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PubMed1981

Chlorpropamide-alcohol flushing in relation to macroangiopathy and peripheral neuropathy in non-insulin dependent diabetes.

Seventy patients with non-insulin dependent diabetes (NIDD) were studied for the chlorpropamide-alcohol flush (CPAF), first degree family history of diabetes, macroangiopathy and for peripheral neuropathy. Positive CPAF challenge tests were found in 65% of the tested subjects and in 77% if there was a family history of diabetes. Signs of macroangiopathy (loss of foot pulses) were significantly (p less than 0.05) less common in the CPAF positive than in the CPAF negative diabetics with a duration of diabetes of ten years or less. With a longer duration this difference between the two groups was reduced. Also signs of peripheral neuropathy (abnormal vibration sense) were less common (p less than 0.05) in the CPAF positive diabetics than in the CPAF negative. Previously a low prevalence of retinopathy in teh CPAF positive non-insulin dependent diabetics has been reported. We have shown that this is also true of peripheral macroangiopathy and peripheral neuropathy. Chlorpropamide-alcohol flushing seems to be related to a relative protection against late complications in diabetes and the test might be used to find patients at risk.

Aged↗

PubMed1979

Bioavailability of chlorpropamide.

1. The serum profiles of chlorpropamide obtained following single doses of two tablet preparations and from a suspension formulation have been compared in healthy volunteers. The amounts of chlorpropamide absorbed from the three formulations were similar but the drug was absorbed more rapidly from the suspension than from either tablet formulation. There was a small but therapeutically insignificant difference in the rate of absorption of the drug from the two tablets. 2. Changes in blood glucose concentrations were found to be related to the drug serum profile characteristics of the formulations.

Adolescent↗

PubMed1984

The role of endogenous opioids in the chlorpropamide alcohol flush.

The response of plasma immunoreactive met-enkephalin (IR-met-enkephalin) to ethanol (8 g by mouth) after chlorpropamide (250 mg daily for 14 d) was studied in three groups of non-insulin dependent diabetics (a) six diabetics who showed chlorpropamide alcohol flush (CPAF) and in whom the reaction could be blocked by indomethacin, (b) five diabetics who showed CPAF but in whom the flush could not be blocked by indomethacin and (c) five diabetics who did not show CPAF. A rise in plasma IR-met-enkephalin was observed in all three groups. When the two groups of flushers were re-tested with the addition of an infusion of naloxone a rise in plasma IR-met-enkephalin was still demonstrated in both groups regardless of whether the flush was blocked by naloxone. Naloxone blocked the flush only in those six subjects whose flush could be blocked by indomethacin. In five subjects, all flushers, CPAF was tested using intravenous and oral ethanol in doses producing similar plasma ethanol levels. A facial flush was induced by both intravenous and oral ethanol. In three flushers, plasma IR-met-enkephalin levels were measured during CPAF testing with both intravenous and oral ethanol. None showed a rise in plasma IR-met-enkephalin after intravenous ethanol, despite the appearance of a facial flush, whereas all showed a rise after oral ethanol. We therefore conclude that CPAF is unlikely to be caused by a rise in plasma IR-met-enkephalin.

Administration, Oral↗

PubMed1986

Chlorpropamide lowers serum and lipoprotein cholesterol in insulin-dependent diabetes.

Changes in serum lipids and lipoproteins were examined during eight weeks chlorpropamide therapy in eight C-peptide negative, insulin-dependent diabetic patients (mean age 40 years, mean onset of diabetes 20 years). Chlorpropamide was found to have a generalized cholesterol lowering effect (progressive significant fall in mean total cholesterol, LDL-C, HDL-C, and HDL3-C) with no significant change in the ratio of high-density lipoprotein to low-density lipoprotein cholesterol which was independent of insulin secretion.

Adult↗

PubMed1977

Potentiation of the response to vasopressin (pitressin) by treatment with a combination of chlorpropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus.

1 The effect of a combination of chloropropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI) treated with low doses of vasopressin (Pitressin tannate in oil) was investigated with particular reference to the time course of response from the initiation of treatment. 2 Analysis of the relationship between water intake and body weight indicated no real correlation and body weight accounted for only 4.4% of the variation in water intake. It was therefore decided to use whole body responses as the index in preference to the response per unit body weight. 3 The daily administration of 5 mg chlorpropamide combined with chlorothiazide in the drinking water (4 mg/1) to Pitressin-treated DI rats potentiated the response to small doses of vasopressin (25 and 50 mu Pitressin/24 hours). Water intake was reduced by the drug combination by an average of 12.35 ml/24 h, but only on the second day of treatment was the decrease of any real magnitude (30 ml/24 h but otherwise 9 ml/24 h or less). Analysis of urine volume measurements gave similar results to those obtained for water intake and the potency ratio measured in terms of free water clearance was 1.26 (agreeing closely with the ratio for water intake which was 1.24). 4 A reduction in the solute excretion was observed only in those DI rats treated with the higher dose of Pitressin (50 mu/24 h) combined with the two drugs. 5 Possible reasons for the discrepancy between the effect of the combination of chlorpropamide and chlorathiazide on water metabolism in the DI rat and the DI patient are discussed.

Animals↗

PubMed1987

Naloxone, ethanol, and the chlorpropamide alcohol flush.

The effects of ethanol and subsequent administration of intravenous naloxone were studied in double-blind, placebo-controlled fashion with a group of six male chlorpropamide alcohol flushers (CPAF) and a group of 13 nonflushing males. The effect of ethanol intoxication on fine motor control was measured by a typing test. When sober, the two groups performed in comparable fashion. When intoxicated, the CPAF group displayed significantly greater impairment than the nonflushing group as measured by typing errors committed in 3 min (CPAF: 55.4 +/- 10.1 errors, n = 12; vs. nonflushing: 15.6 +/- 2.3, n = 32; p = 0.0000015 by Student's unpaired t test). Chlorpropamide alcohol flushers appeared to be more sensitive to ethanol. Naloxone reversed this effect for individuals in the CPAF group (saline treatment: 51.0 +/- 11.7 errors per minute; vs. naloxone treatment: 23.7 +/- 4.2; p = 0.034 by Student's paired t test, n = 6). Naloxone had no effect in the nonflushing group. Unlike the normal, nonflushing group, the CPAF group demonstrated an increased sensitivity to ethanol that was partially antagonized by naloxone.

Adult↗

PubMed1988

Prolonged cholestasis and disappearance of interlobular bile ducts following chlorpropamide and erythromycin ethylsuccinate. Case of drug interaction?

A 52-year-old man, having been treated for 4 months with chlorpropamide for diabetes mellitus type II, developed severe cholestatic hepatitis following a short course of erythromycin ethylsuccinate. Despite prompt withdrawal of both drugs, the cholestatic picture worsened and was associated with morphological evidence of disappearing interlobular bile ducts. After a 2-year course of profound cholestasis complicated by steatorrhea and striking hyperlipidemia, the patient died of ischemic cardiomyopathy. It is believed that this is the first published case of irreversible cholestasis with disappearance of ducts potentially related to a metabolic interaction between erythromycin ethylsuccinate and chlorpropamide.

Bile Ducts, Intrahepatic↗

PubMed1977

The effect of composition and ageing on the dissolution rates of chlorpropamide-urea solid dispersions.

Discs of chlorpropamide and urea have been prepared by (a) melting and (b) compression. Intrinsic and relative dissolution rates of the discs have been measured and the dissolution process investigated microscopically. Higher dissolution rates were found from melts than from physical mixes. The optimum dissolution rate composition found was for a melt composed of 30% w/w chlorpropamide which possessed an intrinsic dissolution rate 930 times greater than for the pure drug. Sphere formation, during dissolution rate measurement has been observed and a likely mechanism proposed to account for its occurrence. Dissolution rates generally increased with age for most melt compositions.

Chlorpropamide↗

PubMed1992

The effect of serum Ca2+ compensation on the efficacy of chlorpropamide in alloxan-diabetic rabbits.

A decrease in serum Ca2+ concentration was observed in alloxan-diabetic rabbits, with recovery of serum Ca2+ levels achieved following insulin therapy. This suggested that the diabetic condition directly relates to the decrease in serum Ca2+ levels. The efficacy of chlorpropamide in alloxan-diabetic rabbits after intravenous injection (150 mumol kg-1) was less than that in normal rabbits as measured by the serum insulin levels, and the efficacy did not change when the dose was increased. However, compensation of serum Ca2+ levels in alloxan-diabetic rabbits caused an increase in the efficacy of chlorpropamide observed as an increase in serum insulin and a decrease in serum glucose levels.

Animals↗

PubMed1977

Comparison of metformin and chlorpropamide in non-obese, maturity-onset diabetics uncontrolled by diet.

The clinical effectiveness of metformin was compared with that of chlorpropamide in closely similar groups of 216 non-obese patients recently diagnosed as cases of maturity-onset diabetes that could not be controlled by diet. The incidences of primary and secondary drug failures in each group and the numbers of patients satisfactorily maintained on each of the hypoglycaemic agents throughout the first year proved remarkably similar. In 61 of the successfully treated patients who were studied by crossover to the other drug and observed for a further year the mean blood glucose concentrations at the end of the year were roughly comparable, but the mean weight response was a small loss of 1.5 +/- 3.8 kg with metformin but a gain of 4.6 +/- 3.9 kg with chlorpropamide. Thus for non-obese, maturity-onset diabetics whose disease cannot be controlled by diet and who require oral treatment sulphonylureas and biguanides are equally effective, the choice depending on whether the patient is underweight and the severity of symptoms.

Administration, Oral↗

PubMed1980

Chlorpropamide-alcohol flushing and large-vessel disease in non-insulin-dependent diabetes.

A total of 220 non-insulin-dependent diabetics aged over 45 (139 with a history of chlorpropamide-alcohol flushing and 81 without such a history) were examined for the prevalence of large-vessel disease. Large-vessel disease was significantly more common in the group without a history of flushing (41% v 24% of the two groups respectively; p < 0.05). A history of myocardial infarction was found in 14 (17%) of the patients without flushing but in only 10 (7%) patients with flushing. Similar differences were detected in the prevalences of angina, intermittent claudication, and absent foot pulses. There were, however, no significant differences in the prevalence of cerebrovascular disease or hypertension between the two groups. These results suggest that patients with non-insulin-dependent diabetes who flush in response to chlorpropamide and alcohol are significantly less likely to develop large-vessel disease than those who do not. Hence such flushing is probably related to the pathogenesis not only of small-vessel but also of large-vessel disease.

Cardiovascular Diseases↗

PubMed1982

Chlorpropamide-alcohol flushing, aldehyde dehydrogenase activity, and diabetic complications.

Many diabetics who take chlorpropamide (a sulphonylurea compound) experience facial flushing after drinking even small amounts of alcohol. These flushers have a noticeably lower prevalence of late complications of diabetes (microangiopathy, macroangiopathy, and neuropathy) than non-flushers. This flush reaction is accompanied by increased blood acetaldehyde concentrations, suggesting an inhibition of aldehyde dehydrogenase activity. In the present study the activity of this enzyme in erythrocytes was assessed in the absence of chlorpropamide. Erythrocyte homogenates obtained from flushers and non-flushers were incubated with acetaldehyde and the rate of metabolism studies. Flushers eliminated acetaldehyde more slowly at a low range of concentrations (0--30 mumol/l), suggesting a difference in aldehyde dehydrogenase activity. Further studies are needed to clarify the role of this enzyme in the pathogenesis of diabetic complications.

Acetaldehyde↗

PubMed1981

Chlorpropamide-induced haemolytic anaemia.

A newly diagnosed diabetic patient, recently started on chlorpropamide, required emergency admission because of sudden onset of weakness and syncope. In vitro testing confirmed the diagnosis of chlorpropamide induced haemolysis, and withdrawal of the drug resulted in clinical recovery.

Anemia, Hemolytic↗

PubMedDate not supplied

Hyperglycemia associated with propranolol and chlorpropamide coadministration.

A 59-year-old patient with acute pancreatitis is described, whose treatment was complicated by concomitant diabetes mellitus and arterial hypertension. He received propranolol and insulin without subsequent problems; however, when the insulin was changed to chlorpropamide, a significant increase in blood sugar occurred. It was postulated that this increase in blood sugar was due to an antagonistic action of propranolol at the pancreatic level which interfered with the action of chlorpropamide.

Acute Disease↗

PubMed1984

Chlorpropamide-induced hemolytic anemia.

Acute intravascular hemolysis developed when a diabetic patient, previously treated with glyburide, was started on another oral sulfonylurea drug, chlorpropamide. Immunoglobulins were not found in the patient's serum and the red cells were coated with C3 only, suggesting an "innocent bystander" reaction. This case demonstrates that there is no cross reactivity between glyburide and chlorpropamide in producing hemolytic anemia.

Anemia, Hemolytic↗

PubMed1995

Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors.

Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopressin receptor. Detailed studies on the influence of CP on the AVP receptor, however, have been hampered by lack of a suitable radioligand. Using a newly developed radioiodinated derivative of AVP with high specific activity and high affinity for the AVP V2-receptor (125I-[8-(p-(OH)-phenylpropionyl)]-LVP), we studied the role of AVP V2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated orally with 40 mg CP/day or placebo for 7 days, after which Scatchard analysis was performed using membranes prepared from homogenized renal papilla. After oral water load, CP-treated rats but not control rats showed a significant decrease in plasma osmolality (289 +/- 2.2 to 284 +/- 0.8 mosmol/kg, p < 0.05). The Kd was 0.69 +/- 0.16 nmol/l in controls and 0.70 +/- 0.12 nmol/l after CP treatment (NS); Bmax was 129 +/- 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (Bmax) to 167 +/- 8.4 nmol/kg protein (N = 8) (p < 0.05). Plasma AVP did not change significantly during CP treatment. These data show for the first time that CP in vivo increases the density of AVP V2 receptors without altering plasma AVP. This is associated with an impairment in water excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1977

Potentiation of the hepatic action of insulin by chlorpropamide.

In perfused livers of fed rats, chlorpropamide inhibits glucagon-stimulated glucose production by augmenting the action of insulin. This effect is associated with a decrease in cyclic AMP accumulation in liver and perfusate. Alterations in glucose production appear to correlate more closely with changes in the amount of cyclic AMP in the perfusate than with changes in intrahepatic concentration of nucleotide. Potenitation by chlorpropamide of the hepatic action of insulin does not require administration of the drug prior to perfusion. Further, it is demonstrable at concentrations of insulin and glucagon (10(-11M) that approximate the normal plasma levels of these hormones.

Animals↗

PubMed1982

Islet changes induced by hyperglycemia in rats. Effect of insulin or chlorpropamide therapy.

To investigate the effect of hyperglycemia on normal islets, rats were made diabetic by a 95% partial pancreatectomy and treated with insulin, saline, or chlorpropamide for 3 mo. Histologic examination and morphometry of the residual pancreas showed islet enlargement and fibrosis that correlated with the mean lasting plasma glucose during the experimental period. Treatment of diabetes with insulin prevented the islet disorganization. The B-cell area per islet remained constant and was not affected by hyperglycemia. Chlorpropamide had little effect on the fasting plasma glucose or islet structure, and no "beta cytotrophic" effect was seen. Chronic hyperglycemia induces islet damage that may affect residual B-cell function in diabetes.

Animals↗