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Administration of repaglinide resulted in a significant reduction of plasma glucose at 2 hours (172.8+/-48.4 vs. 138.3+/-41.2 mg/dl; p < 0.001). The flow-mediated dilatation (FMD) 2 hours after the glucose-load was significantly reduced in comparison to fasting in the control group (6.21+/-2.69 vs. 7.98+/-2.24 %; p = 0.028), whereas after theadministration of repaglinide the FMD was not significantly different to fasting values (7.24+/-2.57 vs. 8.18+/-2.93 %; p = n.s.). Linear and logistic regression analysis revealed that only the change of glucose was significantly correlated to the change of FMD observed (p < 0.001). Regression analysis after grouping for treatment and time confirmed the strong negative association of the changes of plasma glucose and FMD and indicate that the effect of repaglinide observed is based on the reduction glycemia.
These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.
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Glycaemic normalisation improved skin microcirculation but not endothelial function in patients with type 2 diabetes with mild cardiovascular engagement.
For rat model studies, in the tacrolimus group, fasting blood glucose (FBG) levels were increased after three months (p < 0.01). After five months, the insulin secretion index and the sensitivity index in the tacrolimus group was significantly lower than in the control group (p < 0.01). For studies of post-transplant diabetes mellitus (PTDM), eighty-six liver transplant recipients were enrolled. 51 were given repaglinide and 35 were given repaglinide combined with glargine. After treatment for 1, 6, and 12 months, FBG, post-prandial blood glucose (PPBG), and HbA1c levels decreased (p < 0.05) in both groups, and no statistically significant changes were observed in the liver and kidney function indicators (p > 0.05). No severe hypoglycemia episodes were reported.
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Ritonavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450 3A4. To treat diabetes mellitus in HIV, repaglinide is coadministered with ritonavir in the clinic. Multiple cytochrome P450 (CYP) isoforms are involved in the metabolism of repaglinide like CYP2C8 and CYP 3A4. In order to predict and understand drug-drug interactions of these two drugs, the pharmacokinetics and pharmacodynamics (PK/PD) of repaglinide and ritonavir were studied in normal, diabetic and hepatic impaired rats. The purpose of the study was to assess the influence of ritonavir on the PK/PD of repaglinide in rats with normal, diabetic and impaired hepatic function.
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Diabetes and its treatment can cause problems for the Muslim population. The aim of this study was to evaluate the effect of different therapy models on clinical and metabolic status in type 2 diabetic patients during Ramadan.
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Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.
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To establish a tacrolimus-induced diabetes rat model and assess efficacy and safety of insulin glargine combined with repaglinide in Chinese patients with diabetes after liver transplantation.
The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single-center, open-label, randomized, three-period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24-hour intervals. Pharmacokinetic profiles, including area under the curve (AUC0-t), maximum serum concentration (Cmax), time to Cmax (tmax), and half-life (t1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC1h) and area under the blood glucose curve (AUGC0-1) at 1 hour after dose were also measured. After oral dosing, both Cmax and AUC0-t increased linearly with dose within the 0.5- to 2.0-mg dose range, regardless of ethnic group. Both Cmax and AUC0-t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, Cmax and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between-group differences in Cmax or AUC0-t. Statistically significant differences in pharmacodynamic parameters (RC1h and AUGC0-1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC1h than AUGC0-1. At a dose of 2.0 mg, the mean decrease in RC1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5- to 2.0-mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5-4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients.
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Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs.
To systematically review available data from the literature regarding the efficacy of oral antidiabetic agents, both as monotherapy and in combination.
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This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.
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Effective and safe clopidogrel combination therapy can be achieved by increasing the awareness of potential changes in efficacy and toxicity, rationally selecting alternatives, tailoring drug therapy based on genotype, checking the appropriateness of physician orders, and performing therapeutic monitoring.
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The purpose of this work was to develop prolonged release binary lipid matrix-based solid lipid nanoparticles (SLN) of repaglinide (RG) for oral intestinal delivery and to improve the bioavailability of RG. SLN were designed by using glycerol monostearate and tristearin as lipid core materials and Pluronic-F68 as stabilizer. SLN were characterised by their particle size, zeta potential, entrapment efficiency, solid-state studies, in vitro drug release, particle surface and storage stability at 30 °C/65% relative humidity for 3 months. Pharmacodynamic (PD) and pharmacokinetic (PK) studies were also performed in diabetes-induced rat. Moreover, an in vitro toxicity study was performed in rat macrophage cells to establish the safety of the prepared SLN. It was observed that binary lipid matrix-based SLN had better drug entrapment, desired release characteristics, spherical shape and maximum storage stability. Pharmacodynamic study indicated that RG delivered through binary SLN significantly reduces blood glucose, blood cholesterol and blood triglycerides level. The area under the curves after oral administration of optimised RG-SLN formulation and RG control were 113.36 ± 3.01 and 08.08 ± 1.98 h/(ng · mL), respectively. The relative bioavailability of RG was enhanced with optimised SLN formulation when compared with RG control. There was a direct correlation found between the plasma drug level (drug concentration) and the peak response (% blood glucose inhibition) in optimised RG-SLN batch. The in vitro toxicity study indicated that the SLN were well tolerated.
Fasting plasma glucose (FPG), glycosylated hemoglobin (HbA(1c)) and fructosamine (FA) were improved in all groups similarly (p>0.05). Rg group was with the highest early-phase insulin secretion index (DeltaI30/DeltaG30) (p=0.026), lower mean amplitude of glycaemic excursion (MAGE) (p<0.05), lowest mean peak value of post-lunch glucose (p=0.043), and lowest postprandial triglyceride (TG) (p=0.039). Postprandial free fatty acid (FFA) was lower after Rg and Gli treatment (p<0.05). Serum 8-iso prostaglandin F(2alpha) (8-iso PGF(2alpha)) was improved in all groups, but the improvement showed statistically significant only in Rg group (p=0.04).
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Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.
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This study investigated plasma protein binding by the novel oral hypoglycemic agent, repaglinide, and assessed the influence of other protein-bound drugs upon this process. Varying concentrations of [3H]-repaglinide (0.01 to 100 micrograms/ml) were incubated in solutions of plasma proteins (human serum albumin, HSA; alpha 1-acid glycoprotein, AAGP), or human plasma in the absence or presence of several test drugs. Protein binding was assessed using an ultrafiltration technique. At all concentrations tested, the mean binding of repaglinide in plasma was 98.5%, binding to HSA averaged 98.6%, and the binding to AAGP was saturable and remained below 50%. Warfarin 10 micrograms/ml, furosemide 0.2 microgram/ml, and tolbutamide 100 micrograms/ml, significantly reduced in vitro binding of repaglinide at 1 and 100 micrograms/ml versus control (p < 0.05), producing an 18-36% increase in free repaglinide. No reduction was found using 0.1 microgram/ml repaglinide. Diazepam, glibenclamide and nicardipine hydrochloride had no significant effects on the in vitro protein binding of repaglinide. These data suggest that the binding of repaglinide to HSA in human plasma has potential clinical significance, and that within the therapeutic range for repaglinide, the presence of the test drugs has no clinically relevant effects on repaglinide binding to plasma proteins.
In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy).
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To explore the determinants of hepatic uptake, 16 compounds were investigated with different physicochemical and disposition characteristics, including five statins, three sartans, saquinavir, ritonavir, erythromycin, clarithromycin, nateglinide, repaglinide, fexofenadine, and bosentan. Freshly isolated rat hepatocytes in suspension were used with the oil-spin method to generate kinetic parameters. Clearances, via passive diffusion (P(diff)) and active uptake (CL(active), characterized by maximal uptake rate and K(m)), were estimated from the initial uptake rate data over a 0.01 to 100 μM concentration range. The K(m) values had a range of 15-fold, with 10 of the 16 drugs with K(m) < 10 μM (median 6 μM). Both CL(active) and P(diff) ranged over 100-fold (median 188 and 14 μl/min/10⁶ cells). Assessment of the relative contribution of P(diff) and CL(active) indicated that, at low concentrations (approximately 0.1 μM), the active process contributes >80% to the overall uptake for 13 drugs. Although high P(diff) values were obtained for ritonavir and repaglinide, active process contributed predominantly to uptake; in contrast, high passive permeability dominates over transporter-mediated uptake for saquinavir over the full concentration range. For bosentan and erythromycin, active and passive processes were equally important. Hepatocyte-to-medium unbound concentration ratio was >10 for 9 of the 16 drugs, ranging from 2 to 494 for bosentan and atorvastatin, respectively. Some drugs showed extensive intracellular binding (fraction unbound range 0.01-0.6), which was not correlated with active uptake. LogD₇.₄ correlated significantly with P(diff) and the extent of intracellular binding but not with active uptake. This study provides systematic assessment of the role of active uptake relative to the passive process; implications of the findings are discussed.
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The study comprised three screening visits, followed by a 7-day inpatient period. Thirty-four patients, with normal renal function (n = 12), mild-to-moderate renal dysfunction (n = 12) or severe renal dysfunction (n = 10), received a single 2-mg dose of repaglinide on day 1, followed by preprandial 2-mg doses with main meals (breakfast, lunch and dinner) on each of days 2-4. A final 2-mg dose of repaglinide was administered on day 5.
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Hyperglycemia is a modifiable risk factor that has a deleterious effect on the development and progression of microvascular and macrovascular complications in patients with type 2 diabetes. The UK Prospective Diabetes Study revealed how reductions in hemoglobin A1c (HbA1c) correlate with a significant reduction in all-cause mortality and the incidence of myocardial infarction. The Diabetes Intervention Study showed that poor control of fasting glycemia does not increase the risk of myocardial infarction or mortality, whereas poor control of post-prandial glucose is associated with a high all-cause mortality rate. HbA1c is the standard measure for metabolic control and therapeutic efficacy, but does not reflect fluctuations in glycemic control. Plasma glucose concentrations in healthy subjects remain within a narrow range, which suggests that the fluctuations in glucose levels caused by inappropriate treatment may have negative consequences. These fluctuations have been associated with acute adverse effects (particularly excessive post-prandial hyperglycemia, pre-meal hypoglycemia and weight gain) that counteract the positive effect of lowering fasting plasma glucose and HbA1c. Post-prandial hyperglycemia and spikes also have deleterious effects on insulin secretion and sensitivity. Prandial oral antidiabetic agents such as alpha-glucosidase inhibitors (acarbose, miglitol) and rapidly acting insulin secretagogues (nateglinide, repaglinide) have recently been introduced to improve the control of post-prandial hyperglycemia.
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English-language journals, abstracts, review articles, and newspaper accounts.
Several new pharmacological agents have recently been developed to optimise the management of type 2 (non-insulin-dependent) diabetes mellitus. The aim of this article is to briefly review the various therapeutic agents available for management of patients with type 2 diabetes mellitus and to suggest a potential approach to drug selection. There are three general therapeutic modalities relevant to diabetes care. The first modality is lifestyle adjustments aimed at improving endogenous insulin sensitivity or insulin effect. This can be achieved by increased physical activity and bodyweight reduction with diet and behavioural modification, and the use of pharmacological agents or surgery. This first modality is not discussed in depth in this article. The second modality involves increasing insulin availability by the administration of exogenous insulin, insulin analogues, sulphonylureas and the new insulin secretagogue, repaglinide. The most frequently encountered adverse effect of these agents is hypoglycaemia. Bodyweight gain can also be a concern, especially in patients who are obese. The association between hyperinsulinaemia and premature atherosclerosis is still a debatable question. The third modality consists of agents such as biguanides and thiazolidinediones which enhance insulin sensitivity, or agents that decrease insulin requirements like the alpha-glucosidase inhibitors. Type 2 diabetes mellitus is a heterogeneous disease with multiple underlying pathophysiological processes. Therapy should be individualised based on the degree of hyperglycaemia, hyperinsulinaemia or insulin deficiency. In addition, several factors have to be considered when prescribing a specific therapeutic agent. These factors include efficacy, safety, affordability and ease of administration.
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The progress of knowledge relating to non-insulin-dependent diabetes mellitus (NIDDM) is associated with new therapeutic developments. Their different respective targets allow to classify them in drugs stimulating insulin secretion (glimepiride, repaglinide, glucagon-like peptide 1), medications reducing insulin resistance (thiazolidinediones) or in insulinmimetic agents (vanadium). Alpha glucosidase inhibitors, available in France since 1993, constitute another therapeutic approach, reducing postprandial hyperglycemia by delaying the digestion of complex carbohydrates. These new medications, safer and sometimes effective in a single daily administration, represent an alternative to classic oral antidiabetic agents allowing therapeutic combinations and a more global management of NIDDM.
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Presentation of six drugs: clopidogrel, raloxifene, mecillinam, natiglinide and repaglinide, pneumococcal conjugate vaccine. For each, positive and negative arguments, questions on hold and rating.
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Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month.
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This was an open uncontrolled randomised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents. Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period (to optimise dosage: repaglinide, 2-4 mg/day; metformin, 1500-2500 mg/day) followed by a 12-month treatment period. Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period.
We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin.
In type 2 diabetic patients, the important post-prandial hyperglycemic peak combined with the defective insulin secretion emphasizes the need for restoring a physiological insulin profile during meals, characterized by insulinemia peaking within 1 hour and returning to basal levels within 4 hours. During type 1 diabetes mellitus, short acting insulin analogs aim at counteracting on post-prandial hyperglycemic peak. During type 2 diabetes mellitus, repaglinide is the first fast-acting oral antidiabetic drug able to stimulate endogenous insulin secretion during meal by mimicking physiological insulin secretion pattern.
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Rosuvastatine, doxazosin, repaglinide and oxcarbazepin are therapeutic drugs available in the market for the treatment of different diseases. Potential to display antitumor activities has also been suggested. The aim of the current study was to evaluate their in vitro effects on some human transformed cell lines.
Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim.