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A 62-year-old man who had been taking 250 mg of chlorpropamide daily for several years received rifampin concomitantly and had a subsequent increased dosing requirement of chlorpropamide. When rifampin was discontinued several months later, the serum chlorpropamide concentration rose dramatically.
In perfused livers of rats fasted for 24 h, glucagon (5 x 10(-10) M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 x 10(-3) M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle. In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.
Chlorpropamide-induced hypoglycemia is often overlooked, misdiagnosed, and mistreated, because of the atypical, insidious, and intermittent clinical picture and because of the normal serum glucose level in some of the patients when arriving at the hospital. These facts are demonstrated in three case reports. Since the correction of low glucose levels in the cerebrospinal fluid occurs hours after its correction in the serum, examining and at times following the cerebrospinal fluid glucose levels in patients with chlorpropamide-induced neuroglycopenia will enable physicians to diagnose and cure more patients. A high index of suspicion should exist in the presence of any atypical encephalopathy, mainly in the elderly diabetic patient treated with chlorpropamide and suffering from impaired cerebral, hepatic, or renal function. By suspecting and identifying neuroglycopenia, disabling residual deficits and even death could eventually be prevented.
The incidence and risk factors of chlorpropamide-induced hyponatremia were assessed in diabetic outpatients. In 176 chlorpropamide-treated patients, 11 (6.3%) exhibited hyponatremia (serum sodium less than or equal to 129 meq/L) during the mean follow-up period of 7.4 yr. In contrast, only one (0.6%) developed hyponatremia in 162 tolbutamide- or glibenclamide-treated patients (P less than 0.005). Moreover, administration to elderly patients and combination with thiazide diuretics were regarded as significantly potent risk factors for the development of hyponatremia in patients receiving chlorpropamide.
Combined halofenate-chlorpropamide was evaluated for the treatment of NIDDM. Four subjects treated with 500 mg/day chlorpropamide were given 500-1000 mg halofenate daily for 48 wk or longer. Fasting plasma glucose fell from 210 +/- 16 (+/- SEM) (11.67 +/- 0.89 mM) to 107 +/- 10 mg/dl (+/- SEM) (5.94 +/- 0.55 mM), P less than 0.005. Twelve additional subjects were entered into a 16-wk double-blind study testing chlorpropamide plus either placebo or halofenate. In the halofenate group, the mean fasting glucose fell from 227 +/- 27 (+/- SEM) (12.61 +/- 1.50 mM) and reached 107 +/- 19 mg/dl (+/- SEM) (5.94 +/- 1.06 mM) during the fourth month, whereas the placebo groups showed a decrease from 242 +/- 22 (+/- SEM) to 208 +/- 29 mg/dl (+/- SEM) (P less than 0.005). In addition, halofenate reduced the height of postprandial glycemic excursions by lowering fasting plasma glucose. When halofenate was used as the only therapy, reduction in fasting plasma glucose was small [179 +/- 12 reduced to 142 +/- 8 mg/dl (+/- SEM); 9.94 +/- 0.67 mM and 7.89 +/- 0.44 mM], P less than 0.05.
Rectal suppositories with chlorpropamide and suppositories with chlorpropamide in the dispersion system with urea were prepared. Witepsol H15 and H19 and a polyoxyethyleneglycol mixture were used as bases. Rabbits were tested for blood-glucose level. The animals have been administered with prepared suppositories and commercial tablets. It was found that the suppositories prepared on the basis Witepsol H 15 with the dispersed chlorpropamide caused a much higher decrease of blood-glucose level than commercial tablets.
In clinical practice of hypoglycemic therapy of diabetes mellitus the problem of the optimal selection of oral hypoglycemic agent, corresponding to the individual patterns of regulatory and metabolic disturbances is of primary importance. The individual, pathophysiological basis should be met as much as possible by the pharmacodynamic properties of the selected, hypoglycemic drug. For this reason group of 23 diabetics type II underwent a prolonged, open trial of controlled pharmacotherapy with 4 sulphonylurea derivatives. Pertinent clinical and metabolic parameters were assessed before, during and after planned periods of therapy with Tolbutamide or Chlorpropamide to Gliclazide and Gliclazide to Glibenclamide. In the same time the levels of serum insulin fasting and after breakfast were determined. Also the comparative efficacy of the exchange of the drug in a subgroup of diabetics with fasting glycemia below and above 160 mg% was assessed. It was shown, that the change of Tolbutamide or Chlorpropamide to Gliclazide or Glibenclamide improved the therapeutical effectiveness in general. The individual responses to such a change were however individually differentiated. The change of Tolbutamide or Chlorpropamide to Gliclazide increased the therapeutical efficacy only in these patients, in whom such a change was associated with an increase of prandial, reactive serum insulin level (IRI). In practice they were patients with the fasting glycemia lower than 160 mg%. In patients with fasting glycemia higher than 160 mg% the change of oral compounds under study was not connected with an increase of prandial serum insulin. The metabolic parameters have not improved either. Perhaps they were patients with diabetes mellitus type II, who should be primarily qualified to insulin.
A previously healthy 59-year-old man received chlorpropamide 250 mg/day for adult-onset diabetes. Within 1 month of starting the drug, he developed cholestatic jaundice and pseudomembranous colitis. The colitis worsened during subsequent treatment with multiple antibiotics and sulfasalazine. Oral vancomycin produced a prompt and total remission. One similar case of chlorpropamide toxicity manifested by jaundice and colitis has been previously reported. It is possible that the sulfonamide moiety of the chlorpropamide was implicated in the development of the colitis.
Twenty cases of familial ADH-responsive diabetes insipidus were identified within five generations, and eight patients were studied by one of two established dehydration protocols. In each case there was partial to total failure of response to the initial administration of ADH which was slowly corrected by continued administration. This initial failure can lead to misinterpretation of the dehydration test unless the medullary solute washout effect is taken into account in chronically polyuric patients.Treatment consisted of thiazides and/or chlorpropamide. All cases responded well.The response to chlorpropamide suggests that the failure of ADH production is not complete in these patients, and that the major defect is a failure of ADH release in response to normal stimuli. Chlorpropamide may act by either facilitating ADH release or by synergistically interacting with available ADH at the tubular level.
A possible influence of oral hypoglycaemic drugs on plasma high density lipoprotein cholesterol (HDL-C) concentrations was examined in streptozotocin diabetic and non-diabetic mice. Treatment of streptozotocin diabetic mice with glibenclamide (0.4 mg/kg/day), chlorpropamide (10 mg/kg/day) or metformin (60 mg/kg/day) for 28 weeks did not significantly alter plasma total cholesterol (TC) or HDL-C in streptozotocin diabetic mice. Plasma TC and HDL-C were not related to the prevailing plasma glucose concentration. Non-diabetic mice treated with glibenclamide or metformin for 46 weeks showed no changes in TC or HDL-C. However, chlorpropamide increased TC and HDL-C, and lowered the TC : HDL-C molar ration after 46 weeks in non-diabetic mice. The effect of chlorpropamide was associated with an excessive gain in weight.
Fasting serum concentrations of high density lipoprotein cholesterol (HDLC) and apolipoprotein A-I (apo A-I) were determined in non-insulin dependent diabetes at diagnosis, diabetics treated by diet alone, diabetics treated by diet plus chlorpropamide, and normal controls matched for sex, age and body weight. Serum concentrations of HDLC and apo A-I were decreased in all groups of diabetics. There were no significant differences in HDLC and apo A-I concentrations between the diabetics at diagnosis and those treated by diet alone or diet plus chlorpropamide. Neither HDLC nor apo A-I concentrations were correlated with glucose concentrations. The results indicate that serum concentrations of HDLC and apo A-I are reduced in non-insulin dependent diabetics at diagnosis, and are not significantly affected by chronic diet and chlorpropamide therapy.
Fifty-nine nursing home patients (average age, 79.9 +/- .9 years) receiving chlorpropamide were screened with a serum sodium determination. Nine patients (15.3 percent) had a serum sodium concentration less than 135 mEq/L; six of these patients (10.2 percent) had a serum sodium equal to or less than 130 mEq/L; none of the patients had a serum sodium less than 125 mEq/L. Five hyponatremic patients (Na less than or equal to 130 mEq/L) and nine normonatremic patients (Na greater than or equal to 135 mEq/L) were screened with a standardized mental status examination and additional laboratory studies. The hyponatremic patients were switched to tolazamide after a one-week wash-out period, and the mental status examination and laboratory studies were repeated in both groups four weeks later. One patient in the hyponatremic group died during the course of the study; the other four became normonatremic on tolazamide. Mental status scores increased significantly in the hyponatremic group, 16.0 +/- 3.6 to 20 +/- 4.6 (a 37.3 +/- 21.5 percent increase), compared with the normonatremic group, 14.5 +/- 2.6 to 15.8 +/- 2.9 (a 7.8 +/- 3.2 percent increase). There were no significant differences in serum glucose, creatinine, chlorpropamide, or antidiuretic hormone concentrations between the two groups. It is recommended that periodic serum sodium determinations be obtained in geriatric patients receiving chlorpropamide.
Two patients with hypodipsia and hypernatremia are described. The first patient, whose hypodipsia was of unknown cause, developed hypernatremia unless large volumes of fluid were urged upon him; upon treatment with chlorpropamide normal serum sodium levels were achieved with spontaneous fluid intake. The second patient had hypodipsia and diabetes insipidus resulting from a craniopharyngioma. Treatment with vasopressin and a prescribed daily water intake resulted in frequent hyper- and hyponatremia, but treatment with chlorpropramide yielded serum sodium values which were more often normal and less variable. In neither patient could the improved water regulation be attributed to an effect of chlorpropamide on renal water excretion. Possible mechanisms for the effect of chlorpropamide on thirst are discussed.
The effect of drinking 40 ml of sherry on peak expiratory flow rate in 16 normal subjects and 19 patients with asthma was assessed after oral administration of either chlorpropamide or placebo. After placebo and sherry normal subjects showed no change in peak expiratory flow rate, while an increase was usually shown by patients with asthma. This bronchodilation was more marked in patients whose base-line peak flow rate was less than 50% predicted. Ingestion of chlorpropamide before sherry significantly modified the bronchodilating properties of sherry; five of the 19 patients with asthma showed airway narrowing on 11 of 19 occasions tested. Further studies in one patient suggest that this bronchoconstriction may be mediated by congeners in sherry rather than ethanol. These findings confirm the observation that chlorpropamide and sherry can cause airway narrowing in patients with asthma but shows that this response is not always reproducible. The bronchodilator effect of alcohol in patients with asthma may have therapeutic implications.
The proposed ADH-releasing capacity of chlorpropamide was tested after intravenous administration of the drug to nine healthy fasted volunteers. When compared with the placebo experiment, no evidence for increased ADH release was found. On the contrary, the AVP values measured after chlorpropamide injection were slightly lower during the first 2 h than after the saline injection. Serum chlorpropamide concentration was also measured. After a rapid distribution phase, a slow elimination phase followed. The calculated t 1/2 for distribution phase was 1.00 +/- 0.26 hrs (mean +/- s.e.m.).
A study was made of the effect of chlorpropamide in rats with pituitary stalk lesion. It was found that the drug made the oliguric interphase more pronounced and protracted, while in the lasting polyuric phase in the absence of endogenous ADH it influenced water intake only moderately. Enhancement of the effect of exogenous ADH was observed after a 2-day chlorpropamide pretreatment. The results support the view that the presence of a small amount of endogenous ADH is necessary for chlorpropamide-antidiuresis. The drug presumably brings about the decrease in diuresis via ADH mobilization, but its peripheral effect is also enhanced.
The clinical effectiveness of glibenclamide and chlorpropamide was compared in 107, uncomplicated, newly diagnosed maturity onset diabetics. The glibenclamide and chlorpropamide groups comprised of 49 and 58 patients respectively and were highly comparable. After a follow up period ranging from 6 months to 2-1/2 years, the failure rate in glibenclamide treated patients was 22.5% and 12% in those taking chlorpropamide. The changes in weight were similar and both drugs were devoid of serious toxic effects in the dosage prescribed. Symptoms of hypoglycaemia were seen in 2 patients on glibenclamide, while 3 patients in each group showed a modest rise of transaminases without any other evidence of liver damage.
Twelve series of rectal suppositories with chlorpropamide in two dispersion systems, containing different quantities of active substance and urea, were prepared upon lipophilic and hydrophilic bases. Liberation of chlorpropamide from suppositories was examined by the dialysis method. It was found out that the process of chlorpropamide liberation from the suppositories depends on the quantity of the carrier included in the dispersion systems and on the type of the medium used.