportunity exists, however, to use high-quality electrocardiogram (ECG) data from first-in-man trials as an exploratory and complementary approach to gain early insight into potential risk of QT prolongation. Methods We collected high-quality, triplicate, 12-lead ECG data during a first-in-man trial of a drug developed for the treatment of Type 2 diabetes that had shown in vitro hERG inhibition and potential to prolong QT intervals in an animal model. Results QTc prolongation was observed at the highest dose, leading to a maximum QTcF prolongation > 19 ms at 6 hours after the 14th daily dose. QTcF increases from time-matched baseline relative to placebo were positively correlated with peak plasma concentrations. Conclusions Clinically relevant QT interval prolongations can be detected during first-in-man studies using high-quality ECG monitoring. Such data may facilitate early decision making on whether to terminate the development of a compound and invest resources in more promising molecules; and it may enable more efficient TQT study design or preclude the need for future TQT studies.

OBJECTIVE To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. METHODS In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. RESULTS Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). CONCLUSIONS Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. Vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.

To investigate the prevalence of anxiety disorder in internal medical outpatients at general hospital, explore some susceptible factors of anxiety disorder patients and assess the physician diagnosis and treatment of anxiety disorders.According to 10:1 random sampling, the outpatients from cardiac medicine, digestive medicine, endocrinology and hypertension at Shanghai Ruijin Hospital were selected during November 2007 to January 2008. Hospital anxiety and depression scale (HADS) was used to screen the subjects. Those whose anxiety sub-score was higher or equal to 8 were interviewed with M.I.N.I. investigators further. The information of the physician diagnosis and treatment was collected from the history cards.The prevalence of anxiety disorders was 2.51%, panic attack 0.9%, agoraphobia 0.47%, social phobia 0.25%, specific phobia 0.31%, obsessive-compulsive disorder 0.28% and general anxiety disorder 1.47%. Women and widows were more susceptible to anxiety disorders (P0.01). And 23% of anxiety disorder patients received treatment. But the physician diagnosis rate of anxiety disorders was only 3.2%.The prevalence of anxiety disorders in internal medical outpatients at general hospital is still high and general anxiety disorders are commonly encountered. Women and widows are more susceptible to anxiety disorders than others. The physician diagnosis rate of anxiety disorders remains low.

To explore the level of identification and related factors of depression in physicians of Beijing tertiary general hospitals.A cross-sectional investigation was used to screen the outpatients, and depression was diagnosed according to Mini International Neuropsychiatric Interview (MINI). Identification of depression was defined as referral to psychiatrist or managed with antidepressant or sedative hypnotics.Among 248 cases of depression, 30 (12.1%) were referred to psychiatrists, 28(8.9%) managed with antidepressant or sedative hypnotics. The identification rate of depression by physicians was 21.0%, and the identification rate by neurologist was 40.4%, which is higher than the rate by cardiologist (22.4%), gastrointestinal physician (3.8%) and gynecologist (2.0%) (χ2=61.077, P0.05). Visiting neurology department, severity of life impairment, with psychotic distress history, had psychological complaints, co-morbidity with anxiety related to the physician's identification of depression. Among the psychological complaints, only mood disorder and insomnia were related to the physician's identification of depression.The level of depression identification by physician was low, the level of neurologist was higher than that of cardiologist, gastrointestinal physician and gynecologist. The patient with serious life impairment, psychotic distress history, mood disorder and insomnia complaints was easily to be identified.

The purpose of the study was to evaluate the frequency of reported sexual dysfunction (SD) in schizophrenia and its associations with sociodemographic and clinical variables in selected Asian countries.A total of 5877 schizophrenia patients in nine Asian countries and territories were examined between 2001 and 2009. The patients' sociodemographic and clinical characteristics, prescription of psychotropic drugs, and drug-induced side effects were recorded using a standardized protocol and data collection. SD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists.The frequency of reported SD in the whole sample in women and men was 3.0%, 0.8%, and 4.6%, respectively, with variations across study sites. In the multivariate analyses, male sex, more second-generation antipsychotics, benzodiazepines, and antidepressants were independently associated with higher likelihood of reported SD, whereas negative symptoms had an inverse association with reported SD.The results of this study indicate that SD was seldom recorded as a side effect by Asian psychiatrists while treating patients with schizophrenia. It is unclear whether the low prevalence of reported SD compared with Western data is real or whether the results are being insufficiently recognized.

Objective: To assess the pharmacokinetics, pharmacodynamics and safety of vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), in Japanese patients with Type 2 diabetes. Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, 62 Japanese patients with Type 2 diabetes received vildagliptin 10 mg, 25 mg or 50 mg twice daily for 7 days. Blood samples were collected for the determination of plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin and glucagon. Results: Exposure to vildagliptin (area under the plasma concentration-time curve from 0 to 12 h (AUC 0―12h ) and the maximum plasma concentration (C max )) increased in an approximately dose-proportional manner, and no accumulation was observed following multiple doses of vildagliptin (accumulation factor 1.00 ― 1.02). DPP-4 activity was completely inhibited for varying durations by all doses ofvildagliptin; the duration of complete DPP-4 inhibition was dose-dependent. DPP-4 inhibition after vildagliptin 50 mg twice daily remained > 80% throughout the 24-h period. Vildagliptin treatment led to a dose-dependent increase in plasma active GLP-1 levels; the overall increases (area under the effect-time course from 0 to 8 h, AUE 0―8h ) after 7 days' treatment were 1.5-, 1.7-, and 1.8-fold with vildagliptin 10 mg, 25 mg and 50 mg twice daily, respectively (all p < 0.0001 vs. placebo). Postprandial plasma glucose during the 4-h period after breakfast was significantly reduced with the 10, 25 and 50 mg vildagliptin doses by 50.3, 92.2 and 69.5 mg·h/dl, respectively. Insulin levels remained unchanged in the context of reduced glucose levels at all doses studied. Conclusions: Vildagliptin demonstrated similar pharmacokinetic and pharmacodynamic effects in Japanese patients to those observed previously in non-Japanese patients with Type 2 diabetes.

Vildagliptin is an orally active, potent inhibitor of dipeptidyl peptidase IV and was developed for the treatment of type 2 diabetes. In clinical trials, once or twice daily dosing with vildagliptin (up to 100 mg day(-1)) has been shown to reduce endogenous glucose production and fasting plasma glucose in patients with type 2 diabetes. The comparative efficacy of vildagliptin under a morning vs. evening dosing regimen has not previously been determined.Once daily dosing with vildagliptin 100 mg for 28 days improved glycaemic control in patients with type 2 diabetes independent of whether vildagliptin was administered in the morning or evening. Morning or evening dosing with vildagliptin had similar effects on 24 h glycaemic control and plasma concentrations of the hormones insulin, glucagon and glucagon-like peptide 1.This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes.Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day -1) and on days 28 and 56 to assess pharmacodynamic parameters.Vildagliptin inhibited DPP-4 activity (80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0-24 h effect-time curve [AUE(0,24 h)]: morning -467 mg dl(-1) h, P= 0.014; evening -574 mg dl(-1) h, P= 0.003) with no difference between regimens (P= 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (-336 vs.-218 mg dl(-1) h, P= 0.192). Only evening dosing significantly reduced fasting plasma glucose (-13 mg dl(-1), P= 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 microU ml(-1) h; morning 354 microU ml(-1) h, P= 0.050).Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.

To investigate the clinical efficacy and safety of the treatment of vitiligo using a 308 nm excimer laser.Thirty-six patients with 44 vitiligo patches were treated using a 308 nm excimer laser, which was performed twice a week, for a total of 30 treatments. The therapeutic efficacy and safety were then evaluated.After 30 treatments: (1) 27/44 patches (61.4%) achieved more than 75% repigmentation, 4/44 lesions (9.1%) showed 51-75% repigmentation, 10/44 (22.7%) showed 26-50% repigmentation and 3/44 (6.8%) showed 1-25% repigmentation. (2) Of the 44 patches of vitiligo, 20/27 (74.1%) lesions on the face/neck, 9/9 (100%) on the trunk and 2/8 (25.0%) on the extremities showedor=50% repigmentation. The repigmentation (or=50%) in face/neck and trunk were much higher than that in the extremities (P0.05). (3) The repigmentation (or=50%) in disease duration ofor=2 years and2 years were 100.0% and 46.2% (P0.05). (4) The average cumulative doses in the face/neck, trunk and extremities were 7.92+/-5.26, 9.93+/-7.36 and 22.13+/-8.15 J/cm(2). The doses in the face/neck and trunk were much lower than those in the extremities. (P0.05). Side effects were limited mainly to symptomatic erythema.The clinical data indicate that the treatment of vitiligo using a 308 nm excimer laser is safe and effective. However, lesion location and disease duration may be the key factors affecting the clinical outcome.

To analyze the clinical characteristics of bone metastasis of malignant tumors.The clinical data and survival time of 355 patients with bone metastasis of malignant tumors were retrospectively analyzed.The bone metastasis occurred more frequently in men (male:female = 1.45:1). The most common primary tumors were lung cancer in men and breast cancer in women. The thoracic vertebrae, ribs, lumbar vertebrae and pelvic were frequently involved metastatic sites and the multiple bone metastasis was common (83.4%). The main symptom was pain (75.2%). Local masses, disfunctions, pathologic fracture and paraplegia occurred in a few patients while many patients were asymptomatic (22.0%). The most frequent radiographic manifestation was the osteolytic bone destruction (82.2%). Integrated treatments were taken, including chemotherapy, hormonal therapy, biological therapy, radiotherapy, surgery, bisphosphonate analgetics, etc. The clinical benefit rate in pain relief was 98.5% and the effective rate was 72.2% in radiographic imaging. The median survival time was 13.9 months. Among them, it was 34.9 months in prostate cancer and 4.6 months in hepatocellular carcinoma. The survival time was longer in bone metastasis without other organ metastasis. There was no significant difference between the single and multiple bone metastases regarding the survival time.It is important to master the clinical features of bone metastasis of malignant tumors for early diagnosis and treatment, and to improve the quality of life and prolong the survival time.

To find the prevalence of depressive and anxiety disorders among general hospital outpatients and to evaluate the diagnoses and treatment provided by physicians in China.A multi-center, hospital-based cross-sectional study was conducted. A total of 8478 subjects were screened by using HADS and PHQ-15 together with medical history review list and were followed by regular clinical visit process. Physician's diagnoses and management were recorded. Mini International Neuropsychiatric Interview (MINI) was used to evaluate by psychiatrists afterwards for 4172 subjects scoredor= 8 on HADS.The adjusted prevalence rates of MINI-diagnosed depressive disorder, anxiety disorder, depression and anxiety, depression or anxiety disorders were 12.0%, 8.6%, 4.1% and 16.5%, respectively. The prevalence of depressive and/or anxiety disorder in outpatients visiting department of neurology and digestive diseases were higher than that in patients visiting departments of cardiovascular diseases and gynecology with statistical significance (P0.0001).High prevalence and low identification and treatment rate of depressive and/or anxiety disorders were found in the general hospitals. In order to improve the status quo, training program for physicians and specialists other than psychiatric professionals in general hospitals should be enhanced together with psychiatric consultation.

To explore the prevalence and physician's recognition of depression and anxiety disorder in gastrointestinal out-patients of three tertiary general hospitals in Beijing.A hospital-based cross-sectional survey was conducted in the gastrointestinal out-patient departments of three tertiary general hospitals in Beijing from May to June 2007. Total 517 subjects were recruited consecutively within a one month period. All the subjects were screened with Hospital Anxiety Depression Scale (HADS). The subjects with HADS score of 8 and over were interviewed and diagnosed by psychiatrists using Mini International Neuropsychiatric Interview (MINI). The physicians made the diagnosis and management without knowing the results of MINI and HADS score.Among the 517 cases, 301 had a HADS score of 8 and above and 244 were interviewed by psychiatrists; the response rate was 81.1%. The prevalence according to Diagnostic and Statistical Manual of Mental Disorders Fourth edition of depressive disorders and anxiety disorders in gastrointestinal outpatients were 15.3%, depressive disorders were 12.0%, anxiety disorders were 6.4%, depression combined anxiety disorder was 3.0%. The prevalence of depression, anxiety, depression combined anxiety were not different between genders (chi2=0.874, chi2=1.797, chi2=0.518, P0.05) and among different age group (18-34, 35-54,or=55 years old) (chi2=1.084, chi2=2.735, chi2=0.350, P0.05). Gastritis and gastrointestinal dysfunction were the major diagnoses in patients with depression and/or anxiety disorders, the rates were 30.6% and 26.4% respectively. The rate of identification of depression and anxiety disorder by physicians was 2.8%.Gastrointestinal out-patients have a high prevalence of depression and anxiety disorder and the rate of identification by physicians was very low.

Metformin is widely used for treating patients with type 2 diabetes, often as first-line therapy; however, many patients with type 2 diabetes are unable to maintain adequate glycemic control with metformin alone. Vildagliptin, an orally active, potent and selective dipeptidyl peptidase IV (DPP-4) inhibitor, may represent an appropriate antihyperglycemic agent for combination with metformin to improve glycemic control in such patients. This study assessed the effects of coadministration of vildagliptin and metformin on the steady-state pharmacokinetics of each drug.In this open-label, single-center, randomized, three-period, three-treatment crossover study, 17 patients with type 2 diabetes received vildagliptin 100 mg once daily; metformin 1000 mg once daily; or vildagliptin 100 mg once daily plus metformin 1000 mg once daily. Blood samples for pharmacokinetic sampling were taken frequently on the final day (Day 5) of each treatment period. Lack of pharmacokinetic interaction was defined as the ratio of geometric mean (GMR) and 90% confidence interval (CI) for combination:monotherapy being within the range 0.80-1.25.Coadministration with metformin had no effect on vildagliptin AUC(0-24) (GMR, 0.94; 90% CI 0.90, 0.99) although there was an 18% decrease in vildagliptin C(max) (GMR 0.82; 90% CI 0.73, 0.91). Coadministration with vildagliptin had no effect on metformin C(max) (GMR 1.04; 90% CI 0.94, 1.16). but caused a 15% increase in AUC(0-24) (GMR 1.15; 90% CI 1.06, 1.25). Both monotherapies and combination therapy were well tolerated. Seven patients reported a total of 10 adverse events; none was serious.Coadministration of vildagliptin and metformin had a small effect on the pharmacokinetics of each drug in patients with type 2 diabetes; however, this is not likely to be clinically relevant. This small, open-label trial suggests that vildagliptin could be coadministered with metformin without any dose adjustment for either agent.

Objective To assess the bioequivalence of vildagliptin/metformin fixed-dose combination tablets (at doses of 50/500, 50/850 and 50/1,000 mg) with free combination of the individual drugs in healthy subjects. Methods The pharmacokinetics of vildagliptin and metformin following administration of a fixed-dose combination tablet of vildagliptin/metformin at doses of 50/500 mg (Study I), 50/850 mg (Study II) and 50/1,000 mg (Study III) compared with administration of the individual drugs as free combinations were investigated. All three studies were open-label, single-center, randomized, two-period, two-treatment crossover studies in healthy subjects. Results Pharmacokinetic parameters (AUC(0-infinity), C(max), t(max), t(1/2) and CL/F) for vildagliptin and metformin across the three studies were similar whether vildagliptin and metformin were administered as a single fixed-dose combination tablet (vildagliptin/metformin 50/500, 50/850 or 50/1,000 mg) or as the respective individual tablets. The point estimates and 90% CI of the geometric mean ratios for vildagliptin and metformin C(max), AUC(0-t), and AUC(0-infinity) were all within the predefined bioequivalence range of 0.80 - 1.25. Administration of the vildagliptin/metformin combination tablets was well tolerated; the incidence of adverse events was similar to that observed with the respective free combinations of vildagliptin and metformin, and the most common individual adverse events were mild gastrointestinal events, which are commonly observed with metformin treatment. Conclusions The fixed-dose combination tablet of vildagliptin/metformin is bioequivalent to administration of the individual drugs as a free combination at dose levels of 50/500, 50/850 and 50/1,000 mg and is well tolerated. Consequently, the fixed-dose combination tablets are considered therapeutically equivalent and exchangeable to the free combination in clinical practice. Furthermore, the fixed-dose combination tablets are expected to enhance convenience and thereby improve compliance and improve glycemic control for patients with Type 2 diabetes on both medications.

Vildagliptin is an orally active, potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha- and beta-cell responsiveness to glucose.This open-label, single-center, randomized, two-period crossover study in healthy subjects (n=23) ages 18-45 years investigated the effect of food on the pharmacokinetics of vildagliptin and metformin following administration of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet.Administration of the fixed-dose combination tablet following a high-fat meal had no effect on vildagliptin AUC(0-infinity) (ratio of geometric mean for fed:fasted state, 1.10 [90% CI 1.03, 1.18]), C(max) (ratio of means 0.98 [90% CI 0.85, 1.13]) or median t(max) (2.5 h in fed and fasted states). The rate of absorption of metformin was decreased when given with food, as reflected by the prolonged t(max) (2-4 h) and reduction in C(max) (by 26%), but the extent of absorption was not changed. The food effect on the metformin component of the fixed-dose combination tablets was consistent with, but of a lesser magnitude compared with data stated.The vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet can be administered in the same manner as metformin, and can be recommended to be taken with meals to reduce the gastrointestinal symptoms associated with metformin.

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Objective: To evaluate the efficacy and safety of a 308 nm excimer laser for the treatment of psoriasis vulgaris patients. Method: Forty subjects with psoriasis vulgaris (26 macular type, and 14 chronic plaque type) were treated by a 308 nm excimer laser. The initial dose was based on multiples of a predetermined minimal erythema dose, while the subsequent doses were adjusted on the response to the intervention, which was twice per week for a total of 15 treatments. The therapeutic efficacy and safety were then evaluated. Results: Of the 40 patients who received and completed the entire 15 times of laser radiation, (1) the Psoriasis Area and Severity Index score was improved by 90.19±10.12% and 77.34±17.04% in macular type and chronic plaque type, respectively (P

What is already known about this subject • Vildagliptin is a new, potent, and selective inhibitor of DPP-4. • The efficacy and safety of vildagliptin in type 2 diabetes has been intensively studied in diverse subject populations. • There has been little information published about the pharmacokinetics and pharmacodynamics of vildagliptin. What this study adds • No clinically relevant changes in pharmacokinetics or pharmacodynamics were observed between young and elderly, male and female, or high body mass index (BMI) and low BMI subjects. • The results suggest that no dose modification is necessary for vildagliptin based on the age, gender, or BMI of a subject. Aims To evaluate the effect of age, gender, and body mass index (BMI) on the pharmacokinetics and pharmacodynamics of vildagliptin. Methods Forty healthy subjects received a single oral dose of 100 mg vildagliptin to assess the effects of age, gender, and BMI on the pharmacokinetics and pharmacodynamics, reflected by the time course of inhibition of DPP-4 activity, of vildagliptin. Results Peak concentration and exposure (AUC(0–∞)) of vildagliptin were 17% (90% CI 2, 35%) and 31% (90% CI 18, 45%) higher in elderly vs. young subjects. Renal clearance was reduced by 32% (90% CI 17, 45%) in elderly subjects. The pharmacokinetics of vildagliptin were not significantly influenced by gender or BMI. Inhibition of DPP-4 activity was similar regardless of age, gender, or BMI. Conclusions The pharmacokinetics of a single oral 100 mg dose of vildagliptin were not affected by gender and BMI. Exposure to vildagliptin was higher in elderly patients, but this was not associated with any difference in the effect of DPP-4 inhibition. Based on these results, no vildagliptin dose adjustment is necessary for age, gender, or BMI.

Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simva statin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. There fore, this study was conducted to determine the potential for pharmacokinetic drug-drug interaction between vildagliptin and simvastatin at steady-state.An open label, single center, multiple dose, three period, crossover study was conducted in 24 healthy subjects. All subjects received once daily doses of either vildagliptin 100 mg or simvastatin 80 mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin beta-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively.The 90% confidence intervals of C(max) and AUC(tau) of vildagliptin, simvastatin, and simvastatin beta-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were admin istered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study.The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.

Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open-label, randomized, 3-period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2-7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC(0-24h), 0.99 [0.95-1.03]; C(max), 0.95 [0.85-1.06]) or to digoxin (AUC(0-24h), 1.02 [0.94-1.12]; C(max), 1.08 [0.97-1.20]). In addition, no changes in t(max), t((1/2)), and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (

Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100 mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium.Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects.The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S-warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S-warfarin maximum plasma concentration (Cmax) were also within the equivalence range 0.80-1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PT(max), 1.00 [90% CI 0.97, 1.04]; AUC(PT), 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUC(INR), 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80-1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication.Co-administration of warfarin with vildagliptin did not alter the pharmacokinetics and pharmacodynamics of R- or S-warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.

The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function.This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors.Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P0.0001) relative to placebo.Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

The safety of using propofol in parturients is controversial, and little information is available on the factors that influence the placental transfer of propofol. In this study, we investigated the effects of uterine and umbilical blood flows on the placental transfer of propofol by using the dually perfused human placental cotyledon. Placental transfer was evaluated on the basis of the placental clearances at various uterine and umbilical flow rates. The placental transfer of propofol was significantly facilitated by the increased uterine flow rates over the range from 7.5 to 25 mL/min. The placental clearances of propofol were also dependent on the umbilical flow rates over the range from 0.5 to 4.0 mL/min. In contrast, the placental transfer of antipyrine was flow dependent when the umbilical flow rate was2.0 mL/min and became permeability limited when it was2.0 mL/min. No differences in either maternal or fetal venous concentrations of propofol were observed as umbilical flow rates varied from 0.5 to 4.0 mL/min, suggesting that an equilibration across the placenta occurs at low flow rates. These results indicate that fetal uptake of propofol can be profoundly altered by the changes in both uterine and umbilical blood flows observed in various pathophysiologic conditions and that lipid solubility greatly influences placental transfer of drugs.Uterine and umbilical blood flows are determinant features in controlling the placental transfer of propofol, and, therefore, changes in these variables would significantly affect the extent of fetal exposure to propofol.

AIM: To investigate the prevalence and physicians’ detection rate of depressive and anxiety disorders in gastrointestinal (GI) outpatients across China. METHODS: A hospital-based cross-sectional survey was conducted in the GI outpatient departments of 13 general hospitals. A total of 1995 GI outpatients were recruited and screened with the Hospital Anxiety and Depression Scale (HADS). The physicians of the GI departments performed routine clinical diagnosis and management without knowing the HADS score results. Subjects with HADS scores ≥ 8 were subsequently interviewed by psychiatrists using the Mini International Neuropsychiatric Interview (MINI) to make further diagnoses. RESULTS: There were 1059 patients with HADS score ≥ 8 and 674 (63.64%) of them undertook the MINI interview by psychiatrists. Based on the criteria of Diagnostic and Statistical Manual of Mental Disorders (4th edition), the adjusted current prevalence for depressive disorders, anxiety disorders, and comorbidity of both disorders in the GI outpatients was 14.39%, 9.42% and 4.66%, respectively. Prevalence of depressive disorders with suicidal problems [suicide attempt or suicide-related ideation prior or current; module C (suicide) of MINI score ≥ 1] was 5.84% in women and 1.64% in men. The GI physicians’ detection rate of depressive and anxiety disorders accounted for 4.14%. CONCLUSION: While the prevalence of depressive and anxiety disorders is high in Chinese GI outpatients, the detection rate of depressive and anxiety disorders by physicians is low.

Background The role of crystalloid preloading to prevent hypotension associated with spinal anesthesia in parturients during cesarean section has been challenged. Direct measurement of blood volume should provide insight regarding the volume-expanding effects. The aim of the current study was to clarify the effects of volume preload with either crystalloid or colloid solution on the changes in blood volume of parturients undergoing spinal anesthesia for cesarean section. Methods Thirty-six healthy parturients scheduled for elective cesarean section during spinal anesthesia were allocated randomly to one of three groups receiving 1.5 l lactated Ringer's solution (LR; n = 12), 0.5 l hydroxyethylstarch solution, 6% (0.5 l HES; n = 12), and 1.0 l hydroxyethylstarch solution, 6% (1.0 l HES; n = 12), respectively. Blood volume and cardiac output were measured before and after volume preloading with indocyanine green (ICG), and the indocyanine green blood concentrations were monitored by noninvasive pulse spectrophotometry. Results After volume preload, the blood volume significantly increased in all three groups (P < 0.01). The volume of infused solution remaining in the vascular space in the LR, 0.5-l HES, and 1.0-l HES groups were 0.43+/-0.20 l, 0.54+/-0.14 l, and 1.03+/-0.21 l, respectively, corresponding to 28% of lactated Ringer's solution and 100% of hydroxyethylstarch solution infused. Significant increases in cardiac output were observed in the 0.5-l and 1.0-l HES groups (P < 0.01). A significant correlation between the percentage increase in blood volume and that of cardiac output was observed by volume preloading (r2 = 0.838; P < 0.001). The incidence of hypotension was 75% for the LR group, 58% for the 0.5-l HES group, and 17% for the 1.0-l HES group, respectively. Conclusions The incidence of hypotension developed in the 1.0-l HES group was significantly lower than that in the LR and 0.5-l HES groups, showing that greater volume expansion results in less hypotension. This result indicates that the augmentation of blood volume with preloading, regardless of the fluid used, must be large enough to result in a significant increase in cardiac output for effective prevention of hypotension.