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PubMed1983

Epidemiological study of prevalence of chlorpropamide alcohol flushing in insulin dependent diabetics, non-insulin dependent diabetics, and non-diabetics.

An epidemiological study was carried out to compare the prevalence of facial flushing in non-diabetics, patients with insulin dependent diabetes, and patients with non-insulin dependent diabetes in response to 40 ml sherry taken 12 hours after 250 mg chlorpropamide or placebo, administered double blind in randomised order. A flush after chlorpropamide but not placebo was reported by 6.2% of non-diabetics (17/273), 9.7% of insulin-dependent diabetics (14/145), and 10.5% of non-insulin dependent diabetics (25/239), excluding those receiving long term chlorpropamide treatment. The differences were not significant. This response was unrelated to age, sex, body mass index, and family history of diabetes in all three groups. Patients taking long term chlorpropamide, however, showed a significantly (p less than 0.01) higher prevalence of flushing after both chlorpropamide and placebo (56.3%; 9/16) compared with the rest of the non-insulin dependent diabetics (16.7%; 40/239), the insulin dependent diabetics (6.9%; 10/145), and the non-diabetics (5.9%; 16/273). Patients receiving long term chlorpropamide would be expected to flush with sherry after a placebo tablet because of therapeutic plasma concentrations of the drug. It is concluded that there is no evidence of an increased prevalence of chlorpropamide alcohol flushing in response to the single challenge test in non-insulin dependent diabetics compared with insulin dependent diabetics and non-diabetics except in selected patients taking chlorpropamide long term. This study does not support the hypothesis that the chlorpropamide alcohol flush is a specific marker for a subtype of non-insulin dependent diabetes.

Adult↗

PubMed1982

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose.

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.

Aged↗

PubMed1985

Comparison of acute and prolonged effects of glibenclamide and chlorpropamide in patients with non-insulin-dependent diabetes.

The effects of single oral dose of glibenclamide (Gilemid 5 mg) and chlorpropamide (250 mg) on serum insulin and glucose levels and electrolyte (sodium, potassium) balance were studied, in a cross-over double-blind manner, in 11 patients with non-insulin-dependent diabetes. Both drugs increased serum insulin for more than 8 h but less than 24 h. The effect of glibenclamide was slightly stronger than that of chlorpropamide. Serum glucose concentration was significantly decreased by glibenclamide only. Glucose excretion in urine was declined for a longer time by glibenclamide than by chlorpropamide. Neither of the drugs essentially effected on sodium and potassium excretion. After the acute study, all the above patients and 5 additional ones were treated in open care with glibenclamide (2.5-10 mg daily) and chlorpropamide (125-500 mg daily) for 8 weeks in a cross-over manner. Both drugs showed practically similar efficacy; 5 mg of glibenclamide corresponded to 250 mg of chlorpropamide. One patient under chlorpropamide treatment exhibited hyponatraemia. Eight weeks after the commencement of therapy, serum potassium concentration was lower under chlorpropamide than under glibenclamide treatment. The results suggest that, in non-insulin-dependent diabetes, a single oral dose of glibenclamide acts as long as that of chlorpropamide, and that in long-term therapy 5 mg of glibenclamide is equipotent with 250 mg of chlorpropamide.

Adult↗

PubMedDate not supplied

Characterization of the chlorpropamide-alcohol-flush in patients with type 1 and type 2 diabetes.

The aim of the present paper was to evaluate the prevalence of the chlorpropamide-alcohol-flush (CPAF) in patients with type 2 and with type 1 diabetes. Ninety-seven patients with type 2 diabetes and 33 with type 1 diabetes drank 40 ml vermouth 12 h after placebo and again 12 h after 1 tablet of chlorpropamide (250 mg) or 12 h after the last of repeated administrations of chlorpropamide (250 mg b.i.d. for 2 days). Skin temperature was recorded in all patients by a thermocouple probe connected to the left cheek. In 47 patients serum concentrations of chlorpropamide and of its metabolite CBSU were also determined. The prevalence of CPAF was similar in type 1 and type 2 diabetes, was greater in women than in men, and was significantly greater after repeated administrations than after one single administration of chlorpropamide. The increase of skin temperature during a 30-min period was significantly higher in patients with CPAF than in patients without CPAF. Serum concentrations of chlorpropamide and of its metabolite CBSU were more elevated after 4 than after 1 tablet of chlorpropamide, but were not significantly different in patients with and without CPAF. These data indicate that both genetic factors and the amount of chlorpropamide used affect the appearance of CPAF. To assess the possible role of serotonin and of dopamine in the CPAF, some patients with CPAF were tested again after treatment with metergoline, an antiserotonin agent, or with bromocriptine, a dopamine-agonist. Neither drug influenced the CPAF, indicating that the two neurotransmitters are not involved in the CPAF.

Bromocriptine↗

PubMed1983

Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics.

The effects of activated charcoal, sodium bicarbonate, and ammonium chloride by mouth on chlorpropamide kinetics was studied in six healthy subjects. Activated charcoal, 50 gm, given immediately after 250 mg chlorpropamide reduced its absorption by 90%, but when given in repeated doses from 6 hr on (50 gm followed by 12.5 gm at 6-hr intervals) it did not shorten the chlorpropamide half-life (t 1/2). The t 1/2 of chlorpropamide was shortened from 49.7 +/- 7.4 to 12.8 +/- 1.1 hr by sodium bicarbonate and prolonged to 68.5 +/- 10.5 hr by ammonium chloride. The 72-hr urinary excretion of chlorpropamide was increased fourfold by alkalinization and decreased to 1/20 of baseline by acidification of the urine. The renal clearance of chlorpropamide correlated with urinary pH, ranging from 1 to 1000 ml/hr at the pH from 5 to 8. Urinary pH is likely to explain at least a part of great interindividual differences in the serum chlorpropamide concentrations during steady-state and variations in amount of urinary metabolites. In chlorpropamide intoxications activated charcoal can reduce absorption and alkalinization of the urine accelerates its elimination.

Adult↗

PubMed1980

Augmentation by chlorpropamide of 1-deamino-8-D-arginine vasopressin-induced antidiuresis and stimulation of renal medullary adenylate cyclase and accumulation of adenosine 3',5'-monophosphate.

The effect of chlorpropamide was determined in Brattleboro diabetes insipidus (DI) rats that were injected with 1-deamino-8-D-arginine vasopressin (dDAVP). Chlorpropamide augmented the antidiuretic responses to 0.78 and 1.56 ng dDAVP but not to larger doses. In an effort to explain this observation we investigated the effect of chlorpropamide on renal medullary adenylate cyclase activation by dDAVP and on phosphodiesterase activity. We found that the injection of chlorpropamide increased adenylate cyclase activation by dDAVP added in vitro to renal medullary cell membrane preparations from Brattleboro DI rats but had no effect on phosphodiesterase activity. When kidneys from Brattleboro DI rats, treated and not treated with chlorpropamide, were perfused in vitro, we found that 10(-4) M dDAVP increased the concentration of cAMP in comparison to untreated and chlorpropamide-treated groups, and that chlorpropamide plus dDAVP resulted in a greater concentration of renal cAMP than was found with dDAVP alone. We believe that treatment with chlorpropamide increases dDAVP-stimulated renal medullary adenylate cyclase activity without altering phosphodiesterase activity and that this leads to increased renal cAMP concentrations. This, in turn, causes an augmented antidiuresis in response to dDAVP.

Adenylyl Cyclases↗

PubMed1982

Further studies on the mechanism by which chlorpropamide alters the action of vasopressin.

The injection of chlorpropamide into Brattleboro homozygous rats (di/di) has previously been shown to result in enhanced activation of renal medullary adenylate cyclase activity and increased renal medullary content of cAMP in response to 1-desamino-8-D-arginine vasopressin (dDAVP). In contrast, in vivo chlorpropamide did not alter GTP, guanylylimidodiphosphate, or fluoride-stimulated adenylate cyclase activities in these renal membranes. We have now found that the effect of in vivo chlorpropamide in enhancing dDVAP-stimulated adenylate cyclase activity involves lowering the Km for ATP. We have also found that dDAVP increases urinary prostaglandin E2 (PGE2) excretion, and treatment with chlorpropamide causes an even greater PGE2 response to dDAVP. In contrast, in vivo chlorpropamide treatment did not increase vascular responses to arginine vasopressin (AVP) in the perfused kidney preparation and, in fact, inhibited the AVP-induced decrease in the glomerular filtration rate. Chlorpropamide, therefore, enhances the renal responses to dDAVP in terms of the cAMP and PG systems, while not increasing responses to postreceptor stimuli of the adenylate cyclase system or vascular responses to AVP. These observations support the concept that in vivo chlorpropamide acts at the receptor of the vasopressin-sensitive part of the tubule to augment responsiveness to vasopressin. In addition, in vivo chlorpropamide may inhibit certain vascular responses to AVP.

Adenylyl Cyclases↗

PubMed2004

The effect of deinsuring chlorpropamide on the prescribing of oral antihyperglycemics for Nova Scotia Seniors' Pharmacare beneficiaries.

On behalf of the Nova Scotia Seniors' Pharmacare Program, the Drug Evaluation Alliance of Nova Scotia developed a multicomponent intervention plan to facilitate the removal of chlorpropamide as an insured benefit. Chlorpropamide has caused serious hypoglycemia in seniors to a greater extent than some other agents. Pharmacy administrative claims were used to compute monthly use rates for insulin and each oral antihyperglycemic drug from January 1, 2000-December 30, 2002, in an intervention cohort (patients receiving chlorpropamide) and a control cohort (patients receiving an antihyperglycemic agent other than chlorpropamide). Initially, 630 patients were receiving chlorpropamide therapy. By the time chlorpropamide was deinsured, only 10% of the treatment cohort continued receiving chlorpropamide; shortly after deinsurance, no beneficiaries continued receiving the drug. The antihyperglycemics with the greatest increase in prescription were glyburide and gliclazide. The deinsuring of chlorpropamide and the educational strategies that accompanied it resulted in the selection of more appropriate antihyperglycemics for Nova Scotia seniors.

Aged↗

PubMedDate not supplied

Comparative bioavailability of chlorpropamide tablet and suspension formulations.

The bioavailability of a chlorpropamide tablet formulation chlorpropamide tablet formulation was assessed by comparing it to a reference suspension of chlorpropamide. Eighteen healthy adult men received chlorpropamide 250 mg as a tablet (Diabinese, Pfizer) and suspension in an open two-way crossover study of Latin-square design with a 14-day washout period between treatments. Serial blood samples were obtained by venipuncture for 96 hours for chlorpropamide serum concentration determinations. Serum glucose concentrations were determined at 0, 0.5, 1, 2, and 4 hours. The area under the serum chlorpropamide concentration-time curve (AUC), peak serum chlorpropamide concentration (Cmax), time to Cmax, and mean glucose concentration at each time point for each treatment were compared using a two-tailed Student's t test for paired data (p less than 0.05). Microrate constants for a two-compartment model for oral absorption computed using nonlinear regression were also compared. There were no significant differences between the two formulations regarding AUC, Cmax, time to Cmax, and hypoglycemic response. The absorption rate for the tablet was significantly greater than for the suspension. The results suggest that the oral chlorpropamide tablet and reference suspension are bioequivalent. Although the tablet had a faster absorption rate than the suspension, this probably is not clinically important since both formulations similarly decreased serum glucose concentration.

Adult↗

PubMed1981

Chlorpropamide effect: measurement of neurophysin and vasopressin in humans and rats.

The effect of chlorpropamide on neurohypophyseal function was studied by measurement of neurophysin and vasopressin in humans and in rats. Administration of chlorpropamide was shown to inhibit the ability of the human subjects and of the rats to maximally dilute their urine after administration of water. Comparison of the levels of vasopressin and neurophysin before and after the administration of chlorpropamide in the basal state and after water loading in both the human subjects and in rats showed no lack of suppression due to the chlorpropamide. The levels of both peptides were measured at the limits of detection. In other studies where neurophysin and vasopressin were readily detected, administration of chlorpropamide did not result in any augmented release of neurophysin or vasopressin in response to stimulation of the neurohypophysis in humans nor in rats. Levels of neurophysin in the pituitaries of rats showed no change in rats given chlorpropamide, while the content of vasopressin was increased, possibly indicating a chronic decreased secretion of vasopressin in rats given chlorpropamide.

Adult↗

PubMed2004

Effect of the chlorpropamide and fructose-1,6-bisphosphate of soluble TNF receptor II levels.

Inflammatory cytokines are central to the pathogenesis of septic shock, and future therapies will depend on interfering with the effects of these cytokines. The aim of this study was to investigate the effect of the two drugs, Fructose-1,6-bisphosphate (FBP), a high-energy glycolytic pathway intermediate, and chlorpropamide (sulfonylurea) on proliferation of T-lymphocytes and on the levels of soluble receptors of tumor necrosis factor (sTNFRII). Peripheral blood mononuclear cells (PMBCs) were isolated from the blood of healthy humans by gradient centrifugation. T-lymphocytes were stimulated for 96h with phytohemagglutinin (PHA) and varying concentrations of chlorpropamide and FBP. They were stimulated for 24h with lipopolysaccharide (LPS) and varying concentrations of chlorpropamide and FBP were used. Chlorpropamide at concentrations between 2.5 and 10mM and FBP at concentrations between 1.25 and 10mM decreased proliferation of T-lymphocytes. The chlorpropamide reduced the viability only at a concentration of 10mM and FBP at concentrations of 5.0 and 10mM. The levels of sTNFRII were reduced at chlorpropamide concentrations between 2.5 and 5mM and FBP between 1.25 and 2.5mM. In conclusion, our results suggest that FBP acts, as does chlorpropamide, to inhibit the cellular proliferation and thereby reducing the sTNFRII levels through blockage of the potassium channels. In this way it acts as a powerful immunomodulatory agent.

Cell Survival↗

PubMed1987

Chlorpropamide alcohol flushing: a normal response?

The relationship between chlorpropamide alcohol flushing and non-insulin dependent diabetes remains uncertain. It is known, however, that the frequency of facial flushing with alcohol and the temperature response depend upon both the plasma level of chlorpropamide and the starting facial temperature [10]. We tested 23 young adult non-diabetic subjects with 8 g of ethanol after a dose of chlorpropamide 250 mg twice daily for 2 days or a placebo, in a double blind, cross-over manner. Previously, nine other subjects had participated in a pilot study to assess the safety of the chlorpropamide dose and to ensure that adequate plasma chlorpropamide levels were achieved. No subject was negative for chlorpropamide alcohol flushing, as defined by the following criteria: facial temperature rise of 35% or more of maximum possible rise, observer assessment or subject assessment. In 26 of the total 32 subjects, all three criteria were fulfilled. Thus, among young, healthy non-diabetic adults chlorpropamide alcohol flushing would appear to be a normal phenomenon.

Adult↗

PubMed1978

Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus.

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 mumol/l (100 mug/ml)), yet the variation in dosage was only sixfold (0.5-3.9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 mumol/l (244 mug/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5.4%) of the tolbutamide-treated patients and 10 (16.7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5.5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8.0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.

Adult↗

PubMed1981

Blood concentrations of acetaldehyde during chlorpropamide-alcohol flush.

To test the suggestion that chlorpropamide-alcohol flushing (CPAF) resembles the disulfiram effect and might be mediated by acetaldehyde, the initial metabolite of alcohol, blood concentrations of acetaldehyde were measured after a drink of alcohol in controls and diabetics positive and negative for CPAF. The CPAF-positive diabetics had significantly greater blood acetaldehyde concentrations after alcohol than the CPAF-negative diabetics both with a single dose of chlorpropamide and after two weeks' chlorpropamide treatment. Concentrations in the CPAF-positive group after chlorpropamide were also significantly greater than after a placebo tablet. There was also a clear separation in the increase in facial temperature after two weeks of chlorpropamide between the CPAF-positive and CPAF-negative groups (although there was some overlap after a single tablet). There was no difference in plasma chlorpropamide or alcohol concentrations between CPAF-positive and CPAF-negative diabetics. These findings show that CPAF is distinct from alcohol flushing and that the acetaldehyde concentration in the blood provides an objective measure of CPAF. The difference between flushing and non-flushing diabetics cannot be accounted for by differences in blood concentrations of chlorpropamide or alcohol.

Acetaldehyde↗

PubMed1975

Effect of chlorpropamide on renal response to parathyroid hormone in normal subjects and in patients with hypoparathyroidism and pseudohypoparathyroidism.

Chlorpropamide inhibited by 35 to 65% the increase in the urinary excretion of adenosine 3',5'-monophosphate (cyclic AMP) following a large dose (250 U) of parathyroid hormone (PTH) in normal subjects and patients with hypoparathyroidism and pseudohypoparathyroidism. By contrast, in normal subjects, the response of urinary cyclic AMP excretion to smaller amounts of PTH (15 and 30 U) was not decreased by chlorpropamide. Chlorpropamide did not decrease the phosphaturic response to any dose of PTH. The probable explanation for the discrepant effects of chlorpropamide on urinary cyclic AMP and phosphate excretions is that phosphaturia results from a minimal elevation of cyclic AMP and that chlorpropamide does not decrease cyclic AMP production to such a low level. Chlorpropamide decreased the accumulation of renal cyclic AMP in response to PTH in the parathyroidectomized rat, suggesting that this may be the mechanism of action for this drug in decreasing the urinary excretion of cyclic AMP in response to PTH in man. Tolazamide, another sulfonylurea, did not inhibit the elevation of urinary cyclic AMP excretion after PTH. Therefore, the sulfonylurea part of the molecule is probably not involved in the inhibition produced by chlorpropamide.

Adult↗

PubMed1981

Plasma insulin, C-peptide and glucagon concentrations in patients with insulin-independent diabetes treated with chlorpropamide.

The effect of chlorpropamide on blood glucose, plasma insulin, C-peptide and glucagon levels was studied in 21 patients with insulin-independent diabetes. A metabolic profile of these parameters was obtained throughout a normal day in seven newly-diagnosed diabetic patients (group A), before, and 3 to 8 weeks after treatment with chlorpropamide was established, and in 14 patients on longterm therapy with chlorpropamide (seven taking less than 250 mg. chlorpropamide--group B; seven taking 250-375 mg.--group C), before, and two weeks after withdrawal of the drug. In group A, correction of hyperglycaemia was not accompanied by a significant rise in the mean plasma insulin and C-peptide levels but a fall was observed in the mean plasma pancreatic glucagon concentrations. In groups B and C, withdrawal of chlorpropamide produced no significant change in plasma insulin, C-peptide or glucagon levels, although the mean blood glucose increased. This study supports an extrapancreatic effect of chlorpropamide to lower blood glucose after prolonged administration. In the short-term, it is possible that chlorpropamide may influence the secretion of pancreatic glucagon.

Adult↗

PubMed1992

Effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide.

The effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide was examined in a total of 32 healthy volunteers in two separate, randomized parallel-group studies, with 16 subjects in each study. After an overnight fast, the first group of 8 volunteers ingested 500 mg tolbutamide or 250 mg chlorpropamide with 150 ml water, and the second group the same doses of the active drugs with 150 ml water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the area under the plasma tolbutamide concentration-time curve (AUC) from 0 to 1 h and from 0 to 2 h by 5-fold and 2.5-fold, respectively. The peak plasma concentration, peak time and total AUC were not significantly altered. The incremental insulin area and the decremental glucose area from 0 to 1.5 h were significantly larger in the magnesium hydroxide group than in the controls. The maximum insulin response to tolbutamide was increased fourfold by coadministration of magnesium hydroxide, and it occurred about 1 h earlier than in the control group. In addition, the maximum fall in plasma glucose concentration was attained about 1 h earlier in the antacid group. A tendency to an increased rate of chlorpropamide absorption was observed after magnesium hydroxide, but it did not appear to affect the insulin and glucose responses to chlorpropamide. It is concluded that magnesium hydroxide increased the early bioavailability of tolbutamide, resulting in enhanced insulin and glucose responses. A tendency toward accelerated chlorpropamide absorption by magnesium hydroxide was also observed, but the efficacy of chlorpropamide was unaffected.

Adult↗

PubMed1977

Plasma insulin and glucose levels in maturity onset diabetics treated with chlorpropamide.

19 diabetic patients taking various doses of chlorpropamide were studied throughout a normal day. Plasma chlorpropamide levels were related to the daily dose of the drug and were relatively constant throughout the day. Blood glucose concentration was highest and the plasma insulin concentration lowest in patients taking the largest dose of chlorpropamide. Patients on a small daily dose of chlorpropamide were well controlled and had higher than normal insulin levels. --12 patients were restudied 10 days after stopping chlorpropamide. Although diabetic control deteriorated in all patients, plasma insulin concentration did not change significantly. This suggests that the long-term hypoglycaemic action of chlorpropamide is not dependent on an effect on the concentration of insulin in peripheral venous blood.

Aged↗