UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. 1474 19

Troglitazone (TGZ) was the first glitazone used for the treatment of type II diabetes mellitus. TGZ undergoes an oxidative chroman ring-opening reaction to form a quinone product. Recently, cytochrome P450 (P450) was shown to be able to catalyze the formation of TGZ quinone. TGZ quinone was the major metabolite formed by dexamethasone-induced rat liver microsomes or myeloperoxidase (MPO) incubated with TGZ. The ultimate source for the quinone carbonyl oxygen atom of TGZ quinone was investigated using (18)O water in both enzyme reaction systems followed by liquid chromatography/tandem mass spectometry analysis of the TGZ quinone product. The resultant TGZ quinone formed by either liver microsomes or MPO contained a single atom of (18)O. The (18)O atom was determined to be the quinone carbonyl oxygen by collision-induced dissociation fragmentation of the (18)O-labeled TGZ quinone. The formation of TGZ quinone was inhibited approximately 90% by coincubation with ascorbic acid or cysteine in the MPO reaction system but only 10 to 20% in liver microsomes, which might reflect the difference in the mechanism by which TGZ quinone is formed by P450 and peroxidase. These results suggest that P450 catalyze an atypical reaction to form TGZ quinone, involving the incorporation of an oxygen from water into the quinone carbonyl position.
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PMID:Incorporation of an oxygen from water into troglitazone quinone by cytochrome P450 and myeloperoxidase. 1503 98

Rosiglitazone is a thiazolidinedione antihyperglycemic drug used in the treatment of type 2 diabetes mellitus. Rosiglitazone is extensively metabolized by cytochrome P450 2C8 and so may have some utility as an in vivo probe for this enzyme. A liquid chromatographic method using sensitive fluorescence detection and simplified sample processing involving protein precipitation with acetonitrile was developed. The isocratic mobile phase consisted of 10 mM sodium acetate-acetonitrile (pH 5; 60:40, v/v) and was delivered at a flow rate of 1 ml/min to an Alltima phenyl column (250 mm x 4.6 mm, 5 microm). Detection was by fluorescence at (EX/EM) 247/367 for rosiglitazone and 235/310 for the internal standard betaxolol. Intra- and inter-day precision ranged from 3.1 to 8.5% and 2.3 to 5.7%, respectively. No endogenous interference was observed with either rosiglitazone or the internal standard. The assay is simple, economical, precise, and is directly applicable to human pharmacokinetic studies involving single dose rosiglitazone administration.
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PMID:Simplified method for determination of rosiglitazone in human plasma. 1506 42

The blood glucose lowering effects in KK-Ay mice with type 2 diabetes mellitus (DM) receiving daily an intraperitoneal (i.p.) administration of Zn(II) complexes with maltol, L-threonine, and picolinic acid for 14 days were estimated under the same conditions, and dose-dependent blood glucose lowering effects in the dose range of 0.2-3.0 mg Zn/kg body weight were found. Among them, the bis(maltolato)Zn(II) complex exhibited the highest blood sugar lowering effect at the dose of 3.0 mg Zn/kg. The improvement of DM was confirmed with oral glucose tolerance tests as well as blood HbA1c levels after the administration of the three Zn(II) complexes at the dose of 3.0 mg Zn/kg. For the purpose of the clinical trial of the complexes in the future, we examined the toxic effects of these three Zn(II) complexes in regard of the LD50 values and hepatic cytochrome P450 levels. The LD50 values of the three Zn(II) complexes exhibited high values compared with that of ZnCl2. No changes of both CYP1A1 and CYP2E1 levels in the liver of KK-Ay mice treated with the three Zn(II) complexes were observed. The obtained results will be important when the complexes are tried for clinical use.
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PMID:Blood glucose lowering and toxicological effects of zinc (II) complexes with maltol, threonine, and picolinic acid. 1508 May

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (<or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation. The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy. Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year. Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting. The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy. Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible. Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy. Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)
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PMID:Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus. 1509 24

Troglitazone (TGZ), the first glitazone used for the treatment of type II diabetes mellitus and removed from the market for liver toxicity, was shown to bind covalently to microsomal protein and glutathione (GSH) following activation by cytochrome P450 (P450). The covalent binding of (14)C-TGZ in dexamethasone-induced rat liver microsomes was NADPH-dependent and required the active form of P450; it was completely inhibited by ketoconazole (10 microM) and GSH (4 mM). The covalent binding in P450 3A4 Supersomes (9.2 nmol of TGZ Eq/nmol P450) was greater than that with P450 1A2 (0.7), 2C8 (3.7), 2C19 (1.4), 2E1 (0.6), and 2D6 (1.1) and 3A5 (3.0). The covalent binding in liver microsomes from rats pretreated with dexamethasone (5.3 nmol of TGZ Eq bound/nmol P450) was greater than that from rats pretreated with vehicle (3.5), beta-naphthoflavone (0.4), phenobarbital (1.1), or pyridine (2.5). A TGZ-GSH adduct was detected by liquid chromatography-tandem mass spectrometry and radioactivity detection with a deprotonated quasi-molecular ion [M-H](-) at m/z 745, with fragment ions at m/z 438 (deprotonated TGZ moiety), and at m/z 306 (deprotonated GSH moiety). The TGZ-GSH adduct was determined to be 5-glutathionyl-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-thiazolidine-2,4-dione based on collision-induced dissociation fragmentation, and one- and two-dimensional NMR analysis of the isolated adduct. The synthetic 5-hydroxy TGZ and the benzylidene derivative of TGZ did not react with GSH or GSH ethyl ester. The mechanisms for metabolic activation of TGZ may involve an ultimate reactive sulfonium ion which could be formed from an initial sulfoxide followed by a formal Pummerer rearrangement, or a C5 thiazolidinedione radical or a sulfur cation radical.
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PMID:Metabolic activation of troglitazone: identification of a reactive metabolite and mechanisms involved. 1515 56

The compound, 5-{4-[3-(4-cyclohexyl-2-propylphenoxy)propoxy]phenyl}-1,3-oxazolidine-2,4-dione (compound A) is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. PPARgamma agonists have proven useful in the treatment of type 2 diabetes, which is characterized by hyperglycemia, insulin resistance and/or abnormal insulin secretion. The metabolism of this oxazolidinedione (OZD) was investigated in male rat, dog, monkey and human liver microsomes, and recombinant human cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in the presence of NADPH. Routes of metabolism included monohydroxylation of the cyclohexane ring at multiple positions, monohydroxylation of the n-propyl side chain or the tether linkage, and OZD ring opening, giving rise to the keto amide and alcohol amide entities. Liver microsomes showed subtle qualitative and quantitative metabolic differences among rat, dog, monkey and human preparations. Further, CYP2C8 and CYP2C19 did not display different regioselectivity for hydroxylation on the cyclohexane ring with both of them giving rise to C-3 and C-4 hydroxy metabolites, but they did display different stereoselectivity with CYP2C8 preferring cyclohexane hydroxylation in equatorial positions and CYP2C19 in axial positions.
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PMID:In vitro metabolism of a new oxazolidinedione hypoglycemic agent utilizing liver microsomes and recombinant human cytochrome P450 enzymes. 1570 77

Ritonavir, a protease inhibitor (PI), is a potent inhibitor of cytochrome P450 3A4. This pharmacological effect, even at low doses (</=200 mg/d), is used to "boost" levels of other PIs in the treatment of HIV infection and facilitate once or twice daily dosing with reduced pill burden. Six patients with preexisting HIV-lipodystrophy developed symptomatic Cushing's syndrome when treated with inhaled fluticasone at varying doses for asthma while concurrently treated with low-dose ritonavir-boosted PI antiretroviral therapy (ART) regimens for HIV infection. There was evidence of adrenal suppression in all patients on stimulation studies. After the withdrawal of inhaled fluticasone, four patients became symptomatic of hypocortisolism, and three required oral corticosteroid support for several months. Other complications included evidence of osteoporosis (n = 3), crush fractures (n = 1), and exacerbation of preexisting type 2 diabetes mellitus (n = 1). In part, the diagnosis of fluticasone-induced Cushing's syndrome was delayed because all patients had preexisting body composition changes of ART-associated lipodystrophy, masking the Cushing's features. Practitioners should be aware of the impact on the adrenal axis of coadministration of PI-based ART regimens with inhaled corticosteroids and the potential for exacerbating or even inducing other metabolic conditions, such as osteoporosis or diabetes.
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PMID:Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases. 1575 51

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects. Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.
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PMID:Drug interactions of clinical importance with antihyperglycaemic agents: an update. 1596 7

Gamma-tocopherol (gammaT) is one of the major forms of vitamin E consumed in the diet. Previous reports have suggested increased levels of nitrated gamma-tocopherol (5-NO2-gammaT) in smokers and individuals with conditions associated with elevated nitrative stress. The monitoring of 5-NO2-gammaT and its possible metabolite(s) may be a useful marker of reactive nitrogen species generation in vivo. The major pathway for the metabolism of gammaT is the cytochrome P450 dependent oxidation to its water-soluble metabolite gamma-CEHC, which is excreted in urine. In order to determine if 5-NO2-gammaT could be metabolised via the same route and detected in urine we developed a sensitive gas chromatography-mass spectrometry assay for 5-NO2-gamma-CEHC. 5-NO2-gamma-CEHC was synthesised and its structure confirmed by proton nuclear magnetic resonance and mass spectrometry. While gamma-CEHC was abundant in urine from healthy volunteers, as well as patients with coronary heart disease and type 2 diabetes, 5-NO2-gamma-CEHC was undetectable (limit of detection of 5 nM). To understand this observation we examined the uptake and metabolism of gammaT and 5-NO2-gammaT by HepG2 cells. gammaT was readily incorporated into cells and metabolised to gamma-CEHC over a period of 48 hours. In contrast, 5-NO2-gammaT was poorly incorporated into HepG2 cells and not metabolised to 5-NO2-gamma-CEHC over the same time period. We conclude that nitration of gammaT prevents its incorporation into liver cells and therefore its metabolism to the water-soluble metabolite. Whether 5-NO2-gammaT could be metabolised via other pathways in vivo requires further investigation.
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PMID:Nitration of gamma-tocopherol prevents its oxidative metabolism by HepG2 cells. 1604 20

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