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PubMed1978

The effects of chlorpropamide and insulin on serum lipids, lipoproteins and fractional triglyceride removal.

The effects of chlorpropamide on serum lipids, lipoproteins and fractional triglyceride removal have been studied over 12 months on 10 maturity onset diabetics not controlled on diet alone. Similar studies were carried out in 6 maturity onset diabetics who had failed to respond to sulphonylureas and 6 new insulin requiring diabetics. In the chlorpropamide treated patients there was an initial fall in serum and VLDL triglyceride but this effect was lost at 12 months. There was no change in fractional triglyceride removal. At 12 months there was a fall in LDL and a rise in HDL choelsterol. An initial improvement in glucose tolerance and insulin secretion was maintained at 12 months. In the insulin treated group the initial fall in serum and VLDL triglyceride was maintained at 12 months and was accompanied by an increase in fractional triglyceride removal. There was also a fall in LDL and a rise in HDL cholesterol at 12 months. The failure of chlorpropamide to maintain the reduction in serum and VLDL triglyceride could be of importance in the genesis of coronary heart disease in maturity onset diabetics. The fall in LDL and rise in HDL cholesterol found both with chlorpropamide and insulin might be beneficial.

Adult↗

PubMed1980

Treatment of diabetes insipidus complicated by diabetes mellitus with chlorpropamide and clofibrate.

A patient with severe idiopathic diabetes insipidus, complicated by diabetes mellitus, was first treated with a combination o clofibrate and chlorpropamide. Urine volume dropped from 18 litres/day (CH2O = 10.5 ml/min) to 3.1-5.1 litres/day (CH2O = -0.1 -+1.1 ml/min) under treatment. Ten months after the beginning of therapy treatment was maintained with chlorpropamide alone; no significant rise in urine volume was observed. After 18 months when therapy was stopped for 5 days urine volume rose to 11.7 litres/day maximum (CH2O = 6.6 ml/min). No obvious side effects occurred under treatment during a follow up for over 18 months. Serum levels for arginine vasopressin before and under treatment were below 1.0 pg/ml. Determination of free water clearance (CH2O) proved to be a highly sensitive and simple method for follow up controls. It is discussed whether the coincidental manifestation of diabetes insipidus and diabetes mellitus may be caused by a single molecular lesion. This hypothesis is supported by data which imply that in both disease chlorpropamide acts via a common molecular mechanism, the blocking of endogenous prostaglandin E2 biosynthesis. Finally a treatment with oral "non-hormonal" drugs like clofibrate and chlorpropamide should be taken into consideration in some cases of diabetes insipidus as is demonstrated by this case report.

Adult↗

PubMed1987

Effect of chlorpropamide on glucose transport in rat adipocytes in the absence of changes in insulin binding and receptor-associated tyrosine kinase activity.

In an attempt to elucidate the cellular mechanism(s) by which sulfonylureas exert their extrapancreatic hypoglycemic effects, various parameters of insulin action were examined in vitro, using rat adipocytes maintained in a biochemically defined medium. Cells were maintained for 20 hours in the absence or presence of 175 micrograms/mL chlorpropamide and insulin binding, hexose transport, glucose metabolism, and insulin receptor tyrosine kinase activity were compared. Chlorpropamide treatment had no effect on insulin binding, altering neither receptor number nor affinity. However, the sulfonylurea did enhance 2-deoxyglucose transport in both the absence (17%, P less than .01) and presence (20%, P less than .01) of insulin. Furthermore, glucose metabolism as measured by the conversion of glucose (0.2 mmol/L) to CO2 and total lipids was also significantly increased by chlorpropamide treatment in both the absence (30%, P less than .01) and presence (31%, P less than .05) of insulin. Potentiation of insulin-stimulated transport or metabolism was not explained by an increase in the basal state alone because the incremental responses to 40 ng/mL insulin were potentiated by 19% (P less than .01) and 25% (P less than .05), respectively. Activity of the insulin receptor kinase was unchanged as evaluated by autophosphorylation of partially purified receptors, phosphorylation of an artificial substrate and by phosphorylation of the receptor in situ. These studies demonstrate that the sulfonylurea, chlorpropamide, stimulates glucose transport and potentiates insulin's effect on this process by acting at a site(s) beyond insulin receptor binding and phosphorylation.

Adipose Tissue↗

PubMed1975

Long-term comparative trial of glibenclamide and chlorpropamide in diet-failed, maturity-onset diabetics.

The long-term clinical effectiveness of glibenclamide was compared with chlorpropamide in highly comparable groups of three hundred and twenty-one diet-failed, non-obese, maturity-onset, newly diagnosed diabetics. The overall primary failure-rate in the chlorpropamide-treated patients was significantly less (p<0.05), and more patients were on chlorpropamide at the end of two years than were on glibenclamide (p<0.01). Although there were fewer secondary failures with chlorpropamide treatment, this difference was not significant. The final blood-glucose and change in body-weight were similar in patients from both treatment groups still taking the original sulphonylurea agent 2 years later. Hypoglycaemic episodes were more common and severe in the glibenclamide-treated patients.

Adult↗

PubMed1986

Chlorpropamide-alcohol flush reaction and isoenzyme profiles of alcohol dehydrogenase and aldehyde dehydrogenase.

To investigate the enzymatic basis of the chlorpropamide-alcohol flush reaction (CPAF) we compared the isoenzyme profiles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from liver biopsies, and of ALDH alone from erythrocytes and leucocytes, in CPAF-positive and CPAF-negative subjects. No differences were seen in ADH or ALDH phenotypes, or in the relative activities of the isoenzymes, between the two groups before chlorpropamide was given; in particular, no subjects showed the 'null' ALDH phenotype that is associated with the alcohol flush reaction in oriental subjects. There was a significant decrease in erythrocyte ALDH activity after 7 days' treatment with chlorpropamide in CPAF-positive individuals but no such difference was seen in CPAF-negative subjects. These results indicate that CPAF has a different enzymatic basis from the alcohol flush reaction of oriental subjects and suggest that in CPAF-positive subjects erythrocyte ALDH may be particularly susceptible to inhibition by chlorpropamide.

Alcohol Dehydrogenase↗

PubMed1989

Postreceptor regulation of insulin action in primary cultures of rat hepatocytes by oral hypoglycemic agents: effects of linogliride and chlorpropamide.

We have previously demonstrated the ability of the sulfonylurea tolazamide to potentiate insulin action in primary cultures of hepatocytes prepared from normal and streptozotocin-diabetic rats. To determine whether the pirogliride derivative linogliride, a non-sulfonylurea orally effective hypoglycemic agent, can potentiate insulin action, we evaluated the ability of linogliride to affect insulin-stimulated lipogenesis in primary cultures of hepatocytes prepared from normal rats. In addition, we also evaluated the ability of the sulfonylurea chlorpropamide to affect insulin-stimulated lipogenesis in the same in vitro system. The exposure of hepatocytes for 18 h to either linogliride (100 ug/ml) or chlorpropamide (175 ug/ml) resulted in dose-dependent (0.1 to 100 nM insulin) increases in insulin-stimulated lipogenesis, although the effects of chlorpropamide are approximately two times those of linogliride. This increase in insulin responsiveness was not associated with any change in insulin sensitivity (ED50) or insulin binding. The results provide evidence for an extra-pancreatic effect of linogliride and chlorpropamide in the liver and indicate that these structurally unrelated oral hypoglycemic agents enhance insulin responsiveness through postbinding mechanisms.

Animals↗

PubMed1999

Chlorpropamide toxicity with survival despite 27-day hypoglycemia.

CASE REPORT: In the past 5 years at our institution, 12 cases involving the ingestion of chlorpropamide 3-15 g were fatal. We report a 23-year-old woman with an estimated ingestion of chlorpropamide 5-10 g. Initial cardiovascular collapse, attributed to the blockade of potassium channel transport, responded to intensive support including 3 days of cardiac pacing. Urinary excretion of chlorpropamide and hypoglycemia persisted until day 27. The toxic mechanisms and high risk of chlorpropamide are summarized. A fatal therapeutic dose ratio as low as 4:1 has made this antidiabetic agent obsolete.

Adult↗

PubMed1981

Chlorpropamide-induced Syndrome of Inappropriate Antidiuretic Hormone Secretion.

The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is a rare but serious complication of chlorpropamide therapy. In 2 elderly women who had diabetes mellitus, the SIADH developed two months after the chlorpropamide dosage had been increased to 500 mg daily. The syndrome disappeared after withdrawal of the drug. In one of these patients, re-administration of chlorpropamide resulted in recurrence of the SIADH. A review of the current literature disclosed certain common denominators, i.e., most of the patients are elderly women whose dosage of chlorpropamide was increased shortly before the development of the SIADH.

Aged↗

PubMed1979

The assay and stability of chlorpropamide in solid dispersion with urea.

Thin layer chromatography followed by reflectance densitometry has been used to evaluate the stability of chlorpropamide-urea during the fusion process. Urea was found to decompose to biuret and chlorpropamide to p-chlorobenzenesulphonamide: several other unidentified decomposition products were detected. The energy for decomposition of chlorpropamide was 57.1 kJmol-1 for melts containing 15 and 30% chlorpropamide. Decomposition followed apparent first order kinetics.

Chlorpropamide↗

PubMed1985

Inhibition of hormonal activation of hepatic phosphorylase by chlorpropamide: evidence for an intracellular site of drug action.

Phosphorylase a activity was measured in hepatocytes from fed rats, some of which received ip chlorpropamide injections for 5 days preceding death (20 mg/100 g BW X day for 5 days). Chlorpropamide treatment significantly depressed basal phosphorylase a activity and lessened the increments in the activity of this enzyme induced by 10(-10) -10(-8) M glucagon and arginine vasopressin. The reductions in phosphorylase a activity after treatment with chlorpropamide were more than sufficient to explain the accompanying decreases in hepatic glucose production. Since glucagon and arginine vasopressin stimulate alternate pathways of phosphorylase activation and since chlorpropamide antagonizes both hormones, it is likely that the drug acts at or distal to the intracellular site (phosphorylase kinase) at which the two activation pathways converge.

Animals↗

PubMed1976

Chlorpropamide-induced hyponatremia.

A 29-year-old woman with severe idiopathic diabetes insipidus, while being treated by a combination of chlorpropamide and chlorothiazide, developed the syndrome of inappropriate secretion of ADH (SIADH) following an overdose of chlorpropamide. The syndrome resolved as the serum chlorpropamide level fell. This report demonstrates that a chlorpropamide-induced SIADH can occur in a patient with idiopathic diabetes insipidus, and it appears that the antidiuretic effect of the drug is dose-related.

Adult↗

PubMed1981

Increase of plasma acetaldehyde. An objective indicator of the chlorpropamide alcohol flush.

Chlorpropamide alcohol flushing (CPAF) in non-insulin-dependent diabetics (NIDDs) has been reported to be associated with a lower tendency to develop late complications. The flush was thought to be mediated by enkephalins and prostaglandins. Early studies could not correlate CPAF to increased levels of acetaldehyde in blood and the flush was not regarded as an antabuse-like reaction. In this study, the increase of plasma acetaldehyde during the flush in 13 CPAF positive diabetics was significantly (P less than 0.005) higher than in the 13 CPAF negative diabetics during a CPAF challenge test. The increase of plasma acetaldehyde was reduced to the level of CPAF negative diabetics in three CPAF positive diabetics when they were exposed to alcohol without premedication with chlorpropamide and they did not flush. The normal breakdown of ethanol to acetic acid via acetaldehyde appears to be inhibited by chlorpropamide in the flushers. Acetaldehyde measurement is an objective method to study the chlorpropamide alcohol flush and it appears superior to the measurement of skin temperature.

Acetaldehyde↗

PubMedDate not supplied

Comparison of chlorpropamide and glibenclamide treatment of maturity-onset diabetes: control assessed by fasting plasma glucose concentrations.

Twelve maturity-onset diabetic subjects were treated with chlorpropamide once daily, glibenclamide once daily, or glibenclamide twice daily in a crossover design study. Doses were increased until the fasting blood glucose concentrations became less than 6 mmol/L (108 mg/dl), at which time the patients were admitted for a 24-h study period. There was little difference between the plasma glucose and insulin responses to chlorpropamide or glibenclamide given twice daily (mean doses 489 and 11 mg/day, respectively). When glibenclamide was given once daily (mean dose 9 mg/day), similar plasma glucose concentrations during the day were obtained with slightly higher plasma glucose concentrations during the night. Four patients had chlorpropamide-induced flushing with alcohol, and six patients had postprandial hypoglycemia on glibenclamide. Chlorpropamide once daily or glibenclamide twice daily are suitable for control based on fasting blood glucose measurements.

Adult↗

PubMedDate not supplied

Medication compliance in non-insulin-dependent diabetes: a randomized comparison of chlorpropamide and insulin.

Medication compliance may be a problem in the management of patients with diabetes. Some physicians initially treat patients having non-insulin-dependent diabetes with oral sulfonylureas because they fear greater compliance problems with insulin therapy. We compared compliance with insulin and chlorpropamide in patients newly beginning medication for NIDDM. Seventy-seven adults with hyperglycemia despite diet therapy were randomly assigned to chlorpropamide or insulin. Compliance was measured four times over 24 wk. Patients then crossed over to the other medication and were followed for 24 additional weeks. Overall, there were no differences in compliance with the two medications in terms of percent of prescription used, proportion taking at least 80% of prescribed medication, self-report of medication or diet compliance, or protocol dropout rates. However, treatment satisfaction was higher with chlorpropamide, and most patients preferred chlorpropamide to insulin (P less than 0.0001). While such differences in satisfaction may affect long-term compliance, physicians should not assume that their patients will be less compliant with insulin than with oral sulfonylureas.

Adult↗

PubMedDate not supplied

Modification of gas-chromatographic method for blood chlorpropamide determination and evaluation of its use for clinical and pharmacological purposes.

A gas-chromatographic method for isolation and determination of blood chlorpropamide, described originally in literature [10], was modified and its usefulness for clinical and pharmacological purposes evaluated by testing fluctuations in blood chlorpropamide concentration with time in healthy subjects (control group) and patients with type II diabetes mellitus, in relation to glycemia and insulinemia (IRI). In this respect the effects of a single dose and of prolonged chlorpropamide therapy were studied. Large individual variability in the time-related concentration curves and no statistically significant correlation between chlorpropamide, insulin and glycemia were noted.

Adult↗

PubMed1993

Hypertension secondary to chlorpropamide with amelioration by changing to insulin.

A retrospective analysis of the records of 22 type II diabetics whose treatment had been changed from insulin to chlorpropamide was performed to investigate the relative effects of insulin and chlorpropamide on blood pressure. Although diastolic BP index was not significantly different between the treatments, systolic BP index was significantly higher on chlorpropamide than on insulin (141 +/- 3 v 135 +/- 3 mm Hg, P = .02). In 10 patients in whom insulin was reinstituted, systolic BP fell significantly (P < .005), suggesting that in type II diabetics chlorpropamide exerts a relative hypertensive effect in comparison to insulin.

Blood Pressure↗

PubMed1975

Chlorpropamide-induced hyponatraemia.

A case of hyponatraemia occurring in a 69-year-old diabetic woman taking chlorpropamide is reported. Increasing the dose of chlorpropamide aggravated the hyponatraemia, and the condition corrected itself when the chlorpropamide was withdrawn. It is believed, therefore, that, in the absence of any other cause for the hyponatraemia, chlorpropamide was the cause.

Aged↗

PubMed1976

GLC determination of plasma levels of intact chlorpropamide or tolbutamide.

A GLC procedure was developed for the quantitative estimation of intact chlorpropamide and tolbutamide concentrations in plasma; the drugs are used as mutual internal standards. After extraction of plasma containing the drug and internal standard with toluene, the dried residue is treated with ethereal diazomethane to form the methyl derivatives of tolbutamide and chlorpropamide. Aliquots of the ethereal solution are injected into a gas chromatograph equipped with a glass-lined injection port and glass column packed with a phenyl methyl silicone fluid (OV-25) on Chromosorb W, which facilitates the intact determination of the methyl derivatives of the drugs. The response to the flame-ionization detector was linear over a range of 0.20-25 mug/ml, with a 0.05-mug/ml limit of detectability for both drugs. The method compares favorably with a recently developed high-pressure liquid chromatographic procedure and is adequate for following blood level profiles of single doses of chlorpropamide (125 mg) and tolbutamide (250 mg). Mass spectral evidence showing that intact sulfonylureas are measured is presented.

Biological Availability↗