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PubMed1985

Long-range implications for the mother. The Aberdeen experience.

One hundred twelve women with impaired glucose tolerance (IGT) diagnosed by intravenous glucose tolerance test (IVGTT) after pregnancy were followed up for a period of up to 22 yr (mean 12.9 yr). About one-third have been treated with chlorpropamide and the others by diet only. At the final assessment, approximately 35% had abnormal intravenous glucose tolerance and less than 7% overt diabetes. Chlorpropamide did not prove significantly more effective than diet only. Factors associated with deterioration in glucose tolerance were age at diagnosis and follow-up and the initial fasting plasma glucose (FPG) level (greater than or equal to 5.8 mM), but obesity was less important, although it was associated with an increased rate of vascular complications. Tests for islet cell antibodies (ICA) were weakly positive in 12.5% of 72 subjects and in only 0.5% of an unselected population; they did not correlate with the final state of glucose tolerance. Only three patients developed insulin-dependent diabetes (IDDM) and did so before the ICA study was started. A comparison is made between the results reported by O'Sullivan in patients diagnosed as having gestational diabetes, only 2% of whom still had abnormal oral glucose tolerance postpartum, and the results of our patients, all of whom had IGT after pregnancy. In spite of differences of technique and in the populations studied, the prevalence of IGT and overt diabetes at follow-up was significantly less in the Aberdeen series, who were initially a higher risk group. It seems probable that this is mainly attributable to dietary treatment in the follow-up period as O'Sullivan's cases were treated only during pregnancy.

Adolescent↗
PubMedDate not supplied

Diabinese-Dialume: a potential catastrophe.

An oral hypoglycemic drug (Diabinese-chlorpropamide) was given inadvertently to a nondiabetic with renal insufficiency instead of the prescribed phosphate binder (Dialume-aluminum hydroxide). It was determined from this situation that hemodialysis is of no benefit in removing the drug from serum; the hypoglycemic effect of chlorpropamide is profound in nondiabetics, and the duration of therapy with dextrose infusions can be quite prolonged. We provide recommendations regarding therapy, bedside glucose monitoring, and prevention.

Adult↗
PubMed1961

Clinical experience with chlorpro-pamide.

Seventy-eight patients with mild diabetes were treated with chlorpropamide in doses up to 1 gm. daily. Eight showed primary failure to respond and two showed an initial but not a sustained response. Patients whose diabetes was of recent onset and who had not been treated with insulin or a sulfonylurea, required smaller doses than the remainder except for a group of patients who had been diabetic for more than 15 years. The average dose for the 64 patients who took chlorpropamide for more than three months was 0.46 gm. per day. Serious side effects were uncommon and disappeared when the drug was stopped. One patient became jaundiced, one had a rash, and one showed granulocytopenia. Changes in liver function tests were seen in 17 out of 56 patients treated for more than three months and were correlated with the dosage of the drug and the duration of treatment.

Chlorpheniramine↗
PubMed1992

Effect of glimepiride on the electrical activity of isolated rabbit heart muscle.

The effect of glimepiride (CAS 93479-97-1) on the electrical threshold, conduction time, effective refractory period and automaticity of left atrium and right ventricle in the isolated rabbit heart was investigated and compared with those of chlorpropamide and glibenclamide. From the sulphonylureas investigated only glibenclamide diminished the electrical activity of rabbit heart muscle preparations. Chlorpropamide and glimepiride have a mild effect to change the basic parameters on the opposite direction. It seems that glimepiride does not have a significant effect on cardiac muscle in vitro.

Animals↗
PubMed1985

Incidence of severe sideeffects during therapy with sulfonylureas and biguanides.

The most important side-effect of sulfonylureas is hypoglycaemia. According to surveys in Switzerland and in Sweden it occurs at a frequency of about 2 cases per 10,000 treatment years. Mortality is high, about 10%. The syndrome of inappropriate ADH-secretion has been observed almost exclusively during treatment with chlorpropamide. Asymptomatic cases of SIADH-syndrome are quite frequent, hyponatraemia has been observed in 6-10% of diabetics treated with chlorpropamide. The most dangerous side-effect of biguanides is lactic acidosis. It occurs significantly more frequent during treatment with phenformin compared to metformin. Metformin has been reported to lead to lactic acidosis in 0.4 cases per 10,000 treatment years; mortality is about 30%. Mortality of phenformin-associated lactic acidosis is even higher, 70%. Both biguanides, phenformin and metformin, cause relatively frequently vitamin B12-malabsorption (in about 1/3 of the cases). However, symptomatic vitamin B12-deficiency is extremely rare.

Acidosis↗
PubMed1982

Opiate receptors and the metabolic response to intravenous glucose.

The role of opiate receptors in the metabolic response to an intravenous glucose load was determined in eight non-diabetic subjects (four of whom showed a positive chlorpropamide alcohol flush response and four who did not). Subjects were studied in a double blind randomised fashion receiving either a saline control or the specific opiate receptor antagonist, naloxone (0.4 mg/min), as an infusion for 5 minutes before and 20 minutes after an intravenous bolus of glucose (0.5 g/kg body weight). Naloxone decreased the early plasma glucose peak in all subjects by increasing the distribution volume but did not alter the fractional glucose clearance. Insulin and glucagon responses to glucose were not altered by naloxone. Naloxone delayed the normal post-glucose rise in the levels of the gluconeogenic precursors alanine, lactate, pyruvate and glycerol suggesting a delay in the usual inhibition in gluconeogenesis following a glucose load. There was no difference in the metabolic response between those subjects who were liable to chlorpropamide alcohol flushing and those who were not either with or without naloxone. We conclude that opiate receptors may influence distribution volume and gluconeogenesis but do not play a major role in either insulin or glucagon secretion or in glucose disposal following an intravenous glucose load.

Alanine↗
PubMedDate not supplied

Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of glyburide and glipizide, two second-generation oral sulfonylurea hypoglycemic agents, are reviewed. Glyburide and glipizide are well absorbed after oral administration. The absorption of glipizide is delayed by food; in contrast, glyburide absorption does not seem to be affected by administration with meals. Both drugs are extensively metabolized by the liver. A two-compartment open model adequately describes the pharmacokinetics of these drugs. The apparent elimination half-life of glyburide in oral dosage forms available in the United States ranges from 7 to 10 hours. Glipizide has a terminal elimination half-life of 2-7 hours. The effects of renal and hepatic disease on the pharmacokinetics of glyburide and glipizide have not been well studied. Based on controlled, comparative studies in patients with new-onset, diet-failed, Type II diabetes, glyburide appears to be at least as effective as chlorpropamide and tolazamide in controlling blood glucose. Glipizide has shown efficacy comparable to or greater than that of chlorpropamide and tolbutamide. Glyburide and glipizide appear to be comparable in terms of their ability to control fasting blood glucose in Type II diabetics. The recommended initial dosage of glyburide in newly diagnosed Type II diabetics is 2.5-5 mg once daily. For glipizide, the initial dosage should be 5 mg once daily. Elderly or debilitated patients and those with renal or hepatic impairment should be started on lower dosages initially. Glyburide and glipizide have adverse effects that are similar to those observed with the first-generation oral hypoglycemic agents. Glyburide and glipizide do not appear to offer major therapeutic advantages over first-generation oral sulfonylurea hypoglycemic agents. However, they may represent therapeutic alternatives for some patients who do not respond satisfactorily to other sulfonylureas.

Chemical Phenomena↗
PubMedDate not supplied

[Effect of sulfonylurea preparations on the course of pregnancy and the state of the fetuses of female rats with alloxan prediabetes, latent diabetes and mild forms of manifest diabetes].

The influence of antidiabetic sulphanylamides, used before the occurrence of pregnancy, on the weight of fetuses and placentae was revealed in rats with alloxan "prediabetes", latent diabetes, and manifest diabetes. Diabetes compensation before the occurrence of pregnancy in rats with "prediabetes" and latent diabetes by means of chlorpropamide, and in rats with manifest diabetes with chlorpropamide together with biguanides led to a significant reduction of the weight of fetuses and prevented their death.

Animals↗
PubMed1976

Clinical evaluation of a new sulfonylurea in maturity onset diabetes - glipizide (K-4024).

Glipizide, a new low dose sulfonylurea, was evaluated for its efficacy and toxicity in a double-blind controlled study. Forty adult-onset diabetics were treated with either chlorpropamide or glipizide. In ten out of twenty patients "excellent" to "good" control of hyperglycemia was achieved with glipizide and two patients evidenced "fair" control. In nine out of eighteen patients "excellent" to "good" control was achieved with chlorpropamide. Eight of the sixteen patients who were primary or secondary failures on the two drugs responded to glipizide and phenformin combination with "excellent" to "good" control. No therapeutic advantage was found in giving more than 25 mg/day glipizide in ten patients. Toxicity was low and side effects were uncommon over a period of 26 months.

Adult↗
PubMed1998

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.

BACKGROUND: In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage. METHODS: Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10.7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L) were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268). FINDINGS: Median glycated haemoglobin (HbA1c) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011). Among patients allocated intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032). Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2-275], p=0.039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78). INTERPRETATION: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.

Chlorpropamide↗
PubMed1987

Effects of glucose on neuroblastoma in vitro and in vivo.

Because neuroblastoma cells in vitro are sensitive to changes in glucose levels in growth media, the effects of glucose levels and dietary carbohydrate on the sensitivity of neuroblastoma cells to chemotherapy were studied. In vitro, 20 microM bromoacetylcholine, 3mM 1,3-diaminopropane, and 5 mM 5-fluorouracil were added to the growth medium of strain N2a neuroblastoma cells cultured in Dulbecco's modified Eagle medium with high glucose (4.5 g/L, HG), normal glucose (1.0 g/L, NG), or low glucose (0.1 g/L, LG). Diaminopropane and 5-fluorouracil had some cytotoxic effect on cells in all media. Bromoacetylcholine killed cells in all media, but at a concentration of 20 microM was most effective in LG medium. Mice (A/Jax) were inoculated with neuroblastoma cells for in vivo studies. Mice could not tolerate a carbohydrate-free diet, while a high-carbohydrate diet caused no change in survival time. When mice on a high carbohydrate diet were treated with cyclophosphamide (100 mg/kg, ip) or 5-fluorouracil (125 mg/kg, ip) they died faster than drug-treated mice on a normal diet. Oral chlorpropamide or cimetidine did not prolong survival time. Analysis of blood glucose levels showed neuroblastoma significantly lowered blood glucose levels (p less than 0.05), while chlorpropamide had no significant effect. It is proposed that manipulation of plasma glucose to lower levels will not be effective in enhancing the chemotherapy of neuroblastoma.

Acetylcholine↗
PubMed1983

Sulphonylureas in vitro do not alter insulin binding or insulin effect on amino acid transport in rat hepatocytes.

The effects of four sulphonylureas (gliclazide, glibenclamide, chlorpropamide and glipizide) on insulin binding and insulin action were studied in vitro using primary cultured rat hepatocytes. Cells were cultured for 20 h in the absence or presence of the sulphonylurea. The binding of insulin to rat hepatocyte monolayers was not altered in cells previously exposed to gliclazide at 0.7, 7.0 or 70 micrograms/ml; and to glibenclamide, chlorpropamide, or glipizide at 0.1, 1.0 and 10 micrograms/ml. Insulin-induced down regulation was not affected by a simultaneous exposure of hepatocyte monolayers to any of the four agents. The stimulatory effect of insulin on alpha-aminoisobutyric acid uptake by the cells was not modified following exposure to the drugs. These studies indicate that the sulphonylureas tested do not have a direct effect on insulin receptors in hepatocytes; and that, in vitro, they do not alter the post-receptor events involved in the insulin-induced stimulation of amino acid transport in these cells.

Amino Acids↗
PubMed1981

Alcohol induced discoordination is not reversed by naloxone.

It has previously been reported that prior administration of naloxone may prevent the decrement in performance produced by alcohol. To be clinical value, however, naloxone must be shown to reverse rather than prevent this decrement. This study examined the effect of naloxone given after consumption of alcohol. A double blind balanced crossover protocol was used to examine the effect of either 1.2 mg or 10 mg naloxone on the sensory-motor impairment produced by blood alcohol concentrations maintained between 75 and 85 mg/100 ml. This alcohol concentration significantly impaired two measures of sensory-motor performance, but there was no evidence that either dose of naloxone could reverse this decrement. We tested our subjects for a chlorpropamide alcohol flush but none gave a positive response. These results indicate that naloxone (1.2 mg or 10 mg) does not reverse the sensory-motor impairment produced by alcohol intoxication in subjects who do not exhibit a chlorpropamide alcohol flush. Nearly all the subjects exhibited somnolence after receiving alcohol and naloxone (1.2 mg or 10 mg) but not after receiving alcohol and saline.

Adult↗
PubMed1986

Insulin release from a cloned hamster B-cell line (HIT-T15). The effects of glucose, amino acids, sulphonylureas and colchicine.

Insulin release from statically incubated HIT-T15 cells was maximally stimulated by glucose, L-arginine and L-leucine. L-arginine stimulated insulin release in the absence of glucose. Glucose induced insulin release was potentiated by the addition of L-leucine, L-arginine and the two in combination. Both glibenclamide and chlorpropamide stimulated insulin release from HIT-T15 cells. Glibenclamide was the more potent and equivalent in insulinotrophic action to 7.5 mmol/l glucose. Only chlorpropamide significantly potentiated glucose induced insulin release. Perifused HIT-T15 cells produced a reproducible biphasic insulin response to glucose challenge which was characterised by a pronounced and sustained first phase and a reduced second phase. The stimulation of phase I by glibenclamide alone and the inhibition of phase II of glucose induced insulin release by colchicine suggested the presence of a readily available pool of insulin granules which was not rapidly restored by insulin biosynthesis and granule margination.

Amino Acids↗
PubMed1980

Mutagenicity of sulphonylureas.

The 11 derivatives of beta-cytotropic sulphonylureas commonly used in the treatment of diabetes mellitus were tested in vivo in the highly sensitive sister-chromatid exchange test. Chlorpropamide and tolbutamide gave a positive reaction with a clear dose-response in Chinese hamsters and mice. The two compounds gave a mutagenic response neither in the Salmonella/mammalian-microsome mutagenicity test (with and without microsomal activation) nor in the chromosomal aberration test. In the micronucleus test, chlorpropamide was positive in 3 strains of mouse, tolbutamide in one strain. In Chinese hamsters and in rats the micronucleus test was negative with both compounds.

Animals↗
PubMed1988

Oral hypoglycemic agents.

The sulfonylureas remain the most important oral agents, although their chronic hypoglycemic actions are still unexplained and the evidence on their relative efficacy is inconclusive. Data on relative safety suggest that chlorpropamide is the most toxic sulfonylurea but glyburide causes dangerous hypoglycemia as often as chlorpropamide. For many patients, good blood glucose control will be achieved by taking tolbutamide or another sulfonylurea 30 minutes before breakfast and the main evening meal. The biguanide metformin, which is as safe as glyburide, is of use in treating overweight diabetic patients who do not have cardiovascular, hepatic, or renal dysfunction.

Administration, Oral↗
PubMed1996

Acetaldehyde metabolism by liver mitochondrial ALDH from UChA and UChB rats: effect of inhibitors.

We have observed that blood acetaldehyde (AcH) levels after an ethanol dose were significantly higher in disulfiram-pre-treated UChA (low ethanol consumer) than in UChB (high ethanol consumer) rats. In order to explore these results further, we studied the effect of disulfiram (300 mg/kg i.p.) and chlorpropamide (80) mg/kg i.p.) pre-treatment on blood AcH levels after oral ethanol (60 mmol/kg) and on AcH metabolism by liver mitochondrial aldehyde(s) dehydrogenase(s) from UChA and UChB rats. AcH metabolism by liver mitochondrial aldehyde dehydrogenase (ALDH) was studied by following AcH disappearance rate and the formation of NADH at 340 nm in the incubation medium. The results showed that chlorpropamide, like disulfiram, produced a higher blood AcH level consistent with a greater inhibition of the low-Km mitochondrial ALDH in the UChA rats than in the UChB rats. These drugs did not inhibit the high Km mitochondrial ALDH. Kinetic studies of mitochondrial ALDH show that low-Km mitochondrial ALDH from UChB rats exhibits a higher affinity for NAD than UChA rats. This observation could explain the different inhibition of ALDH by both drugs, assuming that the inhibitors reduce NAD availability, the rate limiting step in the mitochondrial ALDH oxidation.

Journal Article↗
PubMed2004

Position Paper on urine alkalinization.

This Position Paper was prepared using the methodology agreed by the American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT). All relevant scientific literature was identified and reviewed critically by acknowledged experts using set criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not considered. A draft Position Paper was then produced and presented at the North American Congress of Clinical Toxicology in October 2001 and at the EAPCCT Congress in May 2002 to allow participants to comment on the draft after which a revised draft was produced. The Position Paper was subjected to detailed peer review by an international group of clinical toxicologists chosen by the AACT and the EAPCCT, and a final draft was approved by the boards of the two societies. The Position Paper includes a summary statement (Position Statement) for ease of use, which will also be published separately, as well as the detailed scientific evidence on which the conclusions of the Position Paper are based. Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH > or = 7.5. The term urine alkalinization emphasizes that urine pH manipulation rather than a diuresis is the prime objective of treatment; the terms forced alkaline diuresis and alkaline diuresis should therefore be discontinued. Urine alkalinization increases the urine elimination of chlorpropamide, 2,4-dichlorophenoxyacetic acid, diflunisal, fluoride, mecoprop, methotrexate, phenobarbital, and salicylate. Based on volunteer and clinical studies, urine alkalinization should be considered as first line treatment for patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis. Urine alkalinization cannot be recommended as first line treatment in cases of phenobarbital poisoning as multiple-dose activated charcoal is superior. Supportive care, including the infusion of dextrose, is invariably adequate in chlorpropamide poisoning. A substantial diuresis is required in addition to urine alkalinization in the chlorophenoxy herbicides, 2,4-dichlorophenoxyacetic acid, and mecoprop, if clinically important herbicide elimination is to be achieved. Volunteer studies strongly suggest that urine alkalinization increases fluoride elimination, but this is yet to be confirmed in clinical studies. Although urine alkalinization is employed clinically in methotrexate toxicity, currently there is only one study that supports its use. Urine alkalinization enhances diflunisal excretion, but this technique is unlikely to be of value in diflunisal poisoning. In conclusion, urine alkalinization should be considered first line treatment in patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis. Urine alkalinization and high urine flow (approximately 600 mL/h) should also be considered in patients with severe 2,4-dichlorophenoxyacetic acid and mecoprop poisoning. Administration of bicarbonate to alkalinize the urine results in alkalemia (an increase in blood pH or reduction in its hydrogen ion concentration); pH values approaching 7.70 have been recorded. Hypokalemia is the most common complication but can be corrected by giving potassium supplements. Alkalotic tetany occurs occasionally, but hypocalcemia is rare. There is no evidence to suggest that relatively short-duration alkalemia (more than a few hours) poses a risk to life in normal individuals or in those with coronary and cerebral arterial disease.

Alkalies↗