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PubMed1977

Comparison of clofibrate and chlorpropamide in vasopressin-responsive diabetes insipidus.

Six patients with vasopressin-responsive diabetes insipidus (DI) received clofibrate and chlorpropamide, singly and in combination. Decrease in urinary output averaged (mean +/- SEM): (1) clofibrate 2 g/day, 47% +/- 6%; (2) chlorpropamide 250 mg/day 59% +/- 5%; (3) clofibrate 2 g/day plus chlorpropamide 125 mg/day, 54% +/- 7%; (4) clofibrate 2 g/day plus chlorpropamide 250 mg/day 61% +/- 4%. Water deprivation tests before and during treatment showed significantly higher basal, final, and peak urinary osmolalities (Uosm) and lower free water clearance (CH20) on chlorpropamide, singly and in combination: clofibrate raised Uosm less but significantly decreased CH2O. Water load tests before and during treatment showed that chlorpropamide, singly and in combination, markedly decreased maximal urinary flow, maximal CH2O, percentage water load excreted, and increased minimal Uosm; clofibrate significantly decreased maximal urinary flow and CH2O only. One patient responded only to combination therapy. Chlorporpamide caused serious hypoglycemia in three of six patients. Clofibrate had no significant side effects.

Adolescent↗

PubMed1985

Effect of tolbutamide and chlorpropamide on acetaldehyde metabolism in two inbred strains of mice.

The mechanisms by which chlorpropamide and tolbutamide disrupt acetaldehyde metabolism were studied in C57BL and DBA mice. Acute po administration of varying doses of tolbutamide or chlorpropamide 2.5 hr before a 3.0 g/kg ip dose of ethanol to C57BL and DBA mice resulted in significant elevations of blood acetaldehyde when measured 2.5 hr after ethanol dosing. Dose-response analysis revealed a significant (p less than .05) difference in ED50 values for the elevated blood acetaldehyde response to tolbutamide in DBA (60 mg/kg) and C57BL (100 mg/kg) mice. The ED50 value for potentiation by chlorpropamide of blood acetaldehyde concentration was similar (23 to 32 mg/kg) in both inbred strains. At higher doses of chlorpropamide, DBA mice displayed elevations of blood acetaldehyde nearly threefold greater than those measured in C57BL mice treated identically. Measurements of aldehyde dehydrogenase (ALDH) in hepatic subcellular fractions, obtained from both inbred strains treated with 100 mg/kg tolbutamide or chlorpropamide prior to a 3.0 g/kg dose of ethanol, revealed a 50 to 80% inhibition of the low-Km ALDH present in mitochondria. Chlorpropamide and tolbutamide did not inhibit ALDH in vitro, suggesting that metabolites of these hypoglycemic agents may be responsible for the genotypic-dependent alterations in in vivo acetaldehyde oxidation.

Acetaldehyde↗

PubMedDate not supplied

Antidiuretic action of chlorpropamide in diabetes insipidus patients and in normal subjects.

The antidiuretic action of chlorpropamide was studied in 10 diabetes insipidus patients sensitive to vasopressin and 15 normal subjects. After an oral load of water followed by sustained hydration through water ingestion in a volume equivalent to the urinary flow, chlorpropamide (4 mg/kg body weight) was intravenously administered as a single dose, either alone (34 experiments) or simultaneously with pitressin infusion (6 experiments). During the experiments, creatinine clearance as well as osmolal and plasma and urine electrolyte concentrations were measured. Several urine collection periods were made before and after the administration of chlorpropamide. In thes experimental conditions, chlorpropamide promoted a marked antidiuresis (p less than 0.01) in patients with diabetes insipidus and presented no antidiuretic effect (p greater than 0.01) in normal subjects, even with a double dose. However, if previously to the experiment, the normal individuals were dehydrated (mean weight loss of 4.8 per cent) or the diabetes insipidus patients were hydrated (mean weight gain of 6.4 per cent) a reverse behavior was observed: that is, the normal subjects did present (p less than 0.01) and the diabetes insipidus patients did not present (p greater than 0.01) antidiuresis to chlorpropamide. The results suggest that the state of hydration modulates the action of chlorpropamide in a way apparently independent of the antiduretic hormone.

Chlorides↗

PubMed1986

Enhancement by sodium salicylate of the blood glucose lowering effect of chlorpropamide-drug interaction or summation of similar effects?

The ability of sodium salicylate (3 g) to enhance the blood glucose lowering action of chlorpropamide (200 mg) has been confirmed in healthy male volunteers who received an oral test dose of 50 g glucose. Salicylate raised the plasma concentration of insulin and lowered that of cortisol but did not alter the concentration of chlorpropamide. The area under the blood glucose concentration-time curve was used as the measure of drug response and the significance of drug effects was assessed by analysis of variance. In one study on five volunteers the effect of combining salicylate and chlorpropamide was additive. In a second study on six volunteers 200 mg chlorpropamide, 3 g sodium salicylate and 100 mg chlorpropamide + 1.5 g salicylate were equi-effective. The enhancement of chlorpropamide action by salicylate in this single dose study is consistent with the summation of similar effects. It is not necessary to postulate an interaction.

Adult↗

PubMed1974

The effect of chlorpropamide on water balance in pitressin-treated Brattleboro rats.

1 The daily administration of a 5% glucose solution to the heterozygous Brattleboro rat produced an experimental model in a comparable state of polydipsia and polyuria to the homozygous rat with diabetes insipidus (DI).2 The effect of chlorpropamide on water metabolism was then examined in both the homozygous DI rat treated with submaximal doses of pitressin tannate in oil (Pitressin), and in the glucose-hydrated heterozygous rat with and without simultaneous pitressin therapy.3 A dose-response curve for chlorpropamide (5, 10, and 20 mg/24 h) in DI rats treated with Pitressin (25 mu/24 h) indicated that the drug decreased fluid intake further, but only by a maximum of 13.8% (at the 20 mg/24 h dose of chlorpropamide), differing markedly from results obtained in patients with diabetes insipidus. A second experiment in which chlorpropamide (5 mg/24 h) was administered to DI rats treated with Pitressin (either 25 or 50 mu/24 h) confirmed the lack of any significant drug-effect on water metabolism in these animals.4 Chlorpropamide (20 mg/24 h), when administered alone or simultaneously with a submaximal dose of Pitressin (25 mu/24 h), had no obvious effect on the fluid intake of glucose-hydrated heterozygous rats. The absence of any action by chlorpropamide on water metabolism was confirmed in these experimental animals using 5 mg/24 h of the drug together with Pitressin (either 25 or 50 mu/24 hours).5 Indirect evidence for the slower growth-rate in the DI rat being due to an insufficient daily calorific intake was obtained from the study on glucose-hydrated heterozygous rats.

Analysis of Variance↗

PubMed1973

Evaluation of chlorpropamide in chemical diabetes diagnosed during pregnancy.

The intravenous glucose tolerance test (I.V.G.T.T.) was used to diagnose chemical diabetes during pregnancy in 180 women, 50 of whom subsequently received chlorpropamide therapy in a daily dosage of 100 mg; the remainder had no drug therapy.Preliminary work showed the I.V.G.T.T. to be reproducible in the second and third trimesters but not in the puerperium in normal pregnancy. Though intravenous glucose tolerance deteriorates between the second and third trimesters in women with no features of diabetes, a significant improvement occurs after a course of chlorpropamide in a daily dosage of 100 mg during pregnancy in chemical diabetes, but this treatment did not enhance the rate of return to normal glucose tolerance post partum.Plasma glucose and insulin studies showed no evidence of hypoglycaemia or hyperinsulinism in the mother at delivery or in the newborn when chlorpropamide had been used compared with a group receiving no such treatment. In the infants of the chlorpropamide-treated mothers there was a suggestion of an increased rate of glucose disposal in response to a glucose challenge, but no increase in birth weight.There were two fetal deaths in the 50 pregnancies of mothers treated with chlorpropamide, one being due to a mistaken premature delivery and the other to a diaphragmatic hernia. Thus chlorpropamide in a dose of 100 mg a day has been shown to reverse chemical diabetes diagnosed and treated in pregnancy without apparent risk to the fetus.

Birth Weight↗

PubMed1986

Chlorpropamide raises fructose-2,6-bisphosphate concentration and inhibits gluconeogenesis in isolated rat hepatocytes.

The addition of chlorpropamide to hepatocytes isolated from fed rats raised the cellular concentration of fructose-2,6-bisphosphate (F-2,6-P2), a regulatory metabolite that plays a relevant role in the control of hepatic glucose metabolism. The effect of chlorpropamide was dose dependent; a statistically significant increase was already seen at 0.2 mM of the sulfonylurea. The accumulation of F-2,6-P2 caused by chlorpropamide (1 mM) was parallel to the stimulation of L-lactate production (36.6 +/- 4.8 versus 26.1 +/- 2.6 mumol of lactate/g of cells X 20 min; N = 5, P less than 0.05) and to the inhibition of gluconeogenesis (0.57 +/- 0.1 versus 0.94 +/- 0.09 mumol of [U-14C]pyruvate converted to glucose/g of cells X 20 min; N = 5, P less than 0.05). In addition, chlorpropamide enhanced the inhibitory action evoked by insulin on glucagon-stimulated gluconeogenesis. This combined effect of chlorpropamide and insulin seems to be correlated with the synergistic accumulation of F-2,6-P2 provoked by the simultaneous action of these two agents on glucagon-treated hepatocytes. Finally, neither 6-phosphofructo-2-kinase activity nor hepatocyte cyclic AMP levels were significantly changed by the presence of the sulfonylurea in the incubation medium. Our results support the concept that chlorpropamide, by a cyclic AMP-independent mechanism, increases the hepatic content of F-2,6-P2 and, in this way, enhances the glycolytic flux and inhibits glucose output by the liver.

Animals↗

PubMed1975

[Treatment of central diabetes insipidus with a combination of chlorpropamide and carbamazepine (author's transl)].

Three patients suffering from central (=neurohormonal) diabetes insipidus were treated with chlorpropamide and carbamazepine simultaneously. This therapy with a combination of the two drugs was based on the aim of getting a good antidiuretic effect when the centrally-stimulating carbamazepine was combined with the peripherally-potentiating chlorpropamide; it was hoped, too, that the side effects of these two drugs, especially the chlorpropamide-induced hypoglycaemia, could be avoided by administration at low dosage. This combined drug therapy proved effective in all three cases: the good antidiuretic effect of chlorpropamide at high dosage is impaired by hypoglycaemia; the combination of carbamazepine allowed the dosage of chlorpropamide to be decreased without impairment of the obtained antidiuretic effect and with avoidance of hypoglycaemia and other side effects. Hence, the combination of chlorpropamide and carbamazepine seems to be recommendable in the treatment of central forms of diabetes insipidus in childhood.

Carbamazepine↗

PubMed1980

The chlorpropamide alcohol flush. Lack of specificity for familial non-insulin dependent diabetes.

A facial flush provoked by alcohol in chlorpropamide treated diabetics has been described as a genetic marker for a dominantly inherited type of non-insulin dependent diabetes. In this study a chlorpropamide alcohol flush was observed in 16.9% of control subjects (n = 154), 23.3% of insulin dependent diabetics (n = 437) and 16.5% of patients with non-insulin dependent diabetes (n = 145). Among the non-insulin dependent diabetics no difference in the frequency of the chlorpropamide alcohol flush was found between those with and without a family history of diabetes. Specificity was not improved by skin temperature measurement or additional placebo tests. According to these data the chlorpropamide alcohol flush does not seem to be specific for non-insulin dependent diabetes and hypotheses about the aetiology of this type of diabetes based on the chlorpropamide alcohol flush should be regarded with caution.

Chlorpropamide↗

PubMed1988

Association of hyperinsulinemia with chlorpropamide toxicity.

Clinical and metabolic features of chlorpropamide toxicity are described in two patients with diabetes mellitus and accidental chlorpropamide overdosage. Elevated serum insulin levels were found during hypoglycemia in both patients. The world's literature was reviewed for other cases of chlorpropamide toxicity in which insulin levels have been measured during hypoglycemia. A consistent feature of chlorpropamide toxicity is hyperinsulinemia. It is concluded that stimulation of the pancreatic beta cells during chlorpropamide toxicity leads to hyperinsulinemia and hypoglycemia.

Aged↗

PubMed1975

Paradoxical diuresis after vasopressin administration to patients with neurohypophyseal diabetes insipidus treated with chlorpropamide, carbamazepine or clofibrate.

1. Chlorpropamide, carbamazepine and clofibrate have an antidiuretic action in patients with neurohypophyseal diabetes insipidus which is qualitatively similar to that of antidiuretic hormone (ADH). 2. An additive antidiuretic effect is produced by combination of chlorpropamide and carbamazepine with small dosages of ADH. 3. After an immediate and transient antidiuresis, a single intravenous bolus injection of lysine vasopressin given during treatment with chlorpropamide, chlorpropamide with a continuous intravenous infusion of lysine vasopressin, carbamazepine or clofibrate, resulted in increased water diuresis for 12-24 h or longer. 4. This paradoxical diuresis was not observed during treatment with chlorothiazide. 5. It is suggested that the antidiuretic action of chlorpropamide, carbamazepine and clofibrate is localized at the receptor site for ADH in the distal renal tubular cell.

Adolescent↗

PubMedDate not supplied

Acute hemolytic anemia associated with a chlorpropamide-induced apparent auto-anti-Jka.

A patient with acute hemolytic anemia and a positive direct antiglobulin test was found to be Jk(a + b +) with anti-Jka in her serum. For 2 weeks prior to admission, the patient had taken chlorpropamide, a hypoglycemic agent. The drug was discontinued upon the diagnosis of hemolytic anemia, and the hemoglobin concentration gradually increased. When chlorpropamide was added to the patient's serum in vitro, it enhanced the reactivity of the anti-Jka, and 40 days posttransfusion, the serum would only react with Jk(a+) red cells when chlorpropamide was present. These findings suggest that a chlorpropamide-dependent antibody with Jka specificity had formed. We do not know why the antibody induced by chlorpropamide reacted preferentially with Jk(a+) red cells.

Acute Disease↗

PubMedDate not supplied

Diazoxide in the management of chlorpropamide overdose.

Three cases of chlorpropamide overdose are reported. Plasma levels of chlorpropamide, diazoxide, glucose, and insulin are presented for each patient during treatment. The simultaneous analysis of chlorpropamide, hydrochlorothiazide, and diazoxide in plasma by high pressure liquid chromatography (HPLC) is also reported. Although all three cases presented at hospital with potentially lethal plasma levels of chlorpropamide, each was successfully treated with intravenous diazoxide and glucose. Plasma diazoxide concentrations between 50-100 microgram/mL appear to be optimal in achieving therapeutic control of chlorpropamide induced hypoglycemia.

Adolescent↗

PubMed1977

Phase equilibria and stability characteristics of chlorpropamide-urea solid dispersions.

Physical mixtures and melts of various compositions of chlorpropamide and urea have been prepared. The phase diagrams and the effects of ageing of the systems have been measured by differential scanning calorimetry. The eutectic composition was found to contain 89% w/w chlorpropamide. Greater concentrations of chlorpropamide produced solid solutions of urea in chlorpropamide, whereas solid solution formation did not occur at compositions less than 89%. Melts in the range 50-100% chlorpropamide, which included the eutectic, existed as glass solids. The effect of ageing produced generally an increase in the liquidus peak temperature which was considered to be due to a gradual increase in crystal size.

Calorimetry, Differential Scanning↗

PubMed1981

Chlorpropamide alcohol flush and circulating met-enkephalin: a positive link.

Chlorpropamide-alcohol flushing may be due to sensitivity to endogenous opiates. To investigate this possibility the plasma met-enkephalin and beta-endorphin responses to sherry with and without chlorpropamide were studied in six patients with non-insulin dependent diabetes and in six normal subjects. After chlorpropamide all patients showed a rise in met-enkephalin concentrations from a basal level of 50 +/- 7.2 ng/l to a peak of 75 +/- 8.1 ng/l (p less than 0.001). In contrast, before chlorpropamide treatment was started met-enkephalin values did not change after alcohol. No significant changes in beta-endorphin values were observed. In six normal subjects pretreated with chlorpropamide the met-enkephalin concentration also rose from a basal level of 72 +/- 15 ng/l to a peak of 103 +/- 9.4 ng/l (p less than 0.002). Again, the met-enkephalin rise was not observed after placebo. Neither beta-endorphin concentrations nor facial temperature changed significantly. These data suggest that endogenous opiates may be implicated in CPAF. Furthermore, this is the first study in which a significant change in circulating met-enkephalin values has occurred.

Chlorpropamide↗

PubMed1979

Chlorpropamide-induced changes in patients with hyperparathyroidism.

Ten patients with primary hyperparathyroidism were placed on a constant 30 mEq of calcium and 120 meq of sodium diet, and alterations in their calcium balance in response to standard oral doses of chlorpropamide were studied over a 4 day control period and a 4 day treatment period. The 10 patients treated with chlorpropamide significantly increased the urinary excretion of calcium and sodium and decreased the excretion of cyclic adenosine monophosphate (AMP). The serum calcium was lowered in six of the patients treated with chlorpropamide, and three of these patients, who had diabetes mellitus and either refused or were too ill for parathyroidectomy, continued to receive chlorpropamide for periods of 9 to 36 months. These three patients experienced prolonged lowering of the serum calcium level and became less confused, lethargic, and fatigued. The interrelationships between the chlorpropamide-induced changes in excretion of calcium, sodium, and cyclic AMP still must be clarified.

Adenosine Monophosphate↗

PubMedDate not supplied

Comparative study of the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide or chlorpropamide.

This study was designed to compare the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide, chlorpropamide or biguanides in non-insulin-dependent diabetes. It is divided into two parts: a) in the retrospective study (473 subjects), glucose control of patients who were transferred from chlorpropamide, gliclazide, glibenclamide, glibenclamide + biguanide or metformin to the fixed combination glibenclamide-phenformin in the same tablet (2.5 mg and 25 mg, respectively) was monitored. A statistically significant decrease of blood glucose and glycosylated hemoglobin values was found under the combination of glibenclamide-phenformin contained in the same tablet in contrast to the values obtained with the treatment with glibenclamide, gliclazide, chlorpropamide, combination of glibenclamide and biguanides, metformin, and insulin. b) In the prospective study (57 subjects), the patients were transferred from chlorpropamide or gliclazide to glibenclamide for 3 months and then reallocated to the previous treatment for 3 additional months. It was found that under glibenclamide, glucose control was significantly better than under chlorpropamide or gliclazide. In conclusion, glibenclamide, a second generation sulfonylurea, and the fixed combination glibenclamide-phenformin in the same tablet are more effective compared to the other antidiabetic agents here studied and lead to a better control of type II diabetic patients. There was no increase in plasma lactic acid concentration in all patients studied before and after having received the fixed combination of glibenclamide-phenformin in the single tablet form.

Blood Glucose↗

PubMed1983

Metabolic studies in chlorpropamide-alcohol flush positive and negative Type 2 (non-insulin dependent) diabetic patients with and without retinopathy.

Serum insulin and blood metabolite responses to oral glucose with and without intravenous naloxone were measured in 24 chlorpropamide-alcohol flush positive and negative Type 2 (non-insulin dependent) diabetic patients with and without retinopathy. In the chlorpropamide-alcohol flush positive patients with retinopathy, fasting blood glucose was increased greater than 40% and the serum triglycerides were increased over twofold compared with each of the other three groups. Following oral glucose (50 g), the chlorpropamide-alcohol flush positive diabetic patients with complications had a lower serum insulin and higher blood glycerol than the other three groups. Thus, chlorpropamide-alcohol flush positive subjects with retinopathy showed distinct metabolic differences from the other three groups. There was no evidence that opiate-receptors influenced the metabolic response to oral glucose in the Type 2 diabetic patients since the infusion of intravenous naloxone produced no effect on the serum insulin or blood metabolites.

Aged↗