Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes

This 24-week, double-blind, randomized, multicenter, placebo-controlled, parallel-group study performed in 354 drug-na?ve patients with type 2 diabetes (T2DM) assessed efficacy and tolerability of vildagliptin (50mg qd, 50mg bid, or 100mg qd). The primary assessment was change from baseline to endpoint in hemoglobin A1c (A1C), comparing vildagliptin to placebo by ANCOVA. Baseline A1C averaged 8.4% and the between-treatment difference (vildagliptin-placebo) in adjusted mean change (AMDelta) in A1C was -0.5+/-0.2% (P=0.011), -0.7+/-0.2% (P<0.001), and -0.9+/-0.2% (P<0.001) in patients receiving vildagliptin 50 mg qd, 50 mg bid, or 100 mg qd, respectively. Baseline FPG averaged 10.5 mmol/L; the between-treatment difference in AMDelta FPG was -0.6+/-0.4 mmol/L in patients receiving vildagliptin 50mg qd and -1.3+/-0.4 mmol/L (P=0.001) in both groups receiving 100mg daily. Relative to baseline, body weight did not change significantly in any of the three vildagliptin groups and decreased by 1.4+/-0.4 kg in the placebo group. Adverse events (AEs) occurred with similar frequency in each group: 55.8%, 59.3%, 59.3%, and 57.6% of patients receiving vildagliptin 50 mg qd, 50 mg bid, 100 mg qd, or placebo, respectively, experienced an AE. No confirmed hypoglycemia was reported. Conclusion: Vildagliptin is effective and well-tolerated in drug-na?ve patients with T2DM and 100 mg vildagliptin provides similar clinical benefit whether given as single or in divided doses.     

Efficacy and tolerability of vildagliptin in drug-naïve patients with type 2 diabetes and mild hyperglycaemia*

Aim: This study was conducted to assess efficacy and tolerability of vildagliptin in drug‐naïve patients with type 2 diabetes and mild hyperglycaemia. Methods: Multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study of 52‐week treatment with vildagliptin (50 mg q.d.) in 306 drug‐naïve patients with type 2 diabetes (A1C = 6.2–7.5%). A1C, fasting plasma glucose (FPG) and measures of prandial glucose control and beta‐cell function determined during standard meal tests were assessed. Results: Baseline A1C and FPG averaged 6.7% and 7.1 mmol/l, respectively, in patients randomized to vildagliptin (n = 156) and 6.8% and 7.2 mmol/l in those randomized to placebo (n = 150). A1C decreased modestly in vildagliptin‐treated patients (Δ = ?0.2 ± 0.1%) and increased in patients receiving placebo (Δ = 0.1 ± 0.1%). The between‐group difference (vildagliptin ? placebo) in adjusted mean change (AMΔ) in A1C was ?0.3 ± 0.1% (p < 0.001). FPG increased in patients receiving placebo (Δ = 0.5 ± 0.1 mmol/l) and to a significantly lesser extent in vildagliptin‐treated patients (between‐group difference in AMΔ FPG = ?0.4 ± 0.2 mmol/l, p = 0.032). Relative to placebo, 2‐h postprandial glucose (PPG) decreased (?0.9 ± 0.4 mmol/l, p = 0.012), and insulin secretory rate (ISR) relative to glucose [ISR area under the curve (AUC)_{0–2 h}/glucose AUC_{0–2 h}] increased (+5.0 ± 1.2 pmol/min/m²/mM, p < 0.001). Mean body weight decreased by 0.5 ± 0.3 kg in vildagliptin‐treated patients and by 0.2 ± 0.3 kg in patients receiving placebo. The side‐effect profile of vildagliptin was similar to that of placebo, and one hypoglycaemic episode occurred in one patient receiving placebo. Conclusions: In drug‐naïve patients with mild hyperglycaemia, relative to placebo, 52‐week treatment with vildagliptin 50 mg q.d. significantly decreases A1C, FPG and PPG and improves beta‐cell function without weight gain or hypoglycaemia.     

Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: a pooled analysis from a database of clinical trials

Aim: To report the experience with vildagliptin in a patient population with type 2 diabetes mellitus (T2DM) ≥75 years. Methods: Efficacy data from seven monotherapy and three add‐on therapy to metformin studies, respectively, of ≥24 weeks duration were pooled; effects of 24 weeks of treatment with vildagliptin (50 mg bid) in patients ≥75 years were assessed in these two pooled datasets. Safety data were pooled from 38 studies of ≥12 to ≥104 weeks duration; adverse events (AEs) profiles of vildagliptin (50 mg bid) were evaluated relative to a pool of comparators; 301 patients ≥75 years were analysed. Data in patients <75 years are provided as a reference. Results: Mean age of the elderly population was 77 years. Changes in haemoglobin A1c (HbA1c) with vildagliptin in the patient group ≥75 years were ?0.9% from a baseline of 8.3% in monotherapy (p < 0.0001) and ?1.1% from a baseline of 8.5% in add‐on therapy to metformin (p = 0.0004), and these reductions were similar to those seen in the younger patients. The corresponding weight changes in the elderly patients were ?0.9 kg (p = 0.0277) and ?0.2 kg [not significant (NS)], respectively, and no confirmed hypoglycaemic events, including no severe events, were reported. AEs, drug‐related AEs, serious adverse events (SAEs) and deaths were reported with a lower frequency in older patients receiving vildagliptin than comparators [133.9 vs. 200.6, 14.5 vs. 21.8, 8.8 vs. 16.5 and 0.0 vs. 1.7 events per 100 subject year exposure (SYE), respectively], and the incidence of discontinuations due to AEs was similar in the two groups (7.2 vs. 7.5 events per 100 SYE, respectively). The safety profile of vildagliptin was overall similar in younger and older patients. Conclusions: Vildagliptin was effective and well‐tolerated in type 2 diabetic patients ≥75 years (mean age 77 years).     

DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

The development of type 2 diabetes is accompanied by a progressive decline in β-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on β cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased β-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in β cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.     

Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance and β-cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet

Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2(-/-) mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells.     

A randomized controlled clinical trial of combination therapy for type 2 diabetes by vildagliptin,metformin, and α-glucosidase inhibitor

This study aims to evaluate the efficacy and safety of vildagliptin combined with metformin and α-glucosidase inhibitors for treatment of type 2 diabetes. The type 2 diabetic patients with poor blood sugar control after a combination treatment by metformin and α-glucosidase inhibitor for at least two months were randomly assigned to receive vildagliptin or placebo (100 mg/day for 2 times) on the basis of the original treatment. The relevant indicators of the patients before and after the test for 12 weeks were detected. We totally chose 490 cases of subjects who were in Henan Provincial People’s Hospital from February,2013 to July,2013. Compared with the data before the test, the glycated hemoglobin (HbA1c) changed from 8.86?±?1.820 to 6.74?±?1.256 % and fasting blood glucose (FBG), postprandial blood glucose (PPG), and alanine aminotransferase (ALT) in the vildagliptin group significantly decreased; the difference was statistically significant (P?<?0.05). The differences of the index in the placebo group were not statistically significant (P?>?0.05). HbA1c in the vildagliptin group, 12 weeks after the test, was significantly lower than those in the placebo group with a comparison by 6.74?±?1.256 and 8.20?±?1.180 %, as well as FBG, PPG, ALT, and aspartate aminotransferase (AST); the difference was statistically significant (P?<?0.05). Whether the comparisons were performed before and after treatment or between the two groups, the changes of the subject’s body weight and blood lipids had no statistically significant differences (P?>?0.05). Vildagliptin combined with metformin and α-glucosidase inhibitors can efficiently reduce the FBG, PPG, and HbA1c of the patients without gaining weight and may have a protective effect on the liver.     

The role of hypergastrinemia in the pathogenesis of intussusception in infants

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Value of selective chemoembolization in treatment of hepatic metastases in colorectal carcinoma

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Pharmacoeconomic analysis of Metoject(®) in the treatment of rheumatoid arthritis in Spain

ObjectivesThe aim of this study was to compare the clinical and economic consequences of using subcutaneous methotrexate (Metoject^®) with respect to oral methotrexate in the management of rheumatoid arthritis (RA) in Spain.MethodsA cost-effectiveness analysis was performed to compare early treatment of RA using a Markov model. The model allowed us to estimate long term efficacy of RA treatment based on data from the literature and expert opinion, and to combine this data with costs of managing RA in Spain. The perspective of the study was from the National Health System point of view, using a time horizon of 5 years and patient lifetime. All costs were expressed in 2009 euros and a 3% discount rate was applied.ResultsThe cost (only pharmacologic costs) per quality-adjusted life year (QALY) gained with Metoject^® went from 25,173 to 35,807 € at 5 years and from 19,056 to 25,351 € for patient lifetime. When direct costs in RA treatment were considered, it was observed that cost-effectiveness at 5 years went from 29,682 to 42,175 €/QALY gained, and for patient lifetime from 22,514 to 29,848 €/ QALY gained.ConclusionsAdditional costs of Metoject^® with respect to oral methotrexate would be offset by their improved effectiveness, expressed in QALY, showing that Metoject^® could be a cost-effective treatment option for RA in the Spanish Health System assuming a spanish threshold.     

Advances in clinical research of hepatocellular carcinoma in China

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Prevalence of Raynaud’s Phenomenon in General Practice in the East of Spain

Our aim was to establish the prevalence of Raynaud’s phenomenon in a general practice in the east of Spain and compare our results with those of other studies performed in geographical areas with similar climatic characteristics. Two hundred and seventy-six subjects visiting their general practitioner for whatever reason were randomly selected from a particular area of the city of Valencia. Each was interviewed by their GP following the guidelines of a structured questionnaire to establish whether they had Raynaud’s phenomenon or not. There were 205 women and 71 men. The mean age was 54.43, with a standard deviation of 18.22. Raynaud’s phenomenon was present in nine subjects, two men and seven women, with a prevalence of 2.8% and 3.4%, respectively. Of the nine positives (mean age 60.56 years, standard deviation 16.38), two were diagnosed with hypertension and two with migraine. None of them usually took Raynaud’s phenomenon-related drugs or performed physical exercise. No patient had a family history of Raynaud’s phenomenon or had already been diagnosed with it. All the positive males were affected only by the pallor stage. This study shows lower prevalences than those of other studies performed in different geographical areas with similar climatic conditions. Received: 22 November 1999 / Accepted: 6 September 2000     

Assessment of resin perfusion in hepatic failure in vitro and in vivo

AIM:To observe the adsorbent effect of resin on endotoxin,cytokine,bilirubin in plasma of patients with hepatic failureand to determine the resin perfusion as an artificial liversupport system in the treatment of hepatic failure.METHODS:One thousand milliliters of discarded plasmawas collected from each of 6 severe hepatitis patients treatedwith plasma exchange.The plasma was passed through aresin perfusion equipment for 1-2 h via extracorporealcirculation,and then absorbent indicators of transaminase,bilirubin,blood ammonia,endotoxin and cytokines wereexamined.In the meantime,study of in vivo resin plasmaperfusion was performed on 7 severe hepatitis patients tocompare the changes of endotoxin and cytokines in bloodbefore and after perfusion.RESULTS:The levels of total bilirubin,endotoxin,interleukin1β and TNF-α in plasma were significantly decreased afterin vitro resin plasma perfusion.The levels of interleukin 1β,TNF-α and endotoxin in blood were also evidently declinedafter in vivo resin plasma perfusion.Nevertheless,no obviouschanges in IL-6,creatinine (Cr) and urea nitrogen (UN),bloodammonia and electrolytes were found both in vitroand in vivo.CONCLUSION:Bilirubin,endotoxin and cytokines in plasmaof patients with hepatic failure can be effectively adsorbedby resin in vitro.Most cytokines and endotoxin in plasma canalso be effectively removed by resin in vivo.It demonstratesthat resin perfusion may have good treatment efficacy onhepatic failure and can be expected to slow down theprogression of hepatic failure.     

Fumagillin treatment of hepatocellular carcinoma in rats： An in vivo study of antiangiogenesis

AIM: To investigate the effect and possible mechanisms of antiangiogenesis therapy for HCC in rats. METHODS: Adult male LEW/SsN rats were divided into 3 groups, 25 animals each. Group A was the control group. Groups B and C were given diethylnitrosamine, 5 mg/kg/d. In addition, group C rats received an intraperitoneal injection of fumagillin, 30 mg/(kg·d). Five animals in each group were killed at 6th, 12th, 18th, 20th and 24th wk to evaluate the development of HCC and metastasis. Weight of the rats, liver tumors, and number of organs involved by HCC were measured at each stage. We compared methionine aminopeptidase-2 (MetAP-2) mRNA, Bcl-2 mRNA, telomerase mRNA, and telomerase activity at 24th wk in the liver tissue of group A rats and tumor tissue of HCC from group B and C rats. RESULTS: No HCC developed in group A, but tumors were present in group B and C rats by the 18th wk. At wk 20 and 24, the median liver weight in group B was 0.64 g (range: 0.58-0.70 g) and 0.79 g (range: 0.70-0.90 g) (P= 0.04), and that in group C was 0.37 g (range: 0.35-0.42 g) and 0.39 g (range: 0.35-0.47 g) (P= 0.67). The liver weight in group C rats was significantly lower than that in group B rats (P= 0.009). At the same time, the median metastasis score (number of organ systems involved) was 3 (range2-3) in group B, and 1 (range 1-2) in group C, a significant difference between the groups (P= 0.007, 0.004). The levels of MetAP-2 mRNA were significantly higher in groups B and C than in group A (P = 0.025), and significantly higher in group C than in group B (P= 0.047). The level of Bcl-2 mRNA was significantly higher in group B than in group A (P=0.024), but lower in group C than in group B, although not significantly (P = 0.072). Telomerase mRNA was significantly higher in group B than in group A (P = 0.025), but significantly lower in group C than in group B (P= 0.016). The same inter-group relationship was also true for telomerase activity (P= 0.025 and 0.046). CONCLUSION: Fumagillin effectively inhibits both liver tumor growth and metastasis in rats in vivo. A possible mechanism is fumagillin-induced inhibition of MetAP-2, which plays an essential role in endothelial cell proliferation. Inhibition of MetAP-2 also results in inhibition of Bcl-2 and telomerase activity.     

Role of Ribomunyl® in the Prevention of Recurrent Respiratory Tract Infections in Adults

Recurrent respiratory tract infections (RRTIs) in adults are the result of an imbalance between lung defense mechanisms, and bacterial burden. Antibacterial treatments can temporarily restore the equilibrium between host and bacterial load, but do not prevent recurrence of infection. An alternative approach to prevent recurrence of infection is treatment with an immunostimulant, which provides immune protection against repeated bacterial and viral infection. All immunostimulant products are bacterial in origin: lysates (first generation immunostimulants), or bacterial extracts, like bacterial ribosomes, or membrane proteoglycans. This review highlights the current state of knowledge regarding the use of immunostimulants in adults with RRTIs, taking the ribosomal immunostimulant Ribomunyl((R)) as an example. Many studies are available on the mechanism of action and clinical efficacy in prevention of RRTIs in adults treated with Ribomunyl((R)). The effect of this immunostimulant on anti-infectious responses is explained by a stimulation of both nonspecific (innate) and specific (adaptive) immunity. In order to obtain a global overview of the therapeutic efficacy of Ribomunyl((R)) the most pertinent trials were selected from the literature based on adequate patient numbers and good methodology. Results of double-blind placebo-controlled trials using Ribomunyl((R)) for the treatment of different upper or lower RRTIs have demonstrated a statistically significant reduction in the number of infectious episodes and as a consequence, a decrease in antibacterial consumption, after 3 and 6 months of treatment. The tolerance profile of Ribomunyl((R)) was good in all studies. Economic evaluations suggest that savings can be made in healthcare expenditure, in patients with recurrent episodes of infection. It is concluded that Ribomunyl((R)) is effective in preventing and reducing upper and lower respiratory tract infections in adults. The product may also have an impact on reducing the development of bacterial resistance, as a result of fewer courses of antibacterials required to treat patients with RRTIs.     

Role of intestinal barrier in pathogenesis of pigment gallstone in a guinea pig model

BACKGROUND: The function of the intestinal barrier has drawn more and more attention from researchers in recent years for its important role in many diseases such as burns, wounds, and pancreatitis. In our experimental studies on pigment gallstone, we found potential relationships between the function of the intestinal barrier and pigment gallstone formation. This study was undertaken to investigate the possible action and mechanism of the function of the intestinal barrier in the pathogenesis of pigment gallstone. METHODS: Eighty guinea pigs were divided into a normal group (CON), a pigment gallstone group (PS) and an intestinal mucosa protection group (GLN). Normal forage, pigment gallstone-forming forage and pigment gallstoneforming forage with supplemental intestinal mucosa protector (glutamine) were given to each group. In the gallstone-forming rate, morphology of intestinal mucosa, intestinal permeability, serum endotoxin and biliaryβ-glucuronidase were assessed after 8 weeks. RESULTS: The rate of gallstone-formation was 73.9% in the PS group. Damage of intestinal mucosa, endotoxemia (from 77±43×106 EU/L to 1367±525×l06 EU/L, P<0.01) and increased activity of biliaryβ-glucuronidase (endogenousβ-glucuromdase from 122.1±39.5 to 209.8±47.5 Fishman Unit, P<0.01, and exogenous p-glucuronidase from 573.5±476.9 to 2206.6±983.9 Fishman Unit, P<0.01) were observed in the PS group compared with the CON group. The rate gallstone-formation decreased significantly to 44.4% and the other indices except P-glucuronidase were lower in the GLN group than in the PS group. CONCLUSIONS: The function of the intestinal barrier is correlated with pigment gallstone formation. Dysfunction of the intestinal barrier function may promote pigment gallstone formation through bacterial translocation, endotoxemia, and biliaryβ-glucuronidase.