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[Metabolites of hypoglycemic sulfonylureas in kidney failure. Experience with glibenclamide].

Renal insufficiency is a factor which predisposes to hypoglycemic accidents in subjects treated with hypoglycemic sulfonylureas. Glibenclamide (glyburide) is eliminated from the body mainly by metabolism, with the result that renal insufficiency has little effect on its biotransformation. In order to determine to what extent the retention of the metabolities intervenes in such hypoglycemic accidents, rats with ligatured ureters received intraperitoneal injections of 1 mg/kg glibenclamide or hydroxy-glibenclamide (the main metabolite), or of saline. For each animal there was a control animal which had undergone a simulated operation. For six rats with renal insufficiency, glibenclamide caused hypoglycemia of the same intensity as in the control group but more prolonged. With hydroxy-glibenclamide the glycemia was signficantly lower than in the control group. Hydroxy-glibenclamide has an obvious hypoglycemic activity which represents 1/6 of that of the parent drug, but 50--100 times that of tolbutamide. Its retention contributed to the intensification and prolongation of the hypoglycemic effect of glibenclamide in rats with renal insufficiency.

Acute Kidney Injury

Studies on the biochemical aspects of the 'disulfiram-like' reaction induced by oral hypoglycemics.

In vitro experiments, using rat liver homogenates, were designed to examine certain of the proposed enzymatic mechanisms for the interaction of oral hypoglycemic drugs with monoamine and ethanol metabolism. The oxidative degradation of tryptamine was studied by measuring indoleacetic acid (IAA) production and conclusions were drawn with regard to the activity of monoamine oxidase, aldehyde dehydrogenase and ethanol dehydrogenase. Acetohexamide, hydroxyhexamide, tolazamide, tolbutamide and chlorpropamide failed to reveal any specific inhibition of the three enzymes. Ethanol (0.2% w/v) and disulfiram decreased IAA formation, as did a lack of available aldehyde dehydrogenase and NAD, but these reductions were not enhanced by the hypoglycemic agents. The results suggest that the 'disulfiram-like' reaction which occurs in certain patients imbibing ethanol while receiving oral hypoglycemic drugs, depends upon some factor(s) other than, or additional to, a specific interference with monoamine and/or ethanol metabolism.

Administration, Oral

Indolizines II: search for potential oral hypoglycemic agents.

A few 1,2-bis(N-alkylaminomethyl)indolizines, simple indolizinecarboxylic acids, and several 6-alkoxyindolizine-2-carboxylic acids were synthesized and screened as possible oral hypoglycemic agents. The absence of any significant hypoglycemic activity excludes these compounds from the predicted structural lead provided by some hypoglycemic Vinca alkaloids, such as vincamine, vindoline, and vindolinine, having the indolizine ring as one structural component. But an extension of the rationale that indolizines are also the structural components of some carcinolytic Vinca alkaloids, such as vincristine and vinblastine, used in cancer chemotherapy provided encouraging results. One indolizine derivative showed significant antineoplastic activity in Ehrlich ascites carcinoma.

Administration, Oral

[Hypoglycemic sulfonylurea metabolites: clinical interest. Experiences with glibenclamide in the rat].

Glibenclamide, a hypoglycemic sulfonylurea, is extensively metabolized by the body and eliminated primarily in the form of its hydroxylated derivatives. The major metabolite, 4-trans-hydroxy-glibenclamide, is usually cleared rapidly from the bloodstream, but in certain pathological states (e.g. renal failure) blood levels of this product may increase. A protocol therefore was designed to test the hypoglycemic potency of this important metabolite in rats. Various quantities were injected intraperitoneally, and alterations in blood glucose concentrations were measured during a 5-hour period and compared to those in animals similarly treated with glibenclamide and in saline-injected controls. Using the dose capable of decreasing blood glucose levels by 30% (ED30) as a comparative index, it was observed that the metabolic has a marked hypoglycemic activity; though 6--7 times less potent than the parent drug, 4-trans-hydroxy-glibenclamide is nevertheless more potent than tolbutamide. Thus, while the glibenclamide metabolite probably has little influence on blood glucose when its clearance is normal, this product may exert marked effects if allowed to accumulate in the blood, as for example in renal failure. Finally, the role of such sulfonylurea metabolites should be taken into account when attempting to explain the occasional excessive and sustained hypoglycemia which occurs in some diabetic patients treated with these drugs.

Animals

Oral hypoglycemic agent update.

The treatment of diabetes is still a problem more than a half-century after the discovery of insulin. Patients are now living significantly longer but until the development of oral hypoglycemic agents, the only direct treatment modalities were exercise, diet, and insulin. Before evaluating the effectiveness of treatment, a therapeutic goal must be determined. While there are no absolutely "hard" facts proving that "good control" is beneficial in preventing chronic complications of diabetes, increasing accumulation of "soft" data strongly suggests that normal blood glucose levels are most desirable, when possible, but not at the cost of severe or disabling hypoglycemic reactions. The development of the oral agents was a great public health advance in that many persons with early diabetes, but fearful of insulin injections, had less dread of "the pills" and sought treatment. The oral agents simplified care but this very simplification process often undermined the need for proper diet and good fundamental care. This often led to mediocre diabetes care. While useful, the oral agents have marked limitations and in some are effective only temporarily. The presently available oral agents are sulfonylureas and require a viable beta-cell system for success. This limits the number of diabetics responsive to such treatment. The general indications for tolbutamide, chlorpropamide, acetohexamide and tolazamide are in maturity-onset diabetics, generally beyond the age of 40 with diabetes of less than 10 years. They are contraindicated in juvenile-onset diabetics, in pregnant women, and usually in patients undergoing major surgery, and can become ineffective during periods of extreme stress or during severe infection. They can lower blood glucose levels if used in proper doses in properly selected patients. Contrary to several decades of documentation, it has become popular to suggest that the oral agents are not effective. They can be effective but for many reasons apparently were not in their use by the U.G.D.P. researchers. This might not be the fault of the oral agent used. If ineffective, they should be discontinued. Many, but not all, patients may respond to diet therapy, which is then the treatment of choice. Obviously insulin, though difficult to use for many persons and in itself able to induce several severe reactions if not used properly, is the only treatment (with diet) for the severe diabetic. There is a large spectrum of patients inbetween in whom the oral agents may be useful. The use of phenformin (phenethyl-biguanide) has been effectively curtailed because of many reported cases of lactic acidosis, and while it is doubtful that phenformin alone, in the absence of complicating factors, is the causative factor, it is capable of being an augmenting influence when other conditions, such as decreased kidney function, prevail...

Administration, Oral

Synthesis and hypoglycemic activity of S-acyl derivatives of 3-mercaptopicolinic acid.

A series of S-alkanoyl and benzoyl derivatives of 3-mercaptopicolinic acid (3-MPA) was prepared and studied for hypoglycemic activity. Three alkanoyl derivatives (propionyl, pivaloyl, and 1-adamantanecarbonyl, 19-21) were prepared with increasing bulk around the thio ester bond. The benzoyl derivatives contained aromatic substituents chosen from a sigma-pi cluster chart so that the esters prepared had a wide range of electronic and solubility properties. In general, compounds with substituents which increased lipid solubility [p-chlorobenzoyl (4), p-trifluoromethylbenzoyl (6), and pivaloyl (20)] had the greatest potency at a dose of 300 mg/kg. Hydrolysis rates, measured at pH 6 and 8, indicated that in vivo breakdown to 3-MPA probably did not account for the observed hypoglycemic activity of the esters. 4, 6, and 20 were less potent than 3-MPA in comparative dose range studies.

Acylation

A pharmacologic profile of McN-3495 [N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide], a new, orally effective hypoglycemic agent.

McN-3495, a new compound unrelated strucuturally to the sulfonylureas or phenformin, has been found to produce a hypoglycemic effect in nondiabetic rats, dogs, mice, and monkeys. The minimum effective dose of McN-3495 that lowers fasting blood glucose and improves glucose tolerance was found to be about 2.5 to 5 mg-per kilogram, per os, except in fasted monkeys, in which a tenfold greater potency was observed. When McN-3495 was given repeatedly for three to five days, no tolerance to the hypoglycemic activity occurred and no changes in other biochemical parameters were observed. In addition to being three to four times more potent than tolbutamide, McN-3495 also differs from the sulfonylureas in lowering blood glucose concentrations of streptozotocin-diabetic rats and db/db mice, and, moreover, oral administration to normal fasted dogs did not produce the characteristic rise in insulin concentrations observed with tolbutamide. Furthermore, unlike the biguanides, McN-3495 can lower dog and rat fasting blood glucose concentrations and can improve glucose tolerance whether the glucose is administered orally or parenterally. However, McN-3495, as phenformin, fails to work in totally depancreatized dogs.

Animals

Prevention of hypoglycemic attacks by propranolol in a patient suffering from insulinoma.

An insulinoma was diagnosed in a fifty-seven-year-old woman suffering from frequent hypoglycemic attacks. Propranolol--a beta-adrenergic blocker--in a dose of 80 mg. per day effectively prevented recurrent hypoglycemic attacks. It also corrected the basal hyperinsulinemia as well as the increased insulin secretion which results from stimulation with glucose or arginine.

Adenoma, Islet Cell

(exo, exo)-2-Aryltropane-3-carboxylic esters, hypoglycemic agents with accompanying analgesic activity.

(exo, exo)-2-Aryltropane-3-carboxylic esters of types 6, 7, and 10 lower circulating blood glucose levels by 60--80%. This activity is accompanied by an analgesic activity roughly equal to that of codeine. Both of these activities reside in the 1R enantiomer and extensive structure-activity studies failed to separate them. The specific opioid antagonist nalorphine blocks the analgesic activity but does not diminish the hypoglycemic action. Conformational integrity afforded by the ethylene bridge is neccessary for the observed activities.

Administration, Oral

Potentiation of hypoglycemic effect of chlorpropamide and phenfromin by halofenate.

The potentiation of oral hypoglycemic drugs by the antilipemic agent halofenate is reported. Forty-seven diabetic patients were treated for 48 weeks with halofenate, clofibrate, or placebo. Five patients in the halofenate group were taking phenformin plus either chlorpropamide or tolbutamide. Their average initial fasting plasma glucose was 160 mg./dl. All five patients experienced a slow but but substantial fall in fasting plasma glucose. The mean fasting plasma glucose for the five patients after 80 days of halofenate treatment was 63 mg./dl. As oral treatment for diabetes was reduced, the fasting plasma glucose returned to prehalofenate levels. In this study, we did ont detect an effect of halofenate on the fasting plasma glucose of diabetic patients treated with insulin or on the fasting plasma glucose levels of patients treated with diet alone.

Blood Glucose

The effects of long-term therapy with oral hypoglycemic agents on the oral glucose tolerance test dynamics in male chemical diabetics.

The effect of fixed doses of oral hypoglycemic agents and placebo (diet alone) on the blood glucose, serum insulin, triglyceride, and cholesterol responses during oral glucose tolerance tests done annually for up to four years' follow-up was studied, in a double-blind manner, in five groups of mild male chemical diabetics. The drugs used were chlorpropamide (100 mg. O.D.), tolbutamide (500 mg. b.i.d.), phenformin (50 mg. O.D.), acetohexamide (250 mg. O.D.), and placebo. Each subject was given an individualized diet aimed at attaining and maintaining ideal weight. Comparison by chi-square analysis between the placebo group and each of the drug groups showed (a) no significant differences with regard to the number of subjects with normal glucose tolerance in each of the tests and (b) no change in the insulin secretion dynamics. Comparison between the initial test and each of the subsequent tests within each group showed (a) a greater number of subjects with normal glucose tolerance in the first follow-up test in the chlorpropamide group only, (b) no change in the insulin secretion dynamics except in the chlorpropamide group, where there was an increased insulin/glucose ratio in the first follow-up test, and (c) no change in the fasting serum triglyceride and cholesterol levels.

Acetohexamide

The prognostic importance of plasma glucose levels and of the use of oral hypoglycemic drugs after myocardial infarction in men.

The relationship of plasma glucose levels to risk of death over a five-year follow-up period was studied in 2,770 male survivors of myocardial infarction in the placebo group of the Coronary Drug Project (CDP). In univariate analyses, a positive association was observed between mortality rates and both fasting and one-hour glucose levels. After adjustment for 38 other baseline characteristics, the strengths of these relationship were substantially diminished; however, an increased mortality persisted in patients with fasting glucose levels larger than or equal to 140 mg./dl. after adjustment for other risk variables. There exists some evidence of an increased mortality risk in users of oral hypoglycemic (OH) agents over that of nonusers at baseline in men with elevated baseline glucose levels. However, the results must be interpreted with great caution both because they are of only borderline statistical significance and also because various factors not recorded in the CDP might have influenced the results.

Administration, Oral

Discriminant--analytical investigation on the structural dependence of hyperglycemic and hypoglycemic activity in a series of substituted o-toluenesulfonylthioureas and o-toluenesulfonylureas.

The influence of a series of substituted o-toluenesulfonylthioureas and o-toluenesulfonylureas on the level of blood sugar was investigated in rats. According to the observed response the compounds were divided into three classes corresponding to hypoglycemic, hyperglycemic, and no activity. The distribution of the compounds over these classes can be described by discriminant functions using substituent constants, RM values, and indicator variables. Most important for the separation of classes are hydrophobic and/or steric properties as well as the presence or absence of the thiomide group. The results indicate that two different mechanisms of action with opposite effect overlap in the case of the series studied.

Animals

Isolated corticotrophin-deficiency found through alcohol-induced hypoglycemic coma.

A case of hypoglycemic coma after alcohol ingestion was observed in a chronic alcoholic. Upon close examination isolated corticotrophin-deficiency was found. It is suggested that ethanol-induced hypoglycemia may be consistent with dysfunction of mitochondria in hepatic cells and that there may be disorder of the hypothalamus in the chronic drinker.

Adrenocorticotropic Hormone

[Semi-automatic determination of blood lactate during hypoglycemic treatment with biguanides].

Blood lactate levels were determined by Lactate Analyzer 640 Kontron in 67 adult insulin-independent diabetics during hypoglycemic treatment with usual therapeutical doses of phenformin. In 5 cases were found lactate values above 2 mmol/l and, in consideration of accompanying conditions prone to lactic acidosis, the drug was discontinued. However, the mean value of blood lactate in diabetics treated with phenformin was not significantly different from that found in a group of insulin-treated diabetics. The semiautomatic determination of blood lactate is proposed as a rapid screening of possible candidates for lactic acidosis during biguanide treatment.

Autoanalysis

[Hypoglycemic convulsions and hypopituitarism].

A case of hypopituitarism in a female, aged 6 months, whose first symptom consisted of hypoglycemic convulsions is reported. Making use of TRH we confirm the hypothalamic origin of pituitary failure. Substitution therapy controlled the episodes of convulsions and normalized the growth rate of the child.

Adrenocorticotropic Hormone

Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemic disorders.

Proinsulin is converted to insulin and C-peptide in the pancreatic in the pancreatic beta cells: the latter two peptides are secreted in equimolar concentrations. Thus, measurements of serum C-peptide provide a means of assessing pancreatic beta cell function in addition to that of insulin. This technique has proved particularly useful in insulin treated diabetic patients in whom the development of circulating insulin antibodies interferes with the radioimmunoassay of the hormone. The C-peptide assay has also been used to facilitate the diagnosis of various hypoglycemic conditions, including islet cell tumors and factitious injection of insulin. The extraction of C-peptide in the urine reflects average serum values over a period of time and urine C-peptide measurements are especially useful in children or individuals in whom repeated blood sampling is difficult.

Adenoma, Islet Cell

[Hypopituitarism in the aged. Report of a case revealed by hypoglycemic coma (author's transl)].

The diagnosis of anterior pituitary insufficiency is difficult in the elderly and frequently made when the patient become comatose. At this age hypoglycemia is rarely the exclusive factor of this coma. The authors report a case revealed by hypoglycemic coma and supported by the lack of stimulation by the releasing factors. None etiology was found. With hormone treatment the patient recovered a normal life.

Aged