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1.
Ir J Psychol Med ; 36(2): 145-151, 2019 06.
Article in English | MEDLINE | ID: mdl-31187724

ABSTRACT

AimTo investigate whether a small regional memory clinic would benefit from engaging with a structured external audit process such as the Royal College of Psychiatrists' Memory Service National Accreditation Program (MSNAP). BACKGROUND: The Psychiatry of Old Age service in Navan operates a public cognitive clinic. Despite the publication of the 2014 National Dementia Strategy, there are currently no national standards for memory clinics in Ireland. It may be beneficial to link in with an external quality control system as part of routine clinical governance. METHODS: Published data from the MSNAP group was reviewed and a set of audit materials extrapolated to replicate the MSNAP self-review process. The audit cycle involved (1) retrospective case review, (2) institution of a range of interventions and (3) a prospective audit, which included service user feedback. RESULTS: Overall the results demonstrated a high standard of service, especially in the areas of accessibility, assessment and communication of diagnosis. The clinic performed well against MSNAP key performance indicators. Patient and carer satisfaction with the service was very high. Clinic policies needed further development, particularly in the areas of referral, consent and data protection. CONCLUSIONS: The process was useful, providing clear pointers for action. It highlighted the need to formalise organisational and practice policies, patient support and education, audit and outreach. Although accreditation is a laborious process requiring financial investment, it provides a strong scaffold to maintain and improve standards and is likely to be a valuable learning experience, where national guidelines are lacking.


Subject(s)
Accreditation/standards , Ambulatory Care Facilities/standards , Memory Disorders/diagnosis , Quality Assurance, Health Care/standards , Dementia/diagnosis , Humans , Ireland , Medical Audit/standards , Prospective Studies , Retrospective Studies , United Kingdom
2.
Diabet Med ; 36(4): 505-513, 2019 04.
Article in English | MEDLINE | ID: mdl-30576013

ABSTRACT

AIM: To assess the long-term clinical benefits of early combination treatment with vildagliptin-metformin vs. standard-of-care, metformin monotherapy in the ongoing VERIFY study. METHODS: We randomized 2001 participants with multi-ethnic background, aged 18-70 years, having HbA1c levels 48-58 mmol/mol (6.5-7.5%) and BMI 22-40 kg/m2 . Baseline data included HbA1c , fasting plasma glucose and homeostasis model ß-cell and insulin sensitivity. Standardized meal-tests, insulin secretion rate relative to glucose, and oral glucose insulin sensitivity were assessed in a subpopulation. RESULTS: Out of 4524 screened, data were collected from the 2001 eligible participants (53% women) across Europe (52.4%), Latin America (26.8%), Asia (17.2%), South Africa (3.1%) and Australia (0.5%). The median (interquartile range) disease duration was 3.4 (0.9, 10.2) months; mean (±SD) age 54.3±9.4 years; weight 85.5±17.5 kg and BMI 31.1±4.7 kg/m2 . Baseline HbA1c was 52±3 mmol/mol (6.9±0.3%), fasting plasma glucose 7.5±1.5 mmol/l and the median (interquartile range) of fasting insulin was 109 (75-160) mU/l. Homeostasis model ß-cell and insulin sensitivity values were 84% (60, 116) and 46% (31, 68), respectively. In those undertaking meal-tests, insulin secretion rate relative to glucose was 28±12 pmol/min/m2 /mmol/l and oral glucose insulin sensitivity was 353±57 ml/min/m2 . CONCLUSIONS: Our current, multi-ethnic, newly diagnosed VERIFY population reflects a characteristic presence of early insulin resistance in participants with increased demand for insulin associated with obesity. The VERIFY study will provide unique evidence in characterizing therapeutic intervention in a diverse population with hyperglycaemia, focusing on durability of early glycaemic control.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Metformin/administration & dosage , Vildagliptin/administration & dosage , Adolescent , Adult , Aged , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Drug Therapy, Combination , Female , Glycated Hemoglobin/drug effects , Glycated Hemoglobin/metabolism , Humans , Insulin Resistance/physiology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/physiology , Male , Metformin/adverse effects , Middle Aged , Time Factors , Vildagliptin/adverse effects , Young Adult
3.
Diabet Med ; 31(10): 1178-84, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24863949

ABSTRACT

AIMS: Durability of good glycaemic control (HbA1c ) is of importance as it can be the foundation for delaying diabetic complications. It has been hypothesized that early initiation of treatment with the combination of oral anti-diabetes agents with complementary mechanisms of action can increase the durability of glycaemic control compared with metformin monotherapy followed by a stepwise addition of oral agents. Dipeptidyl peptidase-4 inhibitors are good candidates for early use as they are efficacious in combination with metformin, show weight neutrality and a low risk of hypoglycaemia. We aimed to test the hypothesis that early combined treatment of metformin and vildagliptin slows ß-cell deterioration as measured by HbA1c . METHODS: Approximately 2000 people with Type 2 diabetes mellitus who were drug-naive or who were treated with metformin for less than 1 month, and who have HbA1c of 48-58 mmol/mol (6.5-7.5%), will be randomized in a 1:1 ratio in VERIFY, a 5-year multinational, double-blind, parallel-group study designed to compare early initiation of a vildagliptin-metformin combination with standard-of-care initiation of metformin monotherapy, followed by the stepwise addition of vildagliptin when glycaemia deteriorates. Further deterioration will be treated with insulin. The primary analysis for treatment failure will be from a Cox proportional hazard regression model and the durability of glycaemic control will be evaluated by assessing treatment failure rate and the rate of loss in glycaemic control over time as co-primary endpoints. SUMMARY: VERIFY is the first study to investigate the long-term clinical benefits of early combination treatment vs. the standard-of-care metformin monotherapy with a second agent added by threshold criteria.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hyperglycemia/prevention & control , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Research Design , Adamantane/therapeutic use , Adolescent , Adult , Aged , Body Mass Index , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Double-Blind Method , Drug Therapy, Combination , Glycated Hemoglobin/analysis , Humans , Intention to Treat Analysis , Middle Aged , Obesity/complications , Overweight/complications , Vildagliptin , Young Adult
4.
Diabetes Obes Metab ; 16(9): 812-8, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24612221

ABSTRACT

AIMS: To determine the effects of dipeptidyl peptidase-4 (DPP-4) inhibition on glucagon dynamics in patients with insulin-treated type 2 diabetes (T2D). METHODS: The study was a single-centre, double-blind, randomized, placebo controlled crossover study in patients with T2D, mean age 59 ± 6 (s.d.) years and mean haemoglobin A1c 7.7 ± 0.8%, treated with exogenous insulin with or without oral antihyperglycaemic agents. Patients received vildagliptin (50 mg BID) or placebo as add-on to insulin for 4 weeks in random order with a 4-week washout in-between. On day 28 of the respective treatment, patients were served a standard meal (500 kcal) followed by a hyperinsulinaemic hypoglycaemic clamp (target 2.5 mmol/l) and a subsequent food re-challenge (700 kcal). The completers population (n = 29) was analysed. RESULTS: Glucose levels were lower with vildagliptin than with placebo during the meal [areas under the curve (AUC) 1.23 ± 0.07 vs. 1.46 ± 0.05 mol/l min, P < 0.001] and similar between the groups during the clamp. During the meal, glucagon levels were lower with vildagliptin (AUC 1.98 ± 0.15 vs. 2.15 ± 0.17 nmol/l min, P = 0.016). In contrast, the glucagon counter-regulation to the insulin-induced hypoglycaemia was sustained by vildagliptin (6.05 ± 1.20 pmol/l during vildagliptin vs.6.94 ± 1.09 pmol/l during placebo, NS). During the food re-challenge after hypoglycaemia, glucagon levels were, again, significantly lower after vildagliptin (AUC 1.30 ± 0.11 vs. 1.52 ± 0.12 nmol/l min, P < 0.039). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels were significantly elevated by vildagliptin compared to placebo during meal, hypoglycaemia and food re-challenge. CONCLUSIONS: Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge.


Subject(s)
Adamantane/analogs & derivatives , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Glucagon/metabolism , Hypoglycemia/chemically induced , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Meals , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Adamantane/therapeutic use , Area Under Curve , Blood Glucose/drug effects , Cross-Over Studies , Diabetes Mellitus, Type 2/blood , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Double-Blind Method , Drug Administration Schedule , Female , Glucagon/drug effects , Glucose Clamp Technique , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/blood , Insulin/metabolism , Insulin Secretion , Male , Middle Aged , Postprandial Period , Treatment Outcome , Vildagliptin
5.
Zoonoses Public Health ; 61(1): 64-71, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23425126

ABSTRACT

In July 2010, a horse from a rural farm (Farm A) in coastal Northern California was diagnosed with Salmonella Oranienburg infection following referral to a veterinary hospital for colic surgery. Environmental sampling to identify potential sources and persistence of Salmonella on the farm was conducted from August 2010 to March 2011. Salmonella was cultured using standard enrichment and selective plating. Pure colonies were confirmed by biochemical analysis, serotyped and compared by pulsed-field gel electrophoresis (PFGE) analysis. A total of 204 clinical and environmental samples at Farm A were analysed, and Salmonella spp. was isolated from six of eight (75%) horses, an asymptomatic pet dog, two of seven (28.6%) water samples from horse troughs, nine of 20 (45%) manure storage pile composites, 16 of 71 (22.5%) wild turkey faeces and four of 39 (10.3%) soil samples from the family's edible home garden. Well water and garden vegetable samples and horse faecal samples from a neighbouring ranch were negative. S. Oranienburg with a PFGE pattern indistinguishable from the horse clinical strain was found in all positive sample types on Farm A. The investigation illustrates the potential for widespread dissemination of Salmonella in a farm environment following equine infections. We speculate that a recent surge in the wild turkey population on the property could have introduced S. Oranienburg into the herd, although we cannot rule out the possibility wild turkeys were exposed on the farm or to other potential sources of Salmonella. Findings from the investigation indicated that raw horse manure applied as fertilizer was the most likely source of garden soil contamination. Viable S. Oranienburg persisted in garden soil for an estimated 210 days, which exceeds the 120-day standard between application and harvest currently required by the National Organic Program. The study underscores the need to educate the public about potential food safety hazards associated with using raw animal manure to fertilize edible home gardens.


Subject(s)
Dog Diseases/microbiology , Horse Diseases/microbiology , Poultry Diseases/microbiology , Salmonella Infections, Animal/microbiology , Salmonella/isolation & purification , Turkeys , Animal Husbandry , Animals , Animals, Wild , California/epidemiology , Dog Diseases/epidemiology , Dogs , Environmental Monitoring , Feces/microbiology , Female , Genetic Variation , Horse Diseases/epidemiology , Horses , Manure/microbiology , Organic Agriculture , Poultry Diseases/epidemiology , Rural Population , Salmonella/genetics , Salmonella Infections, Animal/epidemiology , Soil Microbiology , Turkeys/microbiology
6.
Diabetologia ; 56(8): 1752-60, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23636640

ABSTRACT

AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.


Subject(s)
Adamantane/analogs & derivatives , Diet, High-Fat/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/physiology , Nitriles/therapeutic use , Obesity/drug therapy , Obesity/etiology , Pyrrolidines/therapeutic use , Adamantane/therapeutic use , Animals , Diabetes Mellitus, Type 2/drug therapy , Female , Immunohistochemistry , Mice , Mice, Inbred C57BL , Obesity/metabolism , Vildagliptin
7.
Diabetes Obes Metab ; 15(1): 72-6, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22882290

ABSTRACT

AIM: The present report summarizes rodent studies with vildagliptin, relevant to predicting pancreatitis or pancreatic cancer in man. METHODS: As part of the regulatory development program for vildagliptin, a rodent toxicity program included two 104-week rodent (mouse and rat) carcinogenicity studies that were conducted according to guidelines assigned in Food and Drug Administration's Draft Guidance for Industry. RESULTS: Vildagliptin exposure in animals was evaluated for its effects on endocrine and exocrine pancreas. Two-year carcinogenicity studies were conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose) and in mice at oral doses up to 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). The results from these studies show the expected preservation and growth of the endocrine ß-cells with no significant findings in the exocrine acinar pancreas. There was no evidence of inflammatory infiltrates characteristic of pancreatitis, no palpable mass detection based on gross examination or any microscopic findings indicative of pancreatic islet cell (endocrine), acinar cell (exocrine) or ductal (exocrine) neoplasia in rat or mouse. CONCLUSIONS: Evaluation of vildagliptin in 2-year preclinical carcinogenicity studies in both rats and mice indicates that while vildagliptin results in pharmacological benefits to the endocrine pancreas, this was not associated with any evidence of pancreatitis, pancreatic islet cell, acinar cell or ductal neoplasia. These data predict no increased risk of pancreatic cancer in man.


Subject(s)
Adamantane/analogs & derivatives , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Islets of Langerhans/drug effects , Nitriles/adverse effects , Pancreas, Exocrine/drug effects , Pancreatic Neoplasms/chemically induced , Pancreatitis/chemically induced , Pyrrolidines/adverse effects , Adamantane/adverse effects , Animals , Female , Humans , Islets of Langerhans/pathology , Male , Mice , Mice, Transgenic , Pancreas, Exocrine/pathology , Pancreatic Neoplasms/pathology , Pancreatitis/pathology , Predictive Value of Tests , Rats , Rats, Transgenic , Rats, Wistar , Vildagliptin
8.
Vet Parasitol ; 183(3-4): 364-8, 2012 Feb 10.
Article in English | MEDLINE | ID: mdl-21846583

ABSTRACT

This study was carried out to compare different diagnostic techniques to reveal the presence of piroplasms in asymptomatic cattle kept at pasture. Nineteen blood samples were collected from animals of two different areas of Emilia Romagna Region of Italy and processed for microscopic observation, PCR, serological test (IFAT) for Babesia bovis and Babesia bigemina antibodies and in vitro cultivation. The cultures were performed on both bovine and ovine erythrocytes. Seventeen blood smears (89%) were positive for piroplasms, while PCR was positive on 18 samples (95%). DNA sequencing of 18S rRNA identified the piroplasms as Theileria spp. In vitro cultures were successful for 6 samples (32%) cultured on bovine blood and subsequent identified these as Babesia major by PCR. On IFAT analyses of 16 samples, 36.8% resulted positive for B. bovis and 31.6% positive for B. bigemina. These results show, in the same animals, the co-infection with Babesia spp. and Theileria spp.; the detection of B. major was possible only using the in vitro cultures.


Subject(s)
Babesia/isolation & purification , Babesiosis/veterinary , Cattle Diseases/diagnosis , Coinfection/veterinary , Theileria/isolation & purification , Theileriasis/diagnosis , Animals , Asymptomatic Infections , Babesia/classification , Babesia/genetics , Babesiosis/diagnosis , Babesiosis/epidemiology , Cattle , Cattle Diseases/epidemiology , Cattle Diseases/parasitology , Coinfection/diagnosis , Coinfection/epidemiology , Coinfection/parasitology , DNA, Protozoan/blood , Female , Fluorescent Antibody Technique/veterinary , Italy/epidemiology , Male , Microscopy/veterinary , Molecular Sequence Data , Parasitology/methods , Polymerase Chain Reaction/veterinary , Prevalence , RNA, Protozoan/analysis , RNA, Ribosomal, 18S/analysis , Sensitivity and Specificity , Sequence Analysis, DNA , Sheep , Theileria/classification , Theileria/genetics , Theileriasis/epidemiology
9.
Diabetologia ; 54(8): 1985-91, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21547496

ABSTRACT

AIMS/HYPOTHESIS: Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52 week treatment period with vildagliptin or placebo, and again after a 12 week washout period. METHODS: This study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100 mg (n = 29) or placebo (n = 30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients ≥30 years, with HbA(1c) ≤7.5% and BMI of 22-45 kg/m(2). The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week 0, week 52 and after a 12 week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat). RESULTS: Fifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIR(arg)), by 5.0 ± 1.8 nmol/l × min, while it decreased by 0.8 ± 1.8 nmol/l × min with placebo (n = 25) (between-group difference p = 0.030). No significant between-group difference in AIR(arg) was seen after the 12 week washout period. The between-group difference adjusted mean 52 week changes from baseline was -0.19 ± 0.11, p = 0.098 and -0.22 ± 0.23%, p = 0.343 for HbA(1c) and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events. CONCLUSIONS/INTERPRETATION: One year treatment with vildagliptin significantly increased beta cell secretory capacity. This effect was not maintained after the washout, indicating that this increased capacity was not a disease modifying effect on beta cell mass and/or function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00260156.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Hyperglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin-Secreting Cells/drug effects , Nitriles/pharmacology , Nitriles/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Adamantane/pharmacology , Adamantane/therapeutic use , Aged , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Double-Blind Method , Fasting/blood , Female , Glycated Hemoglobin/metabolism , Humans , Hyperglycemia/blood , Hyperglycemia/metabolism , Male , Middle Aged , Treatment Outcome , Vildagliptin
10.
Diabetes Obes Metab ; 13(9): 775-83, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21507182

ABSTRACT

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/drug effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Glucagon-Like Peptide 1/drug effects , Nitriles/pharmacology , Pyrrolidines/pharmacology , Adamantane/pharmacology , Adamantane/therapeutic use , Diabetes Mellitus, Type 2/physiopathology , Dipeptidyl Peptidase 4/physiology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide 1/physiology , Humans , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Vildagliptin
11.
Diabetes Obes Metab ; 13(3): 193-203, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21205107

ABSTRACT

Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c ∼- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c ∼- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and ß-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Nitriles/administration & dosage , Pyrrolidines/administration & dosage , Adamantane/administration & dosage , Adamantane/pharmacokinetics , Drug Administration Schedule , Drug Therapy, Combination , Evidence-Based Medicine , Humans , Hypoglycemic Agents/pharmacokinetics , Metformin/pharmacokinetics , Nitriles/pharmacokinetics , Pyrrolidines/pharmacokinetics , Treatment Outcome , Vildagliptin
12.
Diabetes Obes Metab ; 13(1): 55-64, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21114604

ABSTRACT

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).


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/analysis , Hypoglycemia/drug therapy , Hypoglycemic Agents/therapeutic use , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Adamantane/therapeutic use , Aged , Aged, 80 and over , Clinical Trials as Topic , Diabetes Mellitus, Type 2/complications , Dipeptidyl-Peptidase IV Inhibitors , Female , Humans , Hypoglycemia/prevention & control , Male , Polypharmacy , Treatment Outcome , Vildagliptin
13.
Diabetes Obes Metab ; 12(9): 780-9, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20649630

ABSTRACT

AIM: To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. METHODS: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. RESULTS: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline > or =0.5% or HbA1c < or =6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. CONCLUSIONS: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.


Subject(s)
Adamantane/analogs & derivatives , Body Weight/drug effects , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Nitriles/administration & dosage , Pyrrolidines/administration & dosage , Sulfonylurea Compounds/administration & dosage , Adamantane/administration & dosage , Adolescent , Adult , Aged , Diabetes Mellitus, Type 2/blood , Double-Blind Method , Drug Therapy, Combination/methods , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/chemically induced , Male , Middle Aged , Treatment Outcome , Vildagliptin , Weight Gain , Young Adult
14.
Diabetes Obes Metab ; 12(6): 485-94, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20518804

ABSTRACT

AIM: To assess the cardiovascular and cerebrovascular (CCV) safety of the dipeptidyl peptidase-IV inhibitor vildagliptin. METHODS: Data were pooled from 25 Phase III studies of vildagliptin, used either as monotherapy or combination therapy, with durations of 12 weeks to > or = 2 years. The safety of vildagliptin [50 mg qd (N = 1393) or 50 mg bid (N = 6116)] was assessed relative to a pool of all comparators [both placebo and active comparators (N = 6061)]. CCV events were adjudicated in a prospective, blinded fashion by an independent CCV adjudication committee. Meta-analysis of confirmed CCV events was performed with Mantel-Haenszel risk ratios (RRs); categories included in the composite endpoint were acute coronary syndrome, transient ischaemic attack (with imaging evidence of infarction), stroke and CCV death. Subgroup analyses by age (< and > or = 65 years), gender and cardiovascular (CV) risk status [high CV risk status defined as a previous history of events in the Standard MedDRA Queries of ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events, arterial) were also carried out. In addition, unadjusted and exposure-adjusted incidences are presented for both the composite endpoint and its components. RESULTS: Relative to all comparators, the RRs for the composite endpoint were < 1 for both vildagliptin 50 mg qd [RR = 0.88; 95% CI (0.37, 2.11)] and vildagliptin 50 mg bid [RR = 0.84; 95% CI (0.62, 1.14)]. The results were consistent across subgroups defined by age, gender and CV risk status, including the higher CV risk subgroups of elderly patients [RR for vildagliptin 50 mg bid vs. all comparators = 1.04; 95% CI (0.62, 1.73)], males [RR = 0.87; 95% CI (0.60, 1.24)] or patients with a high CV risk status [RR = 0.78; 95% CI (0.51, 1.19)]. The exposure-adjusted incidences of each component of the composite endpoint for vildagliptin 50 mg bid were also lower than or similar to those of all comparators. CONCLUSIONS: In a large meta-analysis, vildagliptin was not associated with an increased risk of adjudicated CCV events relative to all comparators in the broad population of type 2 diabetes including patients at increased risk of CCV events.


Subject(s)
Adamantane/analogs & derivatives , Cerebrovascular Disorders/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/chemically induced , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Nitriles/adverse effects , Pyrrolidines/adverse effects , Adamantane/administration & dosage , Adamantane/adverse effects , Cerebrovascular Disorders/drug therapy , Clinical Trials, Phase III as Topic , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Female , Humans , Male , Middle Aged , Nitriles/administration & dosage , Pyrrolidines/administration & dosage , Randomized Controlled Trials as Topic , Vildagliptin
15.
Diabetes Obes Metab ; 12(6): 495-509, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20518805

ABSTRACT

AIM: To assess the safety of vildagliptin versus all comparators (ACs) with regard to organs, systems or tissues of particular interest in type 2 diabetes (T2DM) and areas of potential concern with dipeptidyl peptidase-IV (DPP-4) inhibitors. METHODS: Data were pooled from 38 studies where vildagliptin was given for > or =12 to > 104 weeks in patients with T2DM. Absolute and exposure-adjusted incidence rates and Peto odds ratios (ORs) versus ACs with corresponding 95% confidence intervals (CI) were calculated. RESULTS: There were > 7000 subject-years of exposure (SYE) to vildagliptin 50 mg bid and > 6500 SYE to ACs. For mild hepatic enzyme elevations with and without elevated bilirubin levels, the ORs for vildagliptin 50 mg bid were 1.24 (95% CI: [0.80, 1.93]) and 1.19 (95% CI: [0.29, 4.90]), respectively. The exposure-adjusted incidences of markedly elevated hepatic enzymes and for enzyme elevations with bilirubin > or = 2x ULN with vildagliptin 50 mg bid were < or = those in the ACs group. For hepatic and pancreatitis-related AEs, the ORs for vildagliptin 50 mg bid were 0.87 (95% CI: [0.64, 1.19]) and 0.70 (95% CI: [0.26, 1.88]), respectively, and for any AE in the infections and infestations SOC, this was 1.04 (95% CI: [0.96, 1.13]). The incidences of skin-related AEs were low and the risk with vildagliptin 50 mg bid was not significantly different from ACs [(OR = 1.10 (95% CI: [0.80, 1.51])]. CONCLUSIONS: The present meta-analyses indicate that vildagliptin was not associated with increased risk of hepatic events or hepatic enzyme elevations indicative of drug-induced liver injury, pancreatitis, infections or skin-related toxicity.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Diabetic Nephropathies/complications , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Hypoglycemic Agents/adverse effects , Immune System/drug effects , Liver/drug effects , Nitriles/adverse effects , Pancreas/drug effects , Pyrrolidines/adverse effects , Skin/drug effects , Adamantane/adverse effects , Aged , Clinical Trials as Topic , Confidence Intervals , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Female , Humans , Hypoglycemic Agents/administration & dosage , Liver/metabolism , Male , Pancreas/metabolism , Risk Factors , Vildagliptin
16.
J Vet Intern Med ; 24(3): 504-13, 2010.
Article in English | MEDLINE | ID: mdl-20337917

ABSTRACT

BACKGROUND: Salmon poisoning disease (SPD) is a trematode-borne disease of dogs caused by Neorickettsia helminthoeca. OBJECTIVES: To determine risk factors and spatial epidemiology of SPD in dogs from northern California; to describe the clinicopathologic, microbiologic, and imaging findings of SPD in these dogs; and to evaluate treatments and outcomes for SPD. ANIMALS: Twenty-nine dogs with SPD based on the finding of trematode ova in the feces, or organisms consistent with N. helminthoeca in specimens submitted for microscopic examination. METHODS: Information regarding signalment, fish exposure, clinical signs, diagnostic evaluation, treatments, and outcomes was obtained for each dog. Archived lymph node aspirates and histopathology specimens were subjected to polymerase chain reaction (PCR) testing for Neorickettsia spp. RESULTS: Labrador Retrievers and intact male dogs were overrepresented. Exposure locations were often distant from the dogs' residence. Some dogs had neurologic signs, including twitching and seizures. Dogs lacking peripheral lymphadenomegaly had abdominal lymphadenomegaly on ultrasound examination. A combination of centrifugation fecal flotation and sedimentation had greatest sensitivity for finding fluke ova. N. helminthoeca DNA was amplified by PCR from 4/10 dogs. Penicillins, cephalosporins, and chloramphenicol did not appear to be effective treatments. Mortality rate was 4/29 (14%). CONCLUSIONS AND CLINICAL IMPORTANCE: SPD should be suspected in dogs with inappetence, gastrointestinal, or neurologic signs, with or without fever or peripheral lymphadenomegaly in the appropriate geographical setting. Diagnosis is facilitated by a combination of fecal sedimentation and centrifugal flotation, abdominal ultrasonography, and PCR-based assays on lymphoid tissue. The treatment of choice is tetracycline antimicrobials.


Subject(s)
Animal Feed , Dog Diseases/parasitology , Food Parasitology , Foodborne Diseases/veterinary , Rickettsia Infections/veterinary , Salmon , Animals , Anthelmintics/therapeutic use , Anti-Bacterial Agents/therapeutic use , California , Dog Diseases/drug therapy , Dog Diseases/epidemiology , Dogs , Female , Male , Rickettsia Infections/drug therapy , Rickettsia Infections/epidemiology , Treatment Outcome , Trematoda/microbiology , Trematode Infections/drug therapy , Trematode Infections/parasitology , Trematode Infections/veterinary
17.
J Vet Intern Med ; 23(6): 1129-41, 2009.
Article in English | MEDLINE | ID: mdl-19761477

ABSTRACT

Anaplasma phagocytophilum is an emerging pathogen of humans, horses, and dogs worldwide that is transmitted by Ixodid ticks and maintained in a variety of small wild mammal species. Recent studies suggest that multiple strains of A. phagocytophilum may be circulating in wild and domestic animal populations, and these strains may have differential host tropisms and pathogenicity. The organism infects and survives within neutrophils by disabling key neutrophil functions, including neutrophil motility, phagocytosis, the oxidative burst mechanism, and neutrophil-endothelial cell interactions, as well as interfering with neutrophil apoptosis. Coinfections with other tick-borne pathogens may occur, especially Borrelia burgdorferi. A. phagocytophilum causes an acute febrile illness in dogs with lethargy and inappetence. Less frequent signs include lameness, coughing, polydipsia, intermittent vomiting, and hemorrhages. Diagnosis is based on finding morulae within granulocytes in the peripheral blood, the combination of acute and convalescent serology using immunofluorescent antibody techniques, and detection of the DNA of A. phagocytophilum using specific polymerase chain reaction assays. Whether persistent infection or reinfection with A. phagocytophilum occurs after natural infection requires additional study, with most reports suggesting that anaplasmosis is a self-limiting disease in dogs that responds well to a 2-week course of doxycycline therapy.


Subject(s)
Anaplasmosis/microbiology , Dog Diseases/microbiology , Anaplasma/classification , Anaplasma/genetics , Anaplasma/isolation & purification , Animals , Dogs , Phylogeny
18.
Horm Metab Res ; 41(12): 905-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19705345

ABSTRACT

This report is part of the overall evaluation of using vildagliptin in the treatment of type 2 diabetes. Here the results of a multi-center, double-blind, randomized, active-controlled study designed to compare the efficacy and safety of two years of monotherapy with vildagliptin 50 mg bid and gliclazide up to 320 mg/day in drug-naïve patients with type 2 diabetes are reported. A total of 546 patients were randomized and approximately 74% of patients completed the study in each group. HbA (1c) values were slightly higher in the gliclazide group (HbA (1c) of 8.7+/-0.1% vs. 8.5+/-0.1% in the vildagliptin group). The mean reduction in HbA (1c) from baseline to Week 104 was -0.5% in the vildagliptin group and -0.6% in the gliclazide group. The associated 95% confidence interval (CI) for the between-group difference (0.13%) in mean change was (-0.06%, 0.33%). Thus, noninferiority based on an upper limit of the CI of 0.3% was not met. In the vildagliptin group, weight increased by 0.8+/-0.2 kg compared to 1.6+/-0.2 kg in the gliclazide group (p<0.01). Mild hypoglycemia was recorded in 0.7% of patients in the vildagliptin group and in 1.7% in the gliclazide group. Both drugs were well tolerated. In summary, vildagliptin monotherapy resulted in improved glycemic control in drug-naïve patients with type 2 diabetes. Although the hypothesis of noninferiority to gliclazide was not borne out statistically, the reductions in HbA (1c) were similar over a two year period and vildagliptin had significant benefits in terms of less weight gain and less hypoglycemia.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Gliclazide/adverse effects , Gliclazide/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Pyrrolidines/adverse effects , Pyrrolidines/therapeutic use , Adamantane/adverse effects , Adamantane/therapeutic use , Demography , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Time Factors , Treatment Outcome , Vildagliptin
19.
J Vet Intern Med ; 23(3): 623-5, 2009.
Article in English | MEDLINE | ID: mdl-19645844

ABSTRACT

BACKGROUND: Equine sarcoidosis is a rare, multisystemic, noncaseating, granulomatous and lymphoplasmacytic disease of unknown etiology. A recent report described a horse with granulomatous skin disease displaying histologic, electron microscopic, and polymerase chain reaction (PCR) findings consistent with equine herpesvirus 2 (EHV-2). OBJECTIVE: To investigate the presence of EHV-2 and equine herpesvirus 1 (EHV-1) in 8 horses with sarcoidosis. ANIMALS: Eight horses with sarcoidosis, reported previously. METHODS: Retrospective study. PCR assays of the tissues were performed to detect DNA associated with EHV-1 and EHV-2. For both herpesviruses the target was their respective glycoprotein B gene. Positive controls consisted of DNA from viral cultures of culturettes from naturally occurring respiratory infections of EHV-1 and EHV-2. RESULTS: The PCR analyses for both equine herpesviruses' DNA were negative in all 8 horses. CONCLUSION: The failure to detect DNA from EHV-1 and EHV-2 in paraffin-embedded skin of these 8 horses does not discount EHV-1 or EHV-2 as causing some cases of ES, but lends support to the presumably multifactorial etiologic nature of the disease.


Subject(s)
Herpesvirus 1, Equid/isolation & purification , Horse Diseases/virology , Rhadinovirus/isolation & purification , Sarcoidosis/veterinary , Animals , Base Sequence , Horses , Paraffin Embedding , Polymerase Chain Reaction/veterinary , Sarcoidosis/virology , Specimen Handling/veterinary
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