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Antidiabetic medications in overdose: a comparison of the inquiries made to a regional poisons unit regarding original sulfonylureas, biguanides and insulin.

OBJECTIVE: The drugs most commonly used to treat diabetes mellitus are sulfonylureas, biguanides and insulin. The most serious effects seen in overdose with these agents are hypoglycemia or lactic acidosis which may be fatal or cause cerebral defects. The present investigation analyzes inquiries made to a regional poisons unit involving overdoses with sulfonylureas, biguanides and insulin. PATIENTS AND METHODS: A total of 218,070 made inquiries between 1995 and 2004 were evaluated. The inquiries were received by telephone and a standardized questionnaire was sent subsequently to the physicians calling for follow-up information. The cases were analyzed with regard to gender, age, etiology, symptoms and clinical outcome. RESULTS: 263 inquiries concerning sulfonylureas (48.3% female, 49.4% male, 2.3% sex unknown, average age 39.1 +/- 26.8 years), 172 concerning biguanides (60.5% female, 37.2% male, 2.3% sex unknown, average age 41.5 +/- 24.1 years), and 191 concerning insulin (53.9% female, 41.9% male, 4.2% sex unknown, average age 44.6 +/- 16.7) were made. In cases involving sulfonylureas, the etiology was deliberate self-poisoning in 62.7% and accidental in 31.9% (biguanides 60.5% and 29.1%, insulin 85.3% and 9.4%). Using the Poisoning Severity Score, no symptoms were observed in 41.4% of the patients with sulfonylurea overdose (biguanides 40.1%, insulin 22.5%), minor symptoms in 37.6% (biguanides 32.6%, insulin 33.5%), major symptoms in 14.4% (biguanides 13.4%, insulin 26.2%) and serious symptoms in 4.6% (biguanides 12.2%, insulin 14.7%). Returned questionnaires reporting clinical outcomes showed that a full recovery occurred in most patients (sulfonylureas 97.4%, biguanides 93.0%, insulin 94.4%), cerebral defects persisted in 1.8% of the cases involving sulfonylureas (biguanides 1.5%, insulin 2.4%), and that 0.9% of the patients with sulfonylurea overdose died (biguanides 6.1%, insulin 3.6%). CONCLUSIONS: Sulfonylureas were the most frequently observed medication in cases of overdose with antidiabetic agents. Insulin overdose caused the highest number of major and serious symptoms. Overdose with biguanides led to the most deaths.

Adult↗

Three-dimensional quantitative structure-activity relationships (3D-QSAR) of antidiabetic thiazolidinediones.

Thiazolidine-2,4-diones (TZDs) are novel insulin resistance releasing compounds that serve as orally active antidiabetic agents. Many TZDs have been synthesized and evaluated by in vivo screening for over 20 years. Recently, TZDs have been found to be selective agonists of peroxisome proliferator-activated receptor-y (PPAR-gamm), which is believed to work in the regulation of insulin resistance. This paper reports our efforts for the pharmacophore modeling study through 3D (three-dimensional) structure-activity relationship of TZDs to gain an insight into their molecular mechanism as well as the relation between antihyperglycemic and PPAR-gamma agonistic activities. The modeling study was carried out by conformational analysis along with the Apex-3D QSAR method to identify molecular features common to a series of 7 selected TZDs. Although the number of compounds included in the study was rather low, the variations in the activities were nicely elucidated with 3D-site specific physiochemical parameters significantly.

Humans↗

Tissue selectivity of antidiabetic agent nateglinide: study on cardiovascular and beta-cell K(ATP) channels.

Nateglinide (NAT) stimulates insulin secretion from pancreatic beta-cells by closing K(ATP) channels. Because K(ATP) channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by examining its effect on K(ATP) channels in enzymatically isolated rat beta-cells, rat cardiac myocytes, and smooth muscle cells from porcine coronary artery and rat aorta with the patch-clamp method. The selectivity of known antidiabetic agents glyburide (GLY) and repaglinide (REP) was also studied for comparison. NAT was found to inhibit K(ATP) channels in the cells from porcine coronary artery and rat aorta with IC(50)s of 2.3 and 0. 3 mM, respectively, compared with 7.4 microM in rat beta-cells, indicating a respective 311- and 45-fold selectivity (p <.01) for beta-cells. With an IC(50) of 5.0 nM in beta-cells, REP displayed an approximately 16-fold (p <.05) selectivity for beta-cells over both types of vascular cells. GLY was nonselective between vascular and beta-cells. At equipotent concentrations (2x respective IC(50)s in beta-cells), NAT, GLY, and REP all caused 62% reduction of pancreatic K(ATP) current but a respective 39, 55, and 66% inhibition of cardiac K(ATP) current. These data collectively indicate that NAT, when compared with GLY and REP, at concentrations effective in stimulating insulin secretion is least likely to cause detrimental CV effects via blockade of CV K(ATP) channels.

Animals↗

Effect of antidiabetic compounds on glyoxalase I activity in experimental diabetic rat liver.

The activity of glyoxalase I from the soluble fraction of diabetic rat liver was found to decrease as compared to the control. Sodium orthovanadate in drinking water and Trigonella foenum graecum seed powder when administered to these diabetic animals were found to reverse the activity of glyoxalase I to control values. A combination of the above two antidiabetic compounds showed a better reversal. Vanadate and Trigonella seed powder treatment separately to diabetic rats also normalized hyperglycemia together with glyoxalase I activity. A combination of vanadate and Trigonella seed powder also restored the other general parameters of the diabetic animals.

Animals↗

Modulation of some gluconeogenic enzyme activities in diabetic rat liver and kidney: effect of antidiabetic compounds.

The effects of insulin, sodium orthovanadate and a hypoglycemic plant material, Trigonella foenum graecum (fenugreek) seed powder were studied on the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase in diabetic liver and kidney. The significantly increased activities of the two enzymes during diabetes in liver and kidney were found to be lowered to almost control values by the use of the antidiabetic compounds. Diabetic liver exhibited a much greater increase in the activities of the two enzymes than diabetic kidney. The highest percentage of reversal to normal values was seen using the combination of vanadate and Trigonella seed powder. The lowered rate of growth of the animals as well as the increased blood sugar were reversed almost to the control levels by the Trigonella seed powder and vanadate treatment. The inclusion of the Trigonella seed powder overcame the toxicity of vanadium encountered when it was given alone as insulin mimetic agent. Much lower levels of vanadate were needed when it was given in combination with Trigonella seed powder. Their combined effects were better at restoring the above parameters than those induced by insulin administration.

Animals↗

Effects of the neoflavonoid coutareagenin, one of the antidiabetic active substances of Hintonia latiflora, on streptozotocin-induced diabetes mellitus in rats.

In the present study, diabetes mellitus was induced with streptozotocin in Wistar rats from the inbred strain F > 28, and a blood sugar lowering effect due to the oral or intragastric administration of a copalchi native extract (Hintoniae latiflorae cortex) or intragastric administration of the pure substance, coutareagenin (neoflavonoid) (5-hydroxy-7-methoxy-4-(3,4-dihydroxyphenyl)-2H-benzo-1-pyran-2-on), was demonstrated with statistically significant results. This study enlarged and confirmed the results of earlier studies by other authors with regard to the antidiabetic effect of the copalchi bark extract in various animal species with hyperglycemia induced by different methods. By the use of the synthetically produced neoflavonoid, coutareagenin, the present series of tests provided evidence that coutareagenin, one of the active substances contained in Hintonia latiflora bark (Copalchi bark), produces a reduction of diabetic elevated blood sugar levels. The native extract as a whole, however, has to be regarded as the active substance (active substance complex) of Hintonia latiflora (Copalchi) bark.

Animals↗

Studies on the in vitro phototoxicity of the antidiabetes drug glipizide.

The phototoxic antidiabetes drug glipizide (1) is photolabile under aerobic conditions and UV-B light. Irradiation of a phosphate-buffered solution of 1 under oxygen atmosphere produces 4 photoproducts as well as singlet oxygen, which was detected by trapping it with 2,5-dimethylfuran and by the histidine test. The photochemistry of 1 involves cleavage of the sulfonamine and the sulfonamine-R bonds. Red blood cell lysis, photosensitized by glipizide and the products of its aerobic photolysis were demonstrated. The photohemolysis rate was lower for 1 than for its photoproducts. Inhibition of this process on addition of 1, 4-diazabicyclo[2.2.2]octane (DABCO), reduced glutathione (GSH), Vitamin C, sodium azide, superoxide dismutase, and a-tocopherol confirmed the possibility of singlet oxygen, superoxide ion and free radicals participation. Furthermore, in a lipid-photoperoxidation test with linoleic acid the in vitro phototoxicity of glipizide was also verified. A low decreasing cell viability of lymphocytes and neutrophils was observed.

Cell Survival↗

Antidiabetic effect of Oenanthe javanica flavone.

AIM: To study the antidiabetic effect of Oenanthe javanica flavone (OjF). METHODS: Mice were injected i.v. with alloxan 90 mg.kg-1 to induce diabetes. Blood glucose, serum lipid, and pancreatic amylase were determined with Automatic Biochemistry Analysor. Serum insulin was determined by radioimmunoassay. The pancreas and islets were examined under microscope. RESULTS: OjF 200 mg.kg-1 reduced the blood glucose in normal mice from 0.5 to 6 h after a single administration ig. OjF 200 and 400 mg.kg-1 ig daily for 10 d decreased the blood glucose in alloxan-induced hyperglycemic mice (P < 0.05, P < 0.01). OjF promoted the release of insulin both in normal and in diabetic mice. OjF decreased serum triglyceride and raised the lowered pancreatic amylases in diabetic mice (P < 0.01, P < 0.01). The islet-injured changes of OjF-treated group were similar to those of control in histology examination, but to a lesser degree. CONCLUSION: OjF possessed the hypoglycemic and hypotriglyceride actions, mainly concerned with promoting release of insulin from B-cells in islets of langerhans.

Amylases↗

[The new oral antidiabetics. Type 2 diabetes under control only with tablets?].

The new oral antidiabetics have expanded our possibilities of treating type 2 diabetes and associated diseases. AGIs and insulin sensitizers represent new principles of action. The insulinotropic substances improve the dynamics of insulin secretion. They enable pathophysiologically-oriented treatment that takes account of the patient's need for simple, low-stress management. This improves the quality of life, in particular of the elderly and disabled patient. However, this fact does not justify delaying treatment with insulin, which is always needed when the goals of treatment cannot be achieved with oral preparations.

Administration, Oral↗

[Evaluation of a thiazolidinedione compound as a new antidiabetic drug].

A thiazolidinedione compound, pioglitazone(Actos) has been used for type 2 diabetes. It ameliorates the insulin resistance of type 2 diabetes and improves hyperglycemia, resulting in the decrease of HbA1c. Pioglitazone activates the nuclear peroxisome proliferator activated receptor-gamma(PPAR gamma) which leads to increased transcription of various proteins. These proteins enhance insulin action. Another thiazolidinedione(troglitazone, Noscal) has been prohibited for description due to its idiosyncratic hepatic toxicity. Actos has never been reported to induce hepatotoxicity but has shown side effects of edema, dysfunction of the liver, and anemia, etc. Nevertheless we would like to recommend the use of Actos for type 2 diabetes mellitus in monotherapy or combination therapy with other antidiabetic drugs because of its benefits.

Diabetes Mellitus, Type 2↗

[News in oral antidiabetic therapy].

In this article two new peroral antidiabetics are introduced. The first is repaglinide, a prandial glucose regulator. The second is rosiglitazone, a member of the thiazolidinediones family, which improves the sensitivity of tissues to insulin and reduces insulin resistance.

Administration, Oral↗

[Oral antidiabetics and lipids].

Lipid abnormalities are a key factor in the vascular risk of type 2 diabetes. In this review, we briefly consider lipid abnormalities associated with type 2 diabetes. The effects of the main oral antidiabetic agents (sulphonylureas and glinides analogues, metformin, inhibitors of alpha-glucosidase) on lipoproteins are described. Thiazolidinedione (pioglitazone and rosiglitazone) effects on lipid metabolism, as well as their effects on mechanisms involved in the promotion of atherosclerosis are discussed.

Administration, Oral↗

[Primary combined oral antidiabetic therapy in type-2 diabetes mellitus].

New target values of the metabolic control and recent directions in the therapeutic strategies of type 2 diabetes mellitus are overviewed. Attention is called to the atherogenic effect of blood glucose elevations exceeding physiological level, even when only post-prandial and with short duration. The significance of early phase prandial insulin secretion in the metabolic state is underlined, and the related new therapeutic possibilities are discussed. Practical guidelines are given to the introduction of oral antidiabetic therapy, and the importance of the early, aggressive, combined treatment with a complex mechanism of action is emphasized.

Administration, Oral↗

The oral antidiabetic agents.

Oral antidiabetic agents can be used to lower blood glucose levels in some adult-onset diabetics who do not have acute complications and in whom control of hyperglycemia by weight reduction alone or insulin treatment is not possible. Except for their investigational use, these agents have no place in the treatment of chemical or latent diabetes, or subclinical or suspected diabetes, and they are contraindicated in patients with diabetic ketoacidosis. Findings from the University Group Diabetes Progcted and judicious use of these drugs.

Administration, Oral↗

Antidiabetic and antioxidant effects of S-methyl cysteine sulfoxide isolated from onions (Allium cepa Linn) as compared to standard drugs in alloxan diabetic rats.

Antidiabetic and antoxidant effects of S-methyl cysteine sulfoxide (SMCS) isolated from A. cepa and two standard drugs, glibenclamide and insulin were studied and compared in alloxan diabetic rats after using each of them for treatment for two months. These drugs ameliorated the diabetic condition significantly, viz. maintenance of body weight and control of blood sugar in rats. Further they lowered the levels of malondialdehyde, hydroperoxide and conjugated dienes in tissues exhibiting antioxidant effect on lipid peroxidation in experimental diabetes. This is achieved by their stimulating effects on glucose utilization and the antioxidant enzymes, viz. superoxide dismutase and catalase. The probable mechanism of action of SMCS and glibenclamide may be partly dependent on the stimulation of insulin secretions and partly due to their individual actions. In the amelioration of diabetes the standard drugs showed a better action, but as an antioxidant SMCS proved to be a better one.

Animals↗

[Glimepiride--an oral antidiabetic agent].

Glimepiride is the oral antidiabetic, second-generation sulfonylurea. It is structurally similar to glyburide. Glimepiride exhibited more potent glucose-lowering effects than glyburide and longer duration of hypoglycemic effect. Glimepiride is useful in the treatment of non-insulin-dependent (type II) diabetes mellitus. Glimepiride is indicated as an adjunct to diet and exercise for non-insulin dependent diabetes mellitus. Glimepiride reduces glucose levels blood by stimulating insulin release from functional pancreatic beta cells in response to glucose. Glimepiride in daily dose 1 to 8 mg is causing a dose-related decrease blood glucose levels and glycosylated hemoglobin fasting state and postprandially. If the maximum dose of glimepiride fails to lower blood glucose sufficiently, metformine or insuline may be added to glimepiride monotherapy. Glimepiride is very safe drug and adverse effects causing by glimepiride are very rare. The risk of hypoglycemia after use of glimepiride is very small, therefore is the therapy with glimepiride is more preferable than the therapy with glibenclamide.

Diabetes Mellitus, Type 2↗

Studies on antidiabetic effects of cortex Moutan polysaccharide-2b in type 2 diabetes mellitus rats.

AIM: To study the antidiabetic effects of cortex Moutan polysaccharide-2b (CMP-2b) in type 2 diabetes mellitus (T2DM) rats. METHODS: The T2DM model rats were induced by a single intravenous injection of low dose streptozotocin (STZ) and intake of high sucrose-fat diet. CMP-2b was given to T2DM rats daily through gavage for 4-5 weeks. The body weight, water and food intake, fasting blood glucose (FBG), glucose tolerance, plasma lipids, serum insulin, and insulin receptor (Ins R) were determined. RESULTS: Oral administration of CMP-2b significantly decreased water and food intake, FBG, total cholesterol (Tch), and triglyceride (TG), improved the impaired glucose tolerance (IGT), and remarkably raised the number of low affinity InsR and insulin sensitivity index (ISI) in T2DM rats. CONCLUSION: CMP-2b may be useful for treating T2DM and its complications.

Animals↗

A comparison of costs for four oral antidiabetic regimens within a managed care population.

A retrospective database analysis compared costs among patients with type 2 diabetes receiving four antidiabetic regimens: (1) repaglinide monotherapy, (2) metformin monotherapy, (3) repaglinide and metformin in combination, or (4) metformin and glyburide in combination. Pharmacy, medical, and total costs were measured for each cohort over a nine-month period. Although not statistically significant, total adjusted costs were lowest for the repaglinide-metformin combination ($8,924), followed by metformin monotherapy ($9,448), metformin and glyburide ($9,576), and repaglinide monotherapy ($11,910). These results must be confirmed in larger populations, but they imply that differences in pharmacy costs of repaglinide-metformin therapy are offset by measurable medical cost savings.

Administration, Oral↗