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Healthy participants with SLCO1B1*1A/*1B or *1A/*1A genotype and SLCO1B1 *15/*1A or *5/*1A genotype had significantly higher AUC(0-∞) than participants with SLCO1B1*1B/*1B genotype, with the former showing an increase over the latter of 39.81 and 42.09%, respectively (P = 0.028, 0.032). The clearance in the former two genotype groups was significantly attenuated (by 27.39 and 28.55%, respectively) compared with individuals with SLCO1B1*1B/*1B genotype (P = 0.015, 0.019). No significant differences in blood glucose-lowering effect were observed among three genotype groups.
All elderly residents of the Umbria Region who received at least 2 prescriptions of antidiabetics in 2010 and 2011 were included in the study. Switching was defined as the dispensing of two different products of the same substance in a series of two prescriptions. Single and multiple switchers were identified according to the number of switches during 2011. Switching relevant to the three off-patent substances with generic use ≥ 5% (metformin, gliclazide and repaglinide) was quantified. The effect of switching on adherence, defined as the proportion of days in 2011 covered by prescriptions (Medication Possession Ratio, MPR), was estimated.
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The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032).
beta-Cell-type K(ATP) channels are octamers assembled from Kir6.2/KCNJ11 and SUR1/ABCC8. Adenine nucleotides play a major role in their regulation. Nucleotide binding to Kir6.2 inhibits channel activity, whereas ATP binding/hydrolysis on sulfonylurea receptor 1 (SUR1) opposes inhibition. Segments of the Kir6.2 N terminus are important for open-to-closed transitions, form part of the Kir ATP, sulfonylurea, and phosphoinositide binding sites, and interact with L0, an SUR cytoplasmic loop. Inputs from these elements link to the pore via the interfacial helix, which forms an elbow with the outer pore helix. Mutations that destabilize the interfacial helix increase channel activity, reduce sensitivity to inhibitory ATP and channel inhibitors, glibenclamide and repaglinide, and cause neonatal diabetes. We compared Kir6.x/SUR1 channels carrying the V59G substitution, a cause of the developmental delay, epilepsy, and neonatal diabetes syndrome, with a V59A substitution and the equivalent I60G mutation in the related Kir6.1 subunit from vascular smooth muscle. The substituted channels have increased P(O) values, decreased sensitivity to inhibitors, and impaired stimulation by phosphoinositides but retain sensitivity to Ba(2+)-block. The V59G and V59A channels are either not, or poorly, stimulated by phosphoinositides, respectively. Inhibition by sequestrating phosphatidylinositol 4,5-bisphosphate with neomycin and polylysine is reduced in V59A, and abolished in V59G channels. Stimulation by SUR1 is intact, and increasing the concentration of inhibitory ATP restores the sensitivity of Val-59-substituted channels to glibenclamide. The I60G channels, strongly dependent on SUR stimulation, remain sensitive to sulfonylureas. The results suggest the interfacial helix dynamically links inhibitory inputs from the Kir N terminus to the gate and that sulfonylureas stabilize an inhibitory configuration.
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The CORE Diabetes Model was used to simulate long-term outcomes for a cohort of individuals with type 2 diabetes treated with either repaglinide/metformin or nateglinide/metformin. HbA1c changes for each regimen were taken from a comparative study. At the end of the study, changes in HbA1c from baseline were -1.28% points and -0.67% points for repaglinide/metformin and nateglinide/metformin, respectively. Median final doses were 5.0 mg/day for repaglinide, 360 mg/day for nateglinide and 2000 mg/day metformin in each treatment arm. Costs were calculated as the annual costs for drugs plus costs of complications (US Medicare perspective) over a 30-year period. Life expectancy (LE) and quality-adjusted life expectancy (QALE) were calculated. Outcomes and costs were discounted at 3% annually.
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As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.
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The permeation of repaglinide across excised rat epidermis was 7-fold higher in the presence of AA-E (5% w/v) as compared to propylene glycol:ethanol (7:3) mixture. The extract was found to perturb the lipid microconstituents in both excised and viable rat skin, although, the effect was less intense in the later. The enhanced permeation of repaglinide across rat epidermis excised after treatment with AA-E (5% w/v) for different periods was in concordance with the high TEWL values of similarly treated viable rat skin. Further, the observed increase in intercellular space, disordering of lipid structure and corneocyte detachment indicated considerable effect on the ultrastructure of rat epidermis. Treatment of HaCaT cell line with AA-E (0.16% w/v) for 6 hrs influenced ZO-1 as evidenced by reduced immunofluorescence of anti-TJP1 (ZO-1) antibody in Confocal Laser Scanning Microscopy studies (CLSM) studies. The plasma concentration of repaglinide from transdermal formulation was maintained higher and for longer time as compared to oral administration of repaglinide.
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As an example, drug consumption (2001-2005) at the University Hospital Rijeka was expressed with the corresponding DDD in each year; and with the DDD value of the last year of the observation time window. By visual appraisal, results with both methods were compared with the graph of drug consumption trends expressed in physical units (mg, IU, etc.).
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Estimated repaglinide CLuptake corresponded to 217 and 113 μL/min/10(6) cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.
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The findings of our study indicate that RG may play an important role in protecting the kidney from oxidative insult.
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The searches identified 19 studies (28 references). Three studies (107 participants) are included: one comparing insulin with oral repaglinide and no medication (short-term single-center study of seven patients with cystic fibrosis-related diabetes and normal fasting glucose); one comparing insulin with oral repaglinide and placebo (long-term multi-center study with 81 patients, 61 of whom had cystic fibrosis-related diabetes); and one 12-week single-center study comparing the long-acting insulin, glargine to short-term neutral protamine Hagedorn insulin. The long-term trial of insulin and repaglinide demonstrated no significant difference between treatments. In the smaller study comparing insulin and oral repaglinide, there were two incidents of significant hypoglycemia in the insulin group compared to one in the repaglinide group; in the larger study there were five incidents of significant hypoglycemia in the insulin group and six in the repaglinide group. The study comparing glargine to neutral protamine Hagedorn insulin demonstrated a statistically non-significant weight increase in with longer-acting insulin given at bedtime and reported a mean of six hypoglycemia events in the glargine group compared to five events in the neutral protamine Hagedorn insulin group. None of the three included studies were powered to show a significant improvement in lung function.
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In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.
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Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues-glipizide, glyburide, glimepiride, repaglinide, and nateglinide-to cause serious hypoglycemia.
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Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype-genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.
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The aim of this study was to investigate the association of PAX4 variants with therapeutic effect of oral antidiabetic drugs in Chinese type 2 diabtes mellitus (T2DM) patients. A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks, and the therapeutic effects were compared. In the rosiglitazone cohort, rs6467136 GA+AA carriers showed greater decrease in 2-h glucose levels (P=0.0063) and higher cumulative attainment rates of target 2-h glucose levels (Plog rank=0.0093) than GG homozygotes. In the subgroup with defective β-cell function, rs6467136 GA+AA carriers exhibited greater decrements of 2-h glucose level and improvement of homeostasis model assessment of insulin resistance (P=0.0143). Moreover, GA+AA carriers were more likely to attain the target fasting and 2-h glucose level (Plog rank=0.0091 and 0.007, respectively). However, these single-nucleotide polymorphisms showed no effect on repaglinide efficacy. In conclusion, PAX4 variant rs6467136 was associated with the therapeutic effect of rosiglitazone in Chinese T2DM patients.
A high-throughput bioanalytical method using 96-blade thin film microextraction (TFME) and LC-MS/MS for the analysis of repaglinide (RPG) and two of its main metabolites was developed and used for an in vitro metabolism study.
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A total of 424 subjects (154 women, 270 men) participated and had the following characteristics: age, 61 +/- 9 years; duration of diabetes. 8 years (range 0.5-35); BMI, 28.3 +/- 3.5 kg/m2; HbA1c, 7.1 +/- 1.4%; and fasting plasma glucose, 10.8 +/- 3.1 mmol/l. The majority of the subjects (91%) were previously treated with sulfonylurea, alone or in combination with metformin. The patients were randomized to a 2:1 ratio of repaglinide (0.5-4 mg t.i.d.) or glyburide (1.75-10.5 mg daily) treatment. The study protocol included a screening visit to assess patient eligibility; a titration period of 6-8 weeks, during which the dosages of repaglinide and glyburide were optimized; and a subsequent 12-month treatment period on fixed, optimal dosages.
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In this article two new peroral antidiabetics are introduced. The first is repaglinide, a prandial glucose regulator. The second is rosiglitazone, a member of the thiazolidinediones family, which improves the sensitivity of tissues to insulin and reduces insulin resistance.
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Across age quartiles, eGFR declined progressively at a time-linear rate, with an acceleration in older adults, whereas albuminuria increased; age and eGFR were associated with cardiovascular events independently of other confounders. With increasing age, percentage of participants using lifestyle treatments for their T2DM and taking metformin or glitazones fell; percentage taking sulphonylureas and repaglinide rose, and percentage taking insulin remained stable. In eGFR categories 3 and 4, use of metformin was 41.4% and 14.5%, respectively, and that of sulphonylureas was 34.2% and 18.1%, respectively. Inappropriate prescription of these agents, especially sulphonylureas, increased with age. Metformin was independently associated with lower prevalence of cardiovascular disease for any age quartile and eGFR category than all other treatments.
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To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide's pharmacokinetics in healthy Malaysian subjects.
Sulfonylureas and glinides close beta cell ATP-sensitive K(+) (K(ATP)) channels to increase insulin release; the concomitant closure of cardiovascular K(ATP) channels, however, leads to complications in patients with cardiac ischaemia. The insulinotrope repaglinide is successful in therapy, but has been reported to inhibit the recombinant K(ATP) channels of beta cells, cardiocytes and non-vascular smooth muscle cells with similar potencies, suggesting that the (patho-)physiological role of the cardiovascular K(ATP) channels may be overstated. We therefore re-examined repaglinide's potency at and affinity for the recombinant pancreatic, myocardial and vascular K(ATP) channels in comparison with glibenclamide.
Adulteration of herbal antidiabetic products with undeclared pharmaceuticals is a significant yet under-recognized problem. Patients taking these illicit products could be at risk of potentially fatal adverse effects. It is important to educate the public to avoid taking pCMs of dubious source. Effective regulatory measures should be put in place to address the problem.
The aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population.
The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.
The NCS (neuronal calcium sensor) proteins, including neurocalcins, recoverins and visinin-like proteins are members of a family of Ca2+-sensitive regulators, each with three Ca2+-binding EF-hand motifs. In plants, lily CCaMK [chimaeric Ca2+/CaM (calmodulin)-dependent protein kinase] and its PpCaMK ( Physcomitrella patens CCaMK) homologue are characterized by a visinin-like domain with three EF-hands. In the present study, in an effort to discover NCS antagonists, we screened a total of 43 compounds using Ca2+-dependent drug affinity chromatography and found that the insulinotropic agent repaglinide targets the NCS protein family. Repaglinide was found to bind to NCS proteins, but not to CaM or S100 proteins, in a Ca2+-dependent manner. Furthermore, the drug antagonized the inhibitory action of recoverin in a rhodopsin kinase assay with IC50 values of 400 microM. Moreover, repaglinide tightly bound to the visinin-like domain of CCaMK and PpCaMK in a Ca2+-dependent manner and antagonized the regulatory function of the domain with IC50 values of 55 and 4 microM for CCaMK and PpCaMK respectively. Although both repaglinide and a potent insulin secretagogue, namely glibenclamide, blocked K(ATP) channels with similar potency, glibenclamide had no antagonizing effect on the Ca2+-stimulated CCaMK and PpCaMK autophosphorylation, mediated by their visinin-like domain. In addition, a typical CaM antagonist, trifluoperazine, had no effect on the CCaMK and PpCaMK autophosphorylation. Repaglinide appears to be the first antagonist of NCS proteins and visinin-like domain-bearing enzymes. It may serve as a useful tool for evaluating the physiological functions of the NCS protein family. In addition, since repaglinide selectively targets NCS proteins among the EF-hand Ca2+-binding proteins, it is a potential lead compound for the development of more potent NCS antagonists.
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Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide.
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In vitro data have recently suggested that sulfonylureas (SUs) enhance GH secretion by modulating the effects of GHRH and somatostatin in pituitary cells. The present study was undertaken to explore in more detail a possible influence of a single dose of SU (glibenclamide) and a non-SU (repaglinide) insulin secretagogue on circulating GH dynamics. Ten C-peptide-negative type 1 diabetic individuals were examined on three occasions in random order. Either glibenclamide (10.5 mg), repaglinide (8 mg), or placebo was administered after overnight normalization of plasma glucose by iv insulin infusion. Subsequently, GH concentrations were measured regularly after stimulation with GHRH (bolus 0.1 micro g/kg) alone and during concomitant infusion with somatostatin (7 ng.kg(-1).min(-1)). Insulin was replaced at baseline levels (0.25 mU.kg(-1).min(-1)) and plasma glucose clamped at 5-6 mmol/liter. Overall, there were no significant statistical differences in GH responses determined as either GH peak concentrations, integrated levels of GH, or secretory burst mass of GH during the experimental protocol. In contrast, plasma glucagon concentrations were significantly increased during glibenclamide and repaglinide exposure. The present experimental design does not support the hypothesis that acute administration of pharmacological doses of the oral antihyperglycemic agents glibenclamide and repaglinide per se enhance GH release in humans. Additionally, this study shows that these potassium channel inhibitors seem to stimulate glucagon secretion in people who have severe intraislet insulin deficiency (e.g. type 1 diabetes). However, extrapolation of our findings to type 2 diabetic individuals should be done with some caution.
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Fifty-two type 2 diabetic patients were included to this study. Twelve of patients were on diabetic diet only before and during Ramadan (Group 1). Forty of patients had had sulfonylurea (Glimepiride 23 patients, gliclazide 17 patients) before Ramadan. Thirteen of these patients were on a single dose sulfonylurea (Glimepiride 8 patients, gliclazide 5 patients) (Group 2) and 27 were on Repaglinide 2 x 2 mg (Group 3) during Ramadan. Beta-hydroxybutyric acid, glucose, fructosamine, HbA1c, lipid levels and body weight were measured before and after Ramadan.