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Sulfonyliminoimidazolidines, a new class of oral hypoglycemic agents. 3. Hypoglycemic activity and mode of action of 1-[p-[2-(crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexyl-2-imino- imidazolidine (CGP 11 112).

1-[p-[2-(Crotonylamino)-ethyl]-phenylsulfonyl]-3-cyclohexyl-2-imino- imidazolidine (CGP 11 112) is a representative of a new class of oral hypoglycemic agents. It lowers blood glucose in normal animals and in streptozocin (streptozotocin)-diabetic rats. In normal mice, rats and dogs the hypoglycemic effect is more potent (range 3-30 times) and has a shorter duration than that of tolbutamide. CGP 11 112 increases plasma insulin after oral administration in normal animals and stimulates release of insulin in perifused rat islets in vitro (sulfonylurea-like effect). In streptozocin-diabetic rats CGP 11 112 decreases blood glucose with a potency comparable to that of phenformin. In contrast to phenformin, CGP 11 112 does not increase blood lactate in diabetic rats or inhibit intestinal absorption of glucose. An effect of CGP 11 112 on gluconeogenesis and glycogenolysis could not be demonstrated. It is suggested that the hypoglycemic activity in streptozocin-diabetic rats may be due to stimulation of glucose efflux from the circulation. In vitro, CGP 11 112 inhibits glucose oxidation and lipolysis in isolated rat fat cells.

Adipose Tissue↗

Adherence to oral hypoglycemic agents in Hawaii.

INTRODUCTION: Adherence to oral hypoglycemic agents is essential to reducing the poor health outcomes of populations at high risk for developing diabetes and its chronic complications. The goal of this study was to identify characteristics of patients in Hawaii least likely to adhere to oral hypoglycemic agents. METHODS: This retrospective administrative data analysis included prescription refill claims for oral hypoglycemic agents from January 1, 1999, through June 30, 2003 (n = 20,685). Multivariate logistic regression analysis was used to examine the relationship between adherence and patient characteristics. RESULTS: Adherence was found to be strongly associated with age and ethnicity. Relative to the age subset 55 to 64 years, adherence increased as age increased, reaching a peak at age 74 (odds ratio [OR] 1.1; 95% confidence interval [CI], 1.0-1.20). Past the age of 85, adherence declined (OR 0.90; 95% CI, 0.82-0.98). Relative to white patients, the odds ratio of adherence was highest for Japanese patients (OR 1.20; 95% CI, 1.0-1.30) and lowest for Filipino patients (OR 0.78; 95% CI, 0.68-0.90). Gender was not associated with adherence. CONCLUSION: Differences in adherence to oral hypoglycemic agents were found to be related to ethnicity and age. Adherence was found to be lowest in younger patients and Filipino patients. This is a significant finding considering that younger diabetic patients have been shown to have the poorest glycemic control and worst health outcomes. Although the literature on adherence to oral hypoglycemic agents and health outcomes in Filipino patients is limited, studies support an increased risk for developing diabetes in this group. This information can be used to target younger patients and Filipino patients to improve their adherence to oral hypoglycemic agents.

Age Factors↗

Ocular effects of second generation oral hypoglycemic agents.

Second generation oral hypoglycemic agents, such as glyburide and glipizide, are often the treatment of choice in non-insulin dependent diabetes mellitus. These sulfonylureas are more potent osmotic agents than their predecessors and may give rise to crystalline lens changes and refractive error shifts in the absence of blood glucose variation. Such a case is presented, as is a detailed description of the mechanism of action of commonly prescribed oral hypoglycemic agents.

Administration, Oral↗

Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited.

BACKGROUND: Patients receiving oral hypoglycemic agents for diabetes mellitus are at increased risk of cardiovascular mortality. Oral hypoglycemic agents are inhibitors of the ATP-sensitive potassium (KATP) channel. Ischemic preconditioning is mediated by KATP channel activation. We therefore hypothesized that myocardium from patients taking long-term oral hypoglycemic agents would be resistant to the protection by ischemic preconditioning. METHODS AND RESULTS: Isolated human right atrial trabeculae were suspended in an organ bath at 37 degrees C, with field stimulation at 1 Hz. Control trabeculae were then subjected to 45 minutes of simulated ischemia (hypoxic, glucose-free buffer with pacing at 3 Hz) and 120 minutes of reperfusion. Ischemic preconditioned (IPC) trabeculae from patients without oral hypoglycemic therapy and from patients taking insulin (Ins+IPC) were given 5 minutes of simulated ischemia before this injury. Trabeculae (Oral Hypo+IPC) were obtained from patients taking long-term oral hypoglycemic agents and were also exposed to 5 minutes of simulated ischemia before this injury. Developed force (DF) was recorded. Recovery of DF relative to preischemic values was 28 +/- 4% in control trabeculae, whereas IPC trabeculae showed 52 +/- 5% recovery (P < .05 versus control). In patients receiving long-term oral hypoglycemic agents (Oral Hypo+IPC), recovery of DF was 27 +/- 3%, but in trabeculae from insulin-treated patients (Ins+IPC), it was 45 +/- 6%. CONCLUSIONS: Human myocardium from patients without long-term exposure to oral hypoglycemic agents is functionally protected by preconditioning. Long-term oral hypoglycemic intake blocks the protection by preconditioning. These data suggest that ischemic preconditioning in human myocardium relies on KATP channels, and long-term inhibition of KATP channels with oral hypoglycemic agents may explain the excess cardiovascular mortality in these patients.

Administration, Oral↗

Suicidal overdoses with hypoglycemic agents.

Suicide attempts using hypoglycemic agents are uncommon but are associated with a high level of morbidity and mortality. Their recognition is sometimes difficult and the duration of hypoglycemic effect is often prolonged. Two cases that illustrate the difficulties encountered in recognition and therapy are described. Effective therapy depends on adequate glucose supplementation to maintain euglycemia. Therapeutic intervention often must be maintained for several days. Glucocorticoids may be useful in difficult cases. Other modes of therapy, including glucagon, are unproven or controversial.

Adolescent↗

Depression in patients with type 2 diabetes: impact on adherence to oral hypoglycemic agents.

BACKGROUND: Adherence to oral hypoglycemic agents (OHAs) is important for adequate glycemic control and prevention of future complications in patients with type 2 diabetes. OBJECTIVE: To examine the impact of depression on adherence to OHAs in patients newly diagnosed with type 2 diabetes. METHODS: Patients newly diagnosed with type 2 diabetes during a 4 year period were identified from a Medicaid claims database. Presence of preexisting depression was determined on the basis of ICD-9-CM codes. Adherence to OHAs was computed using prescription refill data for a 12 month follow-up period from the date of the index OHA prescription. Two separate adherence indices (Medication Possession Ratio-1 [MPR-1], Medication Possession Ratio-2 [MPR-2]) were computed. The impact of depression on adherence was assessed after controlling for confounders such as demographics, comorbidity, provider interaction, complexity of regimen, and diabetes severity. RESULTS: A total of 1326 newly diagnosed patients with type 2 diabetes were identified (depressed = 471; nondepressed = 855). Results of the study indicated that patients with depression had significantly lower adherence (MPR-1 86%; MPR-2 66%) to OHAs compared with patients without depression (MPR-1 89%; MPR-2 73%). Multivariate results indicated that depression was a significant predictor of adherence, with depressed patients being 3-6% less adherent to OHAs than nondepressed patients, after controlling for confounding factors. CONCLUSIONS: Depression significantly impacts adherence to OHAs in patients with type 2 diabetes. The study results imply that depression screening and treatment need to be included in the protocol for management of patients with type 2 diabetes.

Administration, Oral↗

Stimulation of insulin release by non-sulfonylurea hypoglycemic agents: the meglitinide family.

Several new non-sulfonylurea hypoglycemic agents such as A-4166, KAD-1229 and repaglinide are structurally related to meglitinide, previously known as the non-sulfonylurea moiety of glibenclamide, or its analog S 3075. There is no parallelism between the ionophoretic and insulinotropic efficiency of these compounds. They are all able, however, to decrease K+ conductance in islet cells as documented by a decrease in 86Rb outlfow from prelabelled pancreatic islets. In terms of concentrations of equal insulinotropic capacity, a difference of at least two orders of magnitude is observed between the weakest (meglitinide) and most potent (S 3075) compound. All these agents exert little effect upon insulin release in nutrient-deprived islets, but markedly augment glucose-stimulated insulin release. The hexose can be replaced, however, by a non-glucidic nutrient such as the methyl ester of succinic acid to support the insulinotropic action of the meglitinide analogs. The question is raised as to the potential advantage of these non-sulfonylurea insulinotropic agents over hypoglycemic sulfonylureas.

Animals↗

Oral hypoglycemic agents for noninsulin-dependent diabetes mellitus in the cat.

The use of oral hypoglycemic agents for the treatment of noninsulin-dependent diabetes mellitus (NIDDM) is still in its infancy. The purpose of this article is to summarize the current knowledge regarding the use of oral hypoglycemic agents in cats. Oral hypoglycemic therapy is more successful when the veterinarian is aware of the mechanism of action of the drug, as well as its dosage, side effects, and drug interactions. A short section on combining insulin with oral hypoglycemics and monitoring therapy with oral hypoglycemic agents is also included.

Administration, Oral↗

Linogliride fumarate, representing a new class of oral hypoglycemic agent for diabetes.

This study presents the first multiday therapy trial of linogliride fumarate, a representative of a new class of oral hypoglycemic agents. Linogliride demonstrated a significant hypoglycemic activity in 26 patients with non-insulin-dependent diabetes mellitus receiving 1 week of therapy. In a dose range of 150 to 400 mg b.i.d., fasting glucose levels fell from 237 +/- 52 mg to 199 +/- 59 mg by day 7 (P less than 0.01). Eight-hour glucose AUCs fell from 2121 +/- 617 mg/dl/8 hr baseline to 1781 +/- 631 mg/dl/8 hr on day 7 of treatment (P less than 0.01). This was associated with a significant increase in insulin AUC from 380 +/- 327 to 610 +/- 417 on day 7 (P less than 0.01). Thus its initial action appears to be by an insulin secretagogue mechanism. No patient had any major adverse effect. This initial study indicates that linogliride fumarate is an effective hypoglycemic agent that significantly lowers fasting and postprandial glucose levels with short-term use. Linogliride fumarate represents a new group of hypoglycemic agents that may be shown to have therapeutic utility.

Administration, Oral↗

Inhibitory effect of cyclosporine A on the activity of oral hypoglycemic agents in rats.

Diabetic patients often have a kidney or pancreas allograft requiring cyclosporine A (CsA) to prevent transplant rejection. These patients usually take p.o. hypoglycemic agents to control their diabetes. Because of the reported adverse effects of CsA on glucose metabolism as well as its potential use in Type II diabetics, we were interested in evaluating the in vivo effect of CsA on the activity of p.o. hypoglycemic agents. We also wanted to determine if tolbutamide produced any adverse effects on the pharmacokinetics of CsA. Male, Holtzman rats were administered CsA (p.o.) followed 1 hr later with the hypoglycemic agent. Two hours later, blood samples were obtained to determine blood glucose levels. Animals treated with CsA alone produced a significant hyperglycemia. The hypoglycemic effects produced by tolbutamide and glyburide were inhibited in animals treated concomitantly with CsA. This inhibitory effect was not observed during the first 3 hr of CsA-treatment, could not be overcome by increasing the dose of the hypoglycemic agent and occurred using small doses. CsA did not, however, interfere with the activity of exogenous NPH insulin. Tolbutamide was found to have no effect on the acute pharmacokinetics of CsA. The distribution of CsA was similar to controls in all tissues studied except the liver in which CsA levels were less in tolbutamide-treated animals. These studies demonstrate that CsA interferes with the effects of p.o. hypoglycemic agents and, therefore, blood glucose levels should be monitored closely in Type II diabetic patients taking combinations of these drugs.

Administration, Oral↗

Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents.

We assessed the prevalence of hypoglycemic symptoms in patients (aged 40-65 yr) treated with oral hypoglycemic agents (OHAs) attending routine diabetes clinics at our hospital. Symptoms were experienced during the previous 6 mo in 41 of 203 (20.2%) patients treated with sulfonylureas but in none of the 16 patients treated with metformin alone. Hypoglycemic symptoms were experienced at least monthly in 5.9% and less frequently in 14.3% of patients. The prevalence of symptoms decreased with increasing duration of sulfonylurea administration (P less than .01). Mean glycosylated hemoglobin and postprandial plasma glucose were significantly lower in patients reporting hypoglycemic symptoms than in those without symptoms (P less than .001). The prevalence of hypoglycemic symptoms was significantly higher in patients treated with glyburide than in patients treated with gliclazide (P less than .01) or chlorpropamide (P less than .05). The prevalence of symptoms was higher in patients taking medications in addition to OHAs (P less than .01). Ten (24%) of the patients who experienced hypoglycemic symptoms were taking drugs that may potentiate sulfonylureas.

Adult↗

Trends in use of oral hypoglycemic agents 1964-1986.

Oral hypoglycemic (OH) agents have been available in the United States for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) for almost 30 yr. During this time they have been subject to considerable controversy. In this article, we present pharmaceutical marketing research data that provide a review of several facets of OH use. The number of OH prescriptions dispensed peaked in 1973, decreased through 1980, and has been increasing since that year. In 1986, OH agents accounted for 21.5 million prescriptions: 1% of all prescriptions dispensed that year. Chlorpropamide is currently the most frequently ingested OH agent; it is used by 33% of the market. The two OH agents introduced in 1984, glyburide and glipizide, had acquired 41% of the OH market by the end of 1986. The rate of OH use per 1000 diabetes mellitus visits increases with patient's age. Patients aged 60 yr and older received OH prescriptions at a rate of 478 per 1000 diabetes mellitus visits in 1986. Data estimating both the number of patients diagnosed with diabetes and the number of diabetic patients taking OH agents indicate that the percentage receiving OH treatment has increased over the past 5 yr, with approximately 35% of all diabetic patients taking OH agents in 1986.

Diabetes Mellitus, Type 2↗

Conformational analysis of non-sulfonylurea hypoglycemic agents of the meglitinide family.

Non-sulfonylurea hypoglycemic agents of the meglitinide family such as S3075, repaglinide, KAD-1229, and A-4166, were found to display a comparable U-shaped conformation by molecular modelling, with hydrophobic cycles placed at the extremity of each branch and a peptidic bond placed at the bottom of the U. A comparable conformation was observed with the hypoglycemic sulfonylureas glibenclamide and glimepiride. A different conformation with a greater distance between the hydrophobic cycles at the extremity of each branch was found, however, with the biologically inactive enantiomers of A-4166 and repaglinide and the poorly efficient insulinotropic agent meglitinide. The identification of a common conformation of these hypoglycemic agents may help in the design of highly active compounds and provide an imprint of their postulated target receptor on the pancreatic B-cell plasma membrane.

Benzamides↗

Effect of KAD-1229, a nonsulfonylurea hypoglycemic agent, on plasma glucose and insulin in streptozotocin-induced diabetic dogs.

Hypoglycemic agents with a rapid onset and short duration of action should be useful for controlling postprandial hyperglycemia. Our aim was to establish a diabetes mellitus model in dogs, and then during an oral glucose tolerance test to compare the hypoglycemic effect and insulinotropic action of KAD-1229, a new hypoglycemic agent, with that of gliclazide, a conventional sulfonylurea. In this model, KAD-1229 reduced the increase in plasma glucose level without producing hypoglycemia. Gliclazide had a weaker effect on reduction of the glucose increase and caused hypoglycemia via a significantly raised insulin secretion in the late phase. A rapid insulinotropic action of KAD-1229 was clearly observed in the portal venous blood. The results suggest that in type 2 diabetes caused by, at least, insulin deficiency, KAD-1229 may improve impaired insulin secretion in the early phase and attenuate hyperglycemia without causing a sustained hypoglycemia.

Animals↗