Glucobene scientific update |
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2010 Jul;160(5):1135-43.
Oger S, Behr-Roussel D, Gorny D, Lebret T, Validire P, Cathelineau X, Alexandre L, Giuliano F.
Pelvipharm, Orsay Parc Bat Cèdre, Orsay, France.
Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle.
Background and purpose: The mechanism(s) of action responsible for the beneficial effects of phosphodiesterase 5 (PDE5) inhibitors including sildenafil on lower urinary tract symptoms suggestive of benign prostate hyperplasia are unclear. In particular, the role of the NO-cGMP signalling pathway in regulating human bladder dome smooth muscle relaxation is questionable. Thus, we assessed the ability of a PDE5 inhibitor, sildenafil, to relax such tissue, and identified the signalling pathways involved in this relaxation. Experimental approach: Human bladder samples were obtained from 20 patients with no overactive bladder undergoing cystectomy for bladder cancer. Detrusor strips were mounted isometrically in Krebs-HEPES solution. Concentration-response curves for sildenafil (10 nM-30 microM) were generated in the presence of various inhibitors on carbachol-induced pre-contraction. Key results: Sildenafil relaxed carbachol-pre-contracted human detrusor strips, starting at 3 microM. This effect was not modified by NO donors, S-nitroso-N-acetylpenicillamine (10 microM) or sodium nitroprusside (300 nM), but was significantly inhibited by inhibition of guanylate cyclase (with ODQ, 10 microM) or adenylyl cyclase (with MDL-12,330A, 10 microM), by the ATP-sensitive potassium channel inhibitor, glibenclamide (10 microM), or inhibition of the large (with iberiotoxin, 30 nM) or small (with apamin, 100 nM) conductance calcium-activated potassium channels. Conclusions and implications: Sildenafil-induced relaxation of human detrusor smooth muscle involved cGMP-, cAMP- and K(+) channel-dependent signalling pathways, with a minor contribution from NO. The effect of this sildenafil-induced relaxation on the clinical benefit of PDE5 inhibitors on urinary storage symptoms in men deserves further investigation.
2010 Jun 16. [Epub ahead of print]
Holstein A, Hammer C, Hahn M, Kulamadayil NS, Kovacs P.
Lippe-Detmold Clinic, First Department of Medicine, Röntgenstr. 18, D - 32756 Detmold, Germany
Severe sulfonylurea-induced hypoglycemia: a problem of uncritical prescription and deficiencies of diabetes care in geriatric patients.
Objective: Severe sulfonylurea-induced hypoglycemia (SH) remains a life-threatening and under-reported condition. We investigated the incidence of SH and clinical characteristics of patients with type 2 diabetes mellitus (T2DM) to demonstrate typical risk constellations. Methods: In a prospective population-based observational study, all consecutive cases of SH in the period 2000 - 2009 in a German area with 200,000 inhabitants were registered. Severe hypoglycemia was defined as a symptomatic event requiring treatment with intravenous glucose and was confirmed by a blood glucose measurement of < 50 mg/dl. Results: A mean incidence of seven episodes of SH per year and 100,000 inhabitants was registered. The 139 hypoglycemic individuals had been treated with glimepiride (n = 98), glibenclamide (n = 40) or gliquidone (n = 1). No preparation showed a constant dose-effect relationship, SH occurring within a wide dose range. The patients were characterized as follows: age 77.5 +/- 9.4 years, duration of diabetes 11 +/- 7 years, body mass index 26.3 +/- 4.9 kg/m(2), HbA1c 6.6 +/- 1.3%, creatinine clearance 46 +/- 24 ml/min with renal insufficiency in 73% and co-medication 7 +/- 3 drugs. Two-thirds of all subjects lived independently at home whereas a third were cared for by a home nursing service or received care in nursing homes. In all, 30% had participated in diabetes education programs. In 31%, systematic blood glucose monitoring was performed. Conclusions: Uncritical prescription of sulfonylureas neglecting crucial contraindications - particularly renal insufficiency - and deficiencies of diabetes care contributed substantially to the risk of SH in the mainly geriatric patients. There is a need for alternative therapeutic concepts that minimize the risk of hypoglycemia in geriatric patients with T2DM.
2010 Jun 9. [Epub ahead of print]
Hehir MP, Moynihan AT, Morrison JJ.
Department of Obstetrics and Gynecology, Clinical Science Institute, University College Hospital Galway, Galway, Ireland.
Relaxant effect of Levosimendan on human uterine contractility in vitro.
OBJECTIVE: Levosimendan, a compound that exerts effects on calcium sensitivity and intracellular free calcium, in addition to opening ATP-sensitive K-channels, is widely used in the treatment of heart failure. Because of its dual mechanism of action, we hypothesized that it would modulate human uterine contractility. STUDY DESIGN: Biopsies of human myometrium were obtained at elective cesarean section (n = 16). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of levosimendan in the concentration range of 1 nmol/L to 100 mmol/L. In separate experiments, the effects of prior exposure to the K-ATP antagonist glibenclmide (100 mmol) on the effects of levosimendan on myometrial contractility were evaluated. Simultaneous controls were performed for all experiments. RESULTS: Levosimendan exerted an inhibitory effect on spontaneous and agonist induced contractions, when compared with control strips. The mean maximal inhibition (MMI) values were as follows: 45.34% +/- 5.92% for spontaneous contractions (n = 6; P < .05), and 41.88% +/- 5.40% for oxytocin-induced contractions (n = 6; P < .05). The inhibitory effect of levosimendan was significantly antagonized by glibenclamide, resulting in the mean maximal inhibition for levosimendan reduced to 19.04% +/- 3.61% for spontaneous contractions (n = 6; P < .05), and 16.53% +/- 4.08% for oxytocin induced contractions (n = 6; P < .05). CONCLUSION: Levosimendan exerted a potent relaxant effect on spontaneous and agonist-induced human uterine contractility in vitro. This effect was reduced in the presence of K-ATP blockade. Because of the putative role of levosimendan in inflammatory conditions, the findings here may have implications for its future use as therapy for preterm labor. Copyright © 2010 Mosby, Inc. All rights reserved.
2010 Jun 8. [Epub ahead of print]
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G; for the ADOPT Study Group and the RECORD Steering Committee.
ICM - Diabetes, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK,
Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical tr
AIMS/HYPOTHESIS: Observational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes. We extracted data for malignancies from the ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) randomised controlled clinical trials, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone. METHODS: Neoplasm occurrences were collected as adverse events in these studies. We reviewed and re-analysed the individual participant data in both studies for serious adverse events, malignancies reported as adverse events and related neoplasms of special interest. RESULTS: In ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide (known as glyburide in the USA and Canada) developed serious adverse event malignancies (excluding non-melanoma skin cancers). This corresponds to 1.03, 1.12 and 1.31 per 100 person-years, giving hazard ratios for metformin of 0.92 (95% CI 0.63-1.35) vs rosiglitazone and 0.78 (0.53-1.14) vs glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, compared with 56 (5.1%) in the rosiglitazone group (HR 1.22 [0.86-1.74]). On a background of metformin, 74 (6.7%) participants in the sulfonylurea group developed malignant neoplasms, compared with 57 (5.1%) in the rosiglitazone group (HR 1.33 [0.94-1.88]). CONCLUSIONS/INTERPRETATION: The malignancy rates in these two randomised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone. However, they do not refute the possibility of a difference compared with sulfonylureas.
2010 Jan;103(2):212-7. Epub 2009 Sep 1.
Kasabri V, Flatt PR, Abdel-Wahab YH.
Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, University of Jordan, Amman, Jordan.
Terminalia bellirica stimulates the secretion and action of insulin and inhibits starch digestion and protein glycation in vitro.
Traditional plant treatments have been used throughout the world for the therapy of diabetes mellitus. The aim of the present study was to investigate the efficacy and mode of action of Terminalia bellirica used traditionally for the treatment of diabetes in India. T. bellirica aqueous extract stimulated basal insulin output and potentiated glucose-stimulated insulin secretion concentration-dependently in the clonal pancreatic beta-cell line, BRIN-BD11 (P < 0.001). The insulin-secretory activity of the plant extract was abolished in the absence of extracellular Ca2+ and by inhibitors of cellular Ca2+ uptake, diazoxide and verapamil (P < 0.001; n 8). Furthermore, the extract did not increase insulin secretion in depolarised cells and did not further augment insulin secretion triggered by tolbutamide or glibenclamide. T. bellirica extract also displayed insulin-mimetic activity and enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes by 300 %. At higher concentrations, the extract also produced a 10-50 % (P < 0.001) decrease in starch digestion in vitro and inhibited protein glycation (P < 0.001). The present study has revealed that components in T. bellirica extract stimulate insulin secretion, enhance insulin action and inhibit both protein glycation and starch digestion. The former actions are dependent on the active principle(s) in the plant being absorbed intact. Future work assessing the use of T. bellirica as a dietary adjunct or as a source of active anti-diabetic agents may provide new opportunities for the treatment of diabetes.
2009 Sep;71(5):594-8.
Sundaram EN, Reddy PU, Singh KP.
Drug Standardisation Unit (H), O. U. B. No. 32, Street No. 4, Vikrampuri, Habsiguda, Hyderabad-500 007, India.
Effect of alcoholic extracts of Indian medicinal plants on the altered enzymatic activities of diabetic rats.
In present study, the effect of alcoholic extract of Momordica charantia, Aegle marmelos and Eugenia jambolana was studied on serum glutamic oxaloacetate transminase and serum glutamic pyruvate transminase activities and on serum urea, total protein and albumin concentrations of streptozotocin diabetic rats. Diabetes in rats was induced by single dose of streptozotocin (30 mg/kg i. p.). On confirming the diabetes after 48 h of injection, alcoholic extracts of three plants were administered orally in doses of 250 mg and 500 mg/kg/d for 30 d. Glibenclamide (300 mug/kg/d) was used as a reference drug for comparison. Streptozotocin diabetic rats showed a significant increase in serum glutamic oxaloacetate transminase and serum glutamic pyruvate transminase activities and serum urea concentration but a significant decrease in serum total protein and albumin concentrations and albumin/globulin ratio. Oral administration of alcoholic extract of Momordica charantia, Aegle marmelos and Eugenia jambolana in daily doses of 250 mg and 500 mg/kg for a period of 1 mo produced dose- and duration-dependent decrease in serum glutamic oxaloacetate transminase and serum glutamic pyruvate transminase activities as well as decrease in serum urea concentration and restored the serum total protein and albumin concentration and albumin/globulin ratio to a great extent in streptozotocin diabetic rats. The beneficial effects of these plants in 500 mg/kg dose in streptozotocin diabetic rats were comparable to that of glibenclamide (300 mug/kg), a standard oral hypoglycaemic drug used in clinical practice.
2009 Nov-Dec;72(6):27-9.
Spasov AA, Kucheriavenko AF, Maĭstrenko BP.
[Antiaggregant activity of hypoglycemic drugs] [Article in Russian]
We have compared the inhibitory effects of a series of hypoglycemic drugs, including glyclazide, glibenclamide, glucophage, rosiglitazone, diabenol (a new antidiabetic drug), and acetylsalicylic acid (reference antiaggregant preparation), on rabbit platelet aggregation in vitro induced by adding 5 mM ADP solution. All hypoglycemic drugs and acetylsalicylic acid inhibited platelet aggregation in a dose-depended manner. Diabenol, glyclazide and glibenclamide demonstrated the most pronounced activity in comparison to that of acetylsalycilic acid. A comparison of the published data on maximum drug concentrations in the blood plasma (Cmax) and the values of effective concentrations (EC25) of drugs determined in this study suggests that diabenol and glyclazide will produce direct antiaggregant effect under clinical administration conditions. At the same time, it is concluded that the antiaggregant effect of glibenclamide, glucophage and rosiglitazone is indirect and can only be pronounced at concentrations significantly exceeding the therapeutic level.
2009 Oct 1;69(14):1985-2004. doi: 10.2165/11201060-000000000-00000.
Croom KF, McCormack PL.
Adis, a Wolters Kluwer Business, Auckland, New Zealand.
Liraglutide: a review of its use in type 2 diabetes mellitus.
Liraglutide (Victoza) is an acylated analogue of glucagon-like peptide-1 (GLP-1) indicated for the treatment of type 2 diabetes mellitus. In phase III studies, once-daily subcutaneous liraglutide improved glycaemic control compared with placebo or active comparator in adult patients with type 2 diabetes, both as monotherapy and in combination with one or two oral antidiabetic drugs such as metformin, sulfonylureas or thiazolidinediones. Liraglutide provided significantly better glycaemic control than rosiglitazone or insulin glargine in combination trials. At appropriate dosages, liraglutide was noninferior to glimepiride with respect to glycaemic control in a combination trial, but provided significantly better control than glimepiride or glibenclamide in monotherapy trials. Liraglutide improved pancreatic beta-cell function, generally led to weight loss, and was associated with a low risk of hypoglycaemia. Liraglutide was generally well tolerated, with the most common adverse events being gastrointestinal events, such as nausea, which decreased over time. Thus, liraglutide is an effective treatment option for use in patients with type 2 diabetes mellitus.
2009;12(3):280-7.
León-Reyes MR, Castañeda-Hernández G, Ortiz MI.
Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, D.F., Mexico.
Pharmacokinetic of diclofenac in the presence and absence of glibenclamide in the rat.
PURPOSE: There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. METHODS: Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. CONCLUSION: The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.
2009 Jul;10(6):643-58.
Xu H, Murray M, McLachlan AJ.
Faculty of Pharmacy, The University of Sydney, NSW, Australia.
Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs.
Sulfonylurea drugs including chlorpropamide, gliclazide, tolbutamide, glipizide, glibenclamide (glyburide) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes. This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs. CYP2C9 is the major enzyme involved in sulfonylurea drug metabolism. CYP2C9 variant allele carriers have significant lower apparent clearance of these medicines. CYP2C19 genotype is more influential for gliclazide pharmacokinetics when compared to CYP2C9. Sulfonylurea pharmacodynamics is affected by several genes. Sulfonylurea receptor 1 (SUR1, ABCC8 gene) and K+ inward rectifier Kir6.2 (KCNJ11) have been correlated to significant variation in sulfonylurea response. Diabetics with the SUR1 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the KCNJ11 gene was associated with improved clinical efficacy of gliclazide. Carriers of Transcription factor 7-like 2 (TCF7L2) variants are more likely to fail sulfonylurea therapy. On the other hand, patients with HNF-1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes. The Arg972 polymorphism of insulin receptor substrate 1 (IRS1) may lead to secondary failure of sulfonylurea therapy. Calpain 10 gene (CAPN10) polymorphism has also been linked to sulfonylurea drug response. Despite the available evidence, larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes.
2009 Dec;58(12):1681-7. Epub 2009 Sep 29.
Iwanishi M, Ebihara K, Kusakabe T, Chen W, Ito J, Masuzaki H, Hosoda K, Nakao K.
Diabetes and Endocrine Division, Kusatsu General Hospital 1660 Yabase, Kusatsu, Shiga 525-8585, Japan.
Clinical characteristics and efficacy of pioglitazone in a Japanese diabetic patient with an unusual type of familial partial lipodystrophy.
This report describes a 46-year-old Japanese diabetic woman with an unusual type of familial partial lipodystrophy. She has marked loss of subcutaneous fat in her lower limbs and buttocks, with sparing of the face, neck, upper limbs, and trunk. This distribution of fat atrophy appears to be rare in comparison with previous reports. Sequencing of candidate genes LMNA, PPARG, AKT2, caveolin-1, as well as the PPARG4 promoter gene, which are known to be associated with familial partial lipodystrophy, revealed no genetic abnormalities, suggesting that this case may involve a novel gene. Pioglitazone was markedly effective in glycemic control in this case. Her diabetes remained uncontrolled despite a total daily dose of insulin of 30 U and combined treatment with 10 mg of glibenclamide and 0.6 mg of voglibose. We therefore attempted combined treatment with 30 mg of pioglitazone and 30 U/d insulin injection. The hemoglobin A(1c) level was reduced from 11.2% to 6.1% after 6 months of treatment and has since remained stable. Her body weight increased from 62.0 to 71.0 kg after 12 months of treatment, suggesting that weight gain may result from synergism between thiazolidinediones and insulin-promoting adipogenesis. Pioglitazone increased the fat mass in the upper limbs and trunk, while inducing less increase in the lower limbs, where fat atrophy exists in this patient. Pioglitazone may thus have improved the glycemic control in this case through adipocyte differentiation from progenitor cells mainly in the upper limbs and trunk.
2008 Dec;26(12):2326-38.
Long CL, Qin XC, Pan ZY, Chen K, Zhang YF, Cui WY, Liu GS, Wang H.
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia.
BACKGROUND AND OBJECTIVES: It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats. METHODS AND RESULTS: In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid. CONCLUSION: These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.
2008 Sep;108(1):124-30.
Gojkovic-Bukarica L, Novakovic A, Kanjuh V, Bumbasirevic M, Lesic A, Heinle H.
Department of Clinical Pharmacology, Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
A role of ion channels in the endothelium-independent relaxation of rat mesenteric artery induced by resveratrol.
Recently it has been suggested that resveratrol relaxes different isolated arteries. The present study addressed the question whether different ion channels are involved in the endothelium-independent mechanism of vasodilatation induced by resveratrol. For that purpose, we tested the action of resveratrol on the rat mesenteric artery without endothelium. Resveratrol induced concentration-dependent relaxation of rat mesenteric artery. Among the K(+)-channel blockers, 4-amynopiridine (4-AP) moderately antagonized the resveratrol-induced relaxation, while glibenclamide, tetraethylammonium chloride, charybdotoxin, margatoxin, and barium chloride did not inhibit resveratrol-induced vasorelaxation. In rings, precontracted with 100 mM K(+), the relaxant responses to resveratrol were highly significantly shifted to the right compared to those obtained in rings precontracted with phenylephrine, but resveratrol-induced maximal relaxation was only slightly affected. In order to minimize the influence of K(+) channels and voltage-gated Ca(2+) channels (VGCCs) in vascular smooth muscle, the third contraction was made by 100 mM K(+) in the presence of nifedipine. The relaxant response to resveratrol was abolished. Thus, the mechanism of vasorelaxation induced by resveratrol probably involves activation of 4-AP-sensitive K(+) channels. Its ability to completely relax the mesenteric artery precontracted with K(+)-rich solution suggests that K(+) channel-independent mechanism(s) are involved in its vasorelaxant effect. It seems that interaction with VGCCs plays a part in this K(+) channel-independent effect of resveratrol.
2008 Jun;30(5):363-6.
Faruqui AR, Mathai J, George J, Peedicayil J, Ernest K, Neelakantan N.
Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, India.
Inhibitory effect of nicorandil on the contraction of isolated human urinary bladder detrusor muscle.
This study was performed to determine whether the antianginal drug nicorandil relaxes isolated human detrusor muscle. Ten strips of detrusor muscle obtained from 10 pediatric patients who underwent surgery on the urinary bladder were contracted with 80 mM potassium chloride (KCl) before and after incubation with four concentrations of nicorandil (100, 200, 400 and 800 microM). The percent inhibition by nicorandil of the height and area under the curve (AUC) of KCl-induced contractions of the detrusor strips was calculated. The effect of glibenclamide (10 microM) on nicorandil (800 microM)-induced inhibition of KCl-induced detrusor contractions was also studied. Nicorandil caused a concentration-dependent inhibition of KCl-induced contractions of the detrusor strips. The percent inhibition of the height of KCl-induced contractions of the detrusor by nicorandil was significant at concentrations of 200, 400 and 800 microM. The percent inhibition of the AUC for KCl-induced detrusor contractions was significant at all four concentrations of nicorandil used. Glibenclamide reversed the inhibitory effect of 800 microM nicorandil on KCl-induced detrusor contractions. These results suggest that nicorandil inhibits KCl-induced contractions of isolated human detrusor muscle and may therefore be useful in clinical conditions requiring detrusor muscle relaxation. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
2008 Dec;30(6):876-83. Epub 2008 Sep 11.
Yusuff KB, Obe O, Joseph BY.
Department of Clinical Pharmacy & Pharmacy Administration, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria.
Adherence to anti-diabetic drug therapy and self management practices among type-2 diabetics in Nigeria.
OBJECTIVE: To describe the pattern of anti-diabetic drug prescribing; ascertain the level of glycemic control, adherence with prescribed anti-diabetic medications, and diabetes self management practices among patients with type-2 diabetes in a tertiary care setting in Nigeria. SETTING: University College Hospital (UCH); a 900 bed teaching hospital with medical residents located in Ibadan, southwestern Nigeria. METHOD: The study consisted of two phases. A cross-sectional review of randomly selected 200 case notes of type 2 diabetic patients that attended the Endocrinology clinic over 3 month; and crosssectional interviews, with a pre-tested Adherence and Self-Management Monitoring Tool (ASMMT), of 200 consecutive patients that presented their drug prescriptions at the satellite pharmacy unit over a 4 week period at a 900-bed teaching hospital located in Ibadan, South-Western Nigeria. RESULTS: Oral Hypoglycemic Agents (OHA) were prescribed for 86% (171) of cohorts while insulin and OHA was prescribed in 14% (29). About 70.8% (121) of patients on OHA were on combination therapy. The most frequently prescribed OHA combination was glibenclamide and metformin (95.8%). Glibenclamide was prescribed as twice daily regimen in 69% of cohorts. The most frequently documented side effect was hypoglycemia (60.3%). Only 44% (88) of cohorts had adequate glycemic control; of these, 93% (82) were adjudged adherent with prescribed anti-diabetic drugs. Interviews with the structured ASMMT revealed that 59% of patients were non-adherent with the previous anti-diabetic drugs due to lack of finance (51.7%); side effects (34.5%); perceived inefficacy of prescribed anti-diabetic drugs leading to self-medication with local herbs (13.8%). Only 20% of non-adherent patients claimed disclosure to physicians during consultation. The identified factors for non-disclosure were lack of privacy during consultation (58%); and short consultation time (42%). The knowledge and practice of critical components of diabetes self-management behaviours were generally low among the cohort studied. However, it was significantly higher among patient judged adherent with their prescribed anti-diabetic medications (P < 0.05). CONCLUSION: Majority of patients with type 2 diabetes in an ambulatory tertiary care setting in Nigeria are managed with OHA combinations, mainly glibenclamide and metformin. While the current prescribing strategy achieved glycemic control in about one third of patients, majority are still not meeting the recommended blood glucose targets due to poor adherence with prescribed drug regimen, and poor knowledge and practice of successful self-management.
2008 Sep;8(3):160-5.
Kigawa Y, Oba K, Futami-Suda S, Norose J, Yasuoka H, Suzuki K, Ouchi M, Watanabe K, Suzuki T, Nakano H.
Division of Geriatric Medicine, Nippon Medical School, Tokyo, Japan.
Daily blood glucose profiles of glibenclamide and gliclazide taken once or twice daily in elderly type 2 diabetic patients.
AIM: The aim of this study was to evaluate the difference in daily blood glucose profiles between once- and twice-daily regimens of a moderate daily dose of glibenclamide or gliclazide in elderly patients with type 2 diabetes. METHODS: Daily blood glucose profile data were evaluated in 18 elderly type 2 diabetic patients treated with 80 mg/day gliclazide or 5 mg/day glibenclamide as monotherapy. The first daily blood glucose profile of the twice-daily regimen was performed approximately 1 week before hospital discharge, and the second was performed after taking a once-daily regimen for 4-7 days. Plasma glucose and plasma immunoreactive insulin (IRI) concentrations were measured daily at 12 time points: 08.00 (before breakfast); 10.00; 12.00 (before lunch); 14.00; 18.00 (before dinner); 20.00; 0.00; 02.00; 03.00; 04.00; 06.00; and 08.00 hours the next morning. RESULTS: Daily blood glucose profiles and plasma IRI profiles did not differ between the once- and twice-daily regimen groups in either the gliclazide group or the glibenclamide group. Plasma glucose values between midnight and early morning tended to be lower than the 08.00 hours plasma glucose value in the glibenclamide group, but not in the gliclazide group. CONCLUSION: These results suggest that the blood glucose-lowering effects of a once- and twice-daily moderate daily dose of glibenclamide or gliclazide do not differ in elderly type 2 diabetic patients. However, glibenclamide, regardless of the dosage schedule, tends to lower the plasma glucose values between midnight and early morning.
2007;46(22):1837-46. Epub 2007 Nov 16.
Derosa G, D'Angelo A, Fogari E, Salvadeo S, Gravina A, Ferrari I, Cicero AF.
Department of Internal Medicine and Therapeutics, University of Pavia, Italy. giuseppe.derosa@unipv.it
Effects of nateglinide and glibenclamide on prothrombotic factors in naïve type 2 diabetic patients treated with metformin: a 1-year, double-blind, randomized clinical trial.
OBJECTIVE: To evaluate the effect on coagulation and fibrinolysis parameters and on non-conventional cardiovascular risk factors of metformin plus nateglinide or glibenclamide in naïve type 2 diabetes patients. PATIENTS AND METHODS: A total of 248 type 2 diabetic patients were enrolled and randomly assigned to receive nateglinide or glibenclamide, and metformin for 12 months. We assessed body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostasis model assessment index (HOMA index), lipid profile with lipoprotein (a) [Lp(a)], fibrinogen (Fg), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), homocysteine (Hcy), systolic blood pressure (SBP), diastolic blood pressure (DBP). RESULTS: After 9 months of treatment, both tested drug combinations were similarly associated with a significant reduction in FPG (nateglinide, -17.2%; glibenclamide, -16.9%, both p<0.05) compared to the baseline, while HbA1c (-17.3%, p<0.05) and PPG (-15.2%, p<0.05) significantly decreased only in the nateglinide group. After one year of treatment, compared to the baseline the nateglinide group showed a significant reduction in HbA1c (-21%, p<0.01), FPG (-20.7%), p<0.01, PPG (-21.5%, p<0.05), HOMA index (-25.4%, p<0.05); the glibenclamide group, showed a significant reduction in HbA1c (-11%, p<0.05), FPG (-23.2%, p<0.05), PPG (-11.2%, p<0.05), and HOMA index (-23.9%, p<0.05) but to a minor extent. Moreover, the HbA1c difference value from baseline observed in the nateglinide-treated group was significantly higher than that observed in the glibenclamide group. Therefore the nateglinide-treated patients showed a significant reduction in some prothrombotic parameters (PAI-1=-19%, Lp(a)=-31%, and Hcy=-32.3%, all p<0.05), whereas the glibenclamide-treated patients did not. CONCLUSION: Nateglinide appears to improve glycemic control as well as the levels of some prothrombotic parameters compared to glibenclamide when administered in combination with metformin.
2007 Aug;36(8):672-8.
Ho FL, Liew CF, Cunanan EC, Lee KO.
Division of Endocrinology, Department of Medicine, National University Hospital, Singapore.
Oral hypoglycaemic agents for diabetes in pregnancy - an appraisal of the current evidence for oral anti-diabetic drug use in pregnancy.
INTRODUCTION: The use of oral hypoglycaemic drugs in pregnancy is not recommended because of reports of foetal anomalies and other adverse outcomes in animal studies and in some human cases. However, recent studies have suggested that some oral hypoglycaemic drugs may be used in pregnancy. This review will examine these studies critically. METHODS: Literature review of articles obtained from a PubMed search of peer-reviewed journals on oral hypoglycaemic drug use in pregnancy. RESULTS: In two prospective studies, one of which was a randomised controlled trial, glibenclamide was as effective and safe as insulin in gestational diabetes. In several studies, metformin did not increase foetal anomalies or malformations when used during pregnancy in women with polycystic ovary syndrome (PCOS). In one prospective study on infants born to mothers who used metformin in pregnancy, follow-up for 18 months showed no adverse effects. In several prospective and retrospective studies on women with PCOS, metformin was shown to prevent early pregnancy loss, decrease insulin resistance, reduce insulin and testosterone levels, and decrease the incidence of gestational diabetes when these women got pregnant while on metformin and continued to take it throughout their pregnancy. In a single small study, acarbose did not cause any adverse effects during pregnancy. CONCLUSIONS: Recent evidence shows promising findings in the safety and efficacy of some oral hypoglycaemic agents in treating pregnant diabetics. However, larger clinical studies will be needed to ensure the safety and efficacy of these drugs in pregnancy.
2007 Oct;21(5):331-8.
Akar F, Manavbasi Y, Parlar AI, Ulus AT, Katircioglu SF.
Department of Pharmacology, Faculty of Pharmacy, Gazi University, 06330 Ankara, Etiler, Turkey. fakar@gazi.edu.tr
The gender differences in the relaxation to levosimendan of human internal mammary artery.
PURPOSE: The mechanism of the vasorelaxation to levosimendan varies depending on the vascular bed and species studied. Here, we examined the vasorelaxation to levosimendan as well as its modification by various potassium channel antagonists in human internal mammary artery (IMA) obtained from male and female patients. METHODS: IMA grafts were supplied from 27 male and 19 age-matched female patients undergoing coronary bypass operation. The contraction to noradrenaline and relaxation to levosimendan were studied in IMA rings obtained from both gender. The relaxations to levosimendan were also assessed in the presence of glibenclamide (10 microM), an adenosine triphosphate-sensitive potassium channel (K(ATP)) blocker, or charybdotoxin (100 nM), a calcium-activated potassium channel (K(Ca)) blocker, or 4-aminopyridine(1 mM), a voltage-sensitive potassium channel (K(v)) inhibitor. RESULTS: Concentration-response curves to noradrenaline were not different in IMA rings from either gender. Pretreatment with levosimendan (3 x 10(-7) M) slightly modified the contractions to noradrenaline in both gender. Levosimendan (10(-9)-10(-5) M) produced concentration-dependent relaxation in IMA rings, contracted by noradrenaline (5 x 10(-6) M), from males and females. The vasodilatory effects of levosimendan were more pronounced in the arteries from males (83%) than females (69%), in term of the maximal relaxation (E (max)). Charybdotoxin and glibenclamide significantly inhibited the relaxation to levosimendan in the arteries from males but not in those of females. CONCLUSIONS: The vasodilating efficacy of levosimendan and its relaxation mechanism differs between the arteries from males and females, which may have clinical consequences in the treatment of heart failure.
2007 Sep;18(6):455-62.
Bilinska M, Potocka J, Korzeniowska-Kubacka I, Piotrowicz R.
Department of Cardiac Rehabilitation and Noninvasive Electrocardiology, Institute of Cardiology, Warsaw, Poland.
'Warm-up' phenomenon in diabetic patients with stable angina treated with diet or sulfonylureas.
BACKGROUND: Classic sulfonyloureas (SUs) are known to attenuate ischaemic preconditioning. Gliclazide is an SU agent believed to be more protective. We assessed the effects of diet, glibenclamide, or gliclazide on the warm-up effect in type 2 diabetic patients with stable angina. METHODS: The study group consisted of 64 men, aged 54+/-5 years: 17 patients without diabetes (G I) and 47 diabetic patients: 16 patients treated with glibenclamide (G II), 16 with gliclazide (G III) and 15 patients treated with diet (G IV). After the baseline positive exercise test (ET1), all patients reexercised after 30-min rest (ET2). We analysed exercise duration (ED, s), time to 1 mm ST depression (T-STD, s), max STD (mm), heart rate-systolic blood pressure product at 1 mm STD, or ischaemic threshold (mmHg/min x 100) and the total ischaemic time (s). RESULTS: In G I, all analysed variables improved significantly during ET2 relative to ET1. Glibenclamide (G II) completely abolished the protective effect of exercise-induced ischaemia because only ED increased during ET2 (431 vs. 451, P<0.05). In G III, however, ED (486 vs. 537, P<0.001), T-STD (364 vs. 388, P<0.05) and max STD (2.5 vs. 2.0, P<0.05) improved significantly during ET2, whereas ischaemic threshold and total ischaemic time did not (PNS). In G IV, similar to G I, all variables improved significantly during ET2 relative to ET1. CONCLUSION: Warm-up effect is preserved in diabetic patients with stable angina treated with diet, partially preserved in gliclazide-treated and abolished in glibenclamide-treated patients.
2007 Sep;9(5):640-7.
Betteridge DJ.
Department of Medicine, Royal Free and University College Medical School, University College Hospital, London, UK.
Effects of pioglitazone on lipid and lipoprotein metabolism.
Type 2 diabetes is associated with an increased risk of cardiovascular disease (CVD). A major contributing factor to this risk is the abnormal lipid profile known as dyslipidaemia, which is characterized by low HDL cholesterol (HDL-C), raised triglycerides (TGs) and a predominance of small, dense LDL cholesterol (LDL-C) particles. Statins are now widely used first-line in patients with type 2 diabetes due to their proven efficacy in reducing LDL-C and cardiovascular risk. However, despite the use of statins, the absolute risk of CVD in patients remains elevated, highlighting the need to target all aspects of the diabetic lipid profile such as raised TGs or low HDL-C levels. Insulin resistance is thought to be central in the pathogenesis of diabetic dyslipidaemia; therefore, improving insulin sensitivity with a thiazolidinedione offers an attractive treatment option. Indeed, pioglitazone, a member of the peroxisome proliferator-activated receptor-gamma family, has been shown in clinical trials to improve both blood glucose levels and the lipid profile when used either as monotherapy or in combination with other oral antidiabetic agents. In the monotherapy setting, pioglitazone has been associated with greater decreases in TGs and increases in HDL-C when compared with glibenclamide or metformin. Studies investigating the effects of pioglitazone add-on therapy to either metformin or sulphonylurea treatments have shown sustained improvements in serum levels of TGs and HDL-C and favourable effects on LDL-C particle size. In comparison with rosiglitazone, pioglitazone has different and potentially favourable effects on plasma lipids. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events study has given weight to the hypothesis that the beneficial metabolic effects of pioglitazone may be associated with reductions in cardiovascular risk in patients with type 2 diabetes.
Vnitr Lek. 1995 Oct;41(10):677-81.
Rajecová E, Klimes I, Seböková E, Rychnavská E, Pleváková L, Linke-Cvrkalová A, Langrová H.
Ustav TBC a respiracných chorôb, Bratislava.
Etofylline clofibrate in the treatment of diabetic dyslipidemia: results of a 6-month period of therapy
The objective was to investigate the tolerance of ethophylline clofibrate (EPC) and its effectiveness on changes of dyslipidaemia and compensation of diabetes in type II diabetics during six-month administration of the preparation Duolip forte (Merckle). Twenty diabetics with dyslipoproteinaemia IIb and IV according to Frederickson's classification, compensated by diet alone or combined with oral antidiabetics (Glucobene, Merckle) were included in the study consecutively according to uniform basal criteria. The selected hypolipidaemic agent was administered to patients according to the following pattern: the first four weeks 1,000 mg (2 tablets in the evening) the next two weeks 1.5 tablets and then till the end of the investigation 1 tablet in the evening. In all patients treatment with EPC led to a significant reduction of the total cholesterol level (CH) at all time intervals. Changes of ApoB, ApoA1 and Lp(a) serum levels did not attain statistical significance but trends were revealed (e.g. a drop of the ApoB/ApoA1 index) which are consistent with the expected favourable action of EPC on the CH distribution in lipoproteins. The triacylglycerol (TG) serum concentration declined significantly already after one month of treatment and after identification of five patients whose TG were distributed in separate clusters the hypotriacylglycerolaemic effect of EPC persisted still three months after treatment. It may be summarized that treatment of dyslipoproteinaemia of the type II diabetics with ethophylline clofibrate (Duolip forte, Merckle) led a) to a marked reduction (13-15%) of serum cholesterol, which b) diminished (to 8-9%) but persisted still after 6 months of treatment, c) the greatest effect of EPC on the TG serum level was observed one month after treatment, d) all improvements of lipid parameters occurred without affecting the compensation of diabetes, or BMI and were not associated with any side-effects of EPC.
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Drug category:Antidiabetic agents
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