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PubMed1979

Stability-indicating high-performance liquid chromatographic determination of chlorpropamide, tolbutamide, and their respective sulfonamide degradates.

A quantitative high-performance liquid chromatographic method for the determination of chlorpropamide, tolbutamide, and their respective hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, in solid dosage forms was developed. The method is stability indicating and can be used to determine the sulfonamide hydrolysis product and the intact drug in the presence of minor degradates. Method reproducibility, demonstrated by repeated injections of a calibration standard, was 1.21%. The lower limit of quantitation of the hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, was 0.2 microgram/5-microliter injection. The accuracy of the method for intact drugs was determined by comparison of the HPLC results to those obtained by the appropriate USP or BP assays. The mean of the results obtained by the two methods differed by 0.7% for chlorpropamide and 0.3% for tolbutamide. Pure drug samples were spiked with amounts of the hydrolysis products ranging from 20 to 120% of the intact content. The mean percent recovery for p-chlorobenzenesulfonamide was 98.6%; for p-toluenesulfonamide, it was 100.6%. A qualitative TLC procedure for the detection of chlorpropamide, p-chlorobenzenesulfonamide, dipropylurea, propylurea, n-propylamine, tolbutamide, p-toluenesulfonamide, dibutylurea, butylurea, and n-butylamine is also described.

Chlorpropamide↗

PubMed1977

Plasma concentrations, bioavailability and dissolution of chlorpropamide.

The bioavailability of chlorpropamide from two new formulations (Melitase tablets) has been compared to that from a reference formulation which is currently in clinical use as a hypoglycaemic agent. In both rate and extent of bioavailability, all three formulations may be considered equivalent, providing allowances are made for differences in drug content. With 95% confidence, the mean bioavailability of chlorpropamide from the new formulations was within about 16% of the mean from the reference formulaion, and formulation-related differences were not statistically significant. Although all three formulations were shown to have similar dissolution profiles, dissolution of chlorpropamide was pH-dependent in vitro. Dissolution was almost complete during 30 min at pH 7.2, but only 40%-60% had dissolved during 90 min at pH 2.0. A peak mean concentration of 22.7 mug/ml was reached 3 h after administration of 2 x 100 mg tablets of the new formulation and peak mean concentrations of 26.8 mug/ml and 27.4 mug/ml were reached 3 h and 4 hours after administration of one 250 mg tablet of the new formulation and one 250 mg tablet of the reference formulation respectively. Formulation-related differences of mean plasma concentrations (after scaling for equal doses of 250mg) were not significant and each formulation provided similar plasma concentrations at corresponding times after administration. Statistically significant subject-related differences in all the parameters of bioavailability were shown by analyses of variance.

Adolescent↗

PubMedDate not supplied

Association between chlorpropamide-alcohol flushing and fast acetylator phenotype in type I and type II diabetes.

Different prevalences of chlorpropamide alcohol flushing (CPAF) have been reported by different authors in either type I or type II diabetics or in normal subjects and this could be due to different methodological approaches or to different criteria of evaluation of CPAF. Previous studies in small series of patients have also suggested the existence of an association between type I diabetes and the fast acetylator phenotype (AP). The first aim of this study was to find reliable criteria for the assessment of CPAF. The second was to evaluate the prevalence of CPAF and of AP in a large series of type I and type II diabetics; and the third was to evaluate possible associations of CPAF and AP. AP and CPAF were evaluated separately in 256 diabetics (110 with type I and 146 with type II diabetes) and in 183 diabetics (74 with type I and 109 with type II diabetes), respectively. In 156 of these subjects, the two markers were evaluated together. The occurrence of CPAF was studied by subjective and objective assessment and by thermographic recording; CPAF was quantified by the differential value of skin temperature increase [delta T(C-P)] and by the value of differential speed of ascent, expressed in angle-degrees [delta a(C-P)], after treatment with placebo and with chlorpropamide. The fast AP was more frequent in type I than in type II diabetics, was not related to family history of diabetes, sex of the patients, age at onset and duration of diabetes or metabolic control. The most reliable assessment of CPAF was represented by thermographic recording of speed of ascent of skin temperature. CPAF was more frequent in females than in males, more frequent in diabetics than in healthy controls, similarly frequent in type I and in type II diabetes and showed no relationship with family history of diabetes, age at onset, duration of diabetes or metabolic control. An association between fast AP and CPAF was found in type II, but not in type I diabetics: fast acetylators were more frequently CPAF-positive, while slow acetylators were more frequently CPAF-negative. In addition, a linear relationship was found between rate of acetylation and speed of ascent of facial skin temperature after chlorpropamide and alcohol in type II diabetics, not in type I diabetics. The meaning of this association is not clear and deserves further investigations.

Acetylation↗

PubMed1980

Chlorpropamide inhibition of excision repair and postreplication repair of ultraviolet damage in Chinese hamster ovary cells.

Chlorpropamide, an oral hypoglycemic agent, was tested for effects on excision repair and postreplication repair of ultraviolet (UV) damage of DNA in CHO-K1 cells. The technique used to measure excision repair involved isopycnic centrifugation of density- and isotopically-labeled DNA. Alkaline sucrose gradient sedimentation was used to monitor postreplication repair. Administration of chlorpropamide at 250 and 1000 microgram/ml after exposure of cultures to 254-nm UV reduced excision repair to 79 and 67%, resp., of control. Post-irradiation treatment with the drug at 1000 microgram/ml inhibited the postreplication gap-filling mechanism almost as effectively as did 2 mM caffeine. The hypoglycemic agent was also found to reduce UV cell survival but did not appear to alter the rate of semiconservative replication. These results suggest that chlorpropamide inhibition of repair processes may potentiate the effects of known mutagenic hazards and may also be responsible for the increased incidence of chromosome aberrations in patients treated with the drug.

Animals↗

PubMed1983

Chlorpropamide-ethanol induced met-enkephalin secretion in dogs: release mechanisms and biochemical characterisation.

Circulating met-enkephalin-like immunoreactivity (MLI) rises in man after chlorpropamide and ethanol although the origin and molecular forms of circulating MLI are not well defined. We have studied the response to oral ethanol in conscious and anaesthetised dogs pretreated with chlorpropamide. In conscious dogs MLI rose from a basal level of 29 +/- 7 pg/ml to a peak of 55 +/- 14 pg/ml 10 min after ethanol (P less than 0.001). In anaesthetised animals, following ethanol, plasma MLI rose in caval (35 +/- 6 pg/ml to a peak of 70 +/- 10 pg/ml), in portal (28 +/- 6 pg/ml to 51 +/- 6 pg/ml) and in adrenal blood (897 +/- 316 pg/ml to 1483 +/- 298 pg/ml; P less than 0.001). Biogel P-4 chromatography of caval and portal basal plasma showed 87% of MLI measured coeluted with the synthetic pentapeptide, while chromatography of peak plasma showed that only 65% coeluted with the pentapeptide and the remaining 35% was of larger molecular size. Sephadex G75 chromatography of adrenal vein plasma revealed three peaks of MLI of differing molecular sizes (8 k = 69.7%; 3-5 k = 12.1% and the pentapeptide = 18.2%). Treatment of the column fractions with trypsin and carboxypeptidase B resulted in the generation of new MLI with peaks of approximate molecular sizes 31 k (10.4%), and 18 k (37.1%) in addition to 8 k (40.0%), 3-5 k (5.0%) and the pentapeptide (7.5%). Acetaldehyde involvement in MLI release was investigated. Following acetaldehyde infusion, plasma MLI rose both in caval (35 +/- 9 pg/ml to 86 +/- 8 pg/ml) and adrenal vein (417 +/- 121 pg/ml to 1768 +/- 433 pg/ml) bloods. Thus we have established an animal model which enables further study of the mechanisms of MLI release and characterisation of the molecular forms. The adrenal medulla, unlike the gut, may be an important source of circulating met-enkephalin and acetaldehyde formation an essential intrinsic component of chlorpropamide-ethanol induced met-enkephalin release.

Acetaldehyde↗

PubMed2001

Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues.

In our efforts to identify agents that would specifically inhibit ALDH3A1, we had previously studied extensively the effect of an N(1)-alkyl, an N(1)-methoxy, and several N(1)-hydroxy-substituted ester derivatives of chlorpropamide on the catalytic activities of ALDH3A1s derived from human normal stomach mucosa (nALDH3A1) and human tumor cells (tALDH3A1), and of two recombinant aldehyde dehydrogenases, viz. human rALDH1A1 and rALDH2. The N(1)-methoxy analogue of chlorpropamide, viz. 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2), was found to be a relatively selective and potent inhibitor of tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A-catalyzed oxidation, but even more potently inhibited ALDH2-catalyzed oxidation, whereas an ester analogue, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2), selectively inhibited tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A1-, ALDH1A1- and ALDH2-catalyzed oxidations, and this inhibition was apparently irreversible. Three additional chlorpropamide analogues, viz. 4-chloro-N,O-bis(ethoxycarbonyl)-N-hydroxybenzenesulfonamide (NPI-4), N,O-bis(carbomethoxy)methanesulfohydroxamic acid (NPI-5), and 2-[(ethoxycarbonyl)oxy]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (NPI-6), were evaluated in the present investigation. Quantified were NAD-linked oxidation of benzaldehyde catalyzed by nALDH3A1 and tALDH3A1, and NAD-linked oxidation of acetaldehyde catalyzed by rALDH1A1 and rALDH2, all at 37 degrees C and pH 8.1, and in the presence and absence of inhibitor. NPI-4, NPI-5 and NPI-6 were not substrates for the oxidative reactions catalyzed by any of the ALDHs studied. Oxidative reactions catalyzed by the ALDH3A1s, rALDH1A1 and rALDH2 were each inhibited by NPI-4 and NPI-5. NPI-6 was a poor inhibitor of nALDH3A1- and tALDH3A1-catalyzed oxidations, but was a relatively potent inhibitor of rALDH1A1- and rALDH2-catalyzed oxidations. In all cases, inhibition of ALDH-catalyzed oxidation was directly related to the product of inhibitor concentration and preincubation (enzyme+inhibitor) time. As judged by the product values (microMxmin) required to effect 50% inhibition (IC(50)): (1) nALDH3A1 and tALDH3A1 were essentially equisensitive to inhibition by NPI-4 and NPI-5, and both enzymes were poorly inhibited by NPI-6; (2) rALDH1A1 was, relative to the ALDH3A1s, slightly more sensitive to inhibition by NPI-4 and NPI-5, and far more sensitive to inhibition by NPI-6; and (3) rALDH1A1 was, relative to rALDH2, essentially equisensitive to inhibition by NPI-5, whereas, it was slightly more sensitive to inhibition by NPI-4 and NPI-6.

Aldehyde Dehydrogenase↗

PubMed2001

Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues.

In our efforts to identify agents that would specifically inhibit ALDH3A1, we had previously studied extensively the effect of an N(1)-alkyl, an N(1)-methoxy, and several N(1)-hydroxy-substituted ester derivatives of chlorpropamide on the catalytic activities of ALDH3A1s derived from human normal stomach mucosa (nALDH3A1) and human tumor cells (tALDH3A1), and of two recombinant aldehyde dehydrogenases, viz. human rALDH1A1 and rALDH2. The N(1)-methoxy analogue of chlorpropamide, viz. 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2), was found to be a relatively selective and potent inhibitor of tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A-catalyzed oxidation, but even more potently inhibited ALDH2-catalyzed oxidation, whereas an ester analogue, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2), selectively inhibited tALDH3A1-catalyzed oxidation as compared to its ability to inhibit nALDH3A1-, ALDH1A1- and ALDH2-catalyzed oxidations, and this inhibition was apparently irreversible. Three additional chlorpropamide analogues, viz. 4-chloro-N,O-bis(ethoxycarbonyl)-N-hydroxybenzenesulfonamide (NPI-4), N,O-bis(carbomethoxy)methanesulfohydroxamic acid (NPI-5), and 2-[(ethoxycarbonyl)oxy]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (NPI-6), were evaluated in the present investigation. Quantified were NAD-linked oxidation of benzaldehyde catalyzed by nALDH3A1 and tALDH3A1, and NAD-linked oxidation of acetaldehyde catalyzed by rALDH1A1 and rALDH2, all at 37 degrees C and pH 8.1, and in the presence and absence of inhibitor. NPI-4, NPI-5 and NPI-6 were not substrates for the oxidative reactions catalyzed by any of the ALDHs studied. Oxidative reactions catalyzed by the ALDH3A1s, rALDH1A1 and rALDH2 were each inhibited by NPI-4 and NPI-5. NPI-6 was a poor inhibitor of nALDH3A1- and tALDH3A1-catalyzed oxidations, but was a relatively potent inhibitor of rALDH1A1- and rALDH2-catalyzed oxidations. In all cases, inhibition of ALDH-catalyzed oxidation was directly related to the product of inhibitor concentration and preincubation (enzyme+inhibitor) time. As judged by the product values (microM x min) required to effect 50% inhibition (IC(50)): (1) nALDH3A1 and tALDH3A1 were essentially equisensitive to inhibition by NPI-4 and NPI-5, and both enzymes were poorly inhibited by NPI-6; (2) rALDH1A1 was, relative to the ALDH3A1s, slightly more sensitive to inhibition by NPI-4 and NPI-5, and far more sensitive to inhibition by NPI-6; and (3) rALDH1A1 was, relative to rALDH2, essentially equisensitive to inhibition by NPI-5, whereas, it was slightly more sensitive to inhibition by NPI-4 and NPI-6.

Aldehyde Dehydrogenase↗

PubMed1981

Low incidence of chlorpropamide-alcohol flushing in diet-treated, non-insulin-dependent diabetes.

50 diet-treated, non-insulin-dependent diabetics were tested subjectively and objectively for chlorpropamide-alcohol flushing (CPAF) with a single challenge test. Of the 12 (24%) who reported a subjective flush, 9 (18%) also flushed when a placebo was given instead of chlorpropamide, so the true incidence of chlorpropamide-alcohol flushing was 4% (1 patient was not retested with placebo). In a control group of 21 non-diabetics, 2 showed the specific CPAF phenomenon. Temperature measurement did not improve discrimination, but it did show a faster rise in facial temperature in CPAF-positive subjects than in alcohol flushers. This study does not confirm previous higher estimates of the incidence of the CPAF phenomenon in non-insulin-dependent diabetes.

Adult↗

PubMed1990

Effects of lovastatin in diabetic patients treated with chlorpropamide.

Patients with non-insulin dependent diabetes mellitus (NIDDM) have a higher risk of atherosclerotic cardiovascular disease than nondiabetic subjects. In seven patients with both hypercholesterolemia and NIDDM controlled by chlorpropamide, lovastatin (20 mg b.i.d. for 6 weeks) lowered low-density lipoprotein cholesterol by 28%, total cholesterol by 24%, and apolipoprotein B by 24%. Lovastatin levels for a 4-hour period (measured as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory activity) were similar to those measured previously in nondiabetic patients. Lovastatin did not alter chlorpropamide kinetics or glycemic profiles. No patient had an elevation in serum transaminases or creatinine phosphokinase, and no patient had any other laboratory or clinical drug-related adverse experience during the study. Lovastatin was as effective in reducing low-density lipoprotein cholesterol in patients with NIDDM as in nondiabetic subjects. Diabetic control was unaltered, and no evidence of alteration in lovastatin or chlorpropamide blood levels was noted.

Acyl Coenzyme A↗

PubMed1977

Repeated blood glucose and plasma insulin levels in normal volunteer subjects receiving isocaloric meals, before and after chlorpropamide and glibenclamide.

The blood glucose and plasma insulin response to the two hypoglycaemic agents, chlorpropamide (Diabenese) and glibenclamide (Daonil) was determined in normal subjects under strict metabolic control in a double blind study. The subjects were admitted to hospital for the period of the study, during which time they received four isocaloric meals per day and their physical exercise was standardised. Chlorpropamide had a prolonged hypoglycaemic effect compared with the short lived response after glibenclamide. Thy hypoglycaemic characteristics of the two preparations could not be explained simply on the insulin responses. Chlorpropamide was capable of lowering blood glucose without raising plasma insulin levels, whereas glibenclamide produced a prolonged and marked increase in plasma insulin levels only to be associated with a short-lived hypoglycaemic response. The latter suggested that a degree of insulin resistance had been produced secondary to the early profound lowering of the blood glucose following glibenclamide. The data indicate therefore the need for caution in extrapolating to diabetic subjects the hypoglycaemic characteristics of an agent such as glibenclamide derived from studies in normal subjects.

Adolescent↗

PubMed1976

Hypoglycaemic coma due to chlorpropamide: observations on twenty-two patients.

Twenty-two patients with chlorpropamide-induced hypoglycaemic coma were seen at a medical centre serving a region with a large geriatric population. The median age of the patients was 72; seven were over 80 and only one was under 60. Four patients died and in three of them death appeared to be connected with the hypoglycaemia. In two cases, the hypoglycaemia appeared in the postoperative period. Generally accepted contra-indications to the use of chlorpropamide were present in five of the eight patients under 70 and in four of the 14 patients over 70. If full precautions had been taken in presecribing chlorpropamide and if old age had been regarded as a contra-indication, the hypoglycaemia might have been prevented in 19 out of the 22 patients.

Aged↗

PubMed1980

Excessive sensitivity to the hyponatremic effect of chlorpropamide in a patient with diabetes mellitus and anterior pituitary insufficiency.

A 67-year-old diabetic woman with undiagnosed anterior pituitary insufficiency developed hyponatremic coma within 5 weeks after initiation of chlorpropamide therapy. A provocation test with 500 mg chlorpropamide orally led within five hours to hyponatremia and sopor with high urinary sodium excretion. This rapid development of the hyponatremic syndrome excludes water retention due to ADH as the dominant cause. It is more probable that known defects in renal sodium conservation, brought about by the anterior pituitary failure, have been potentiated by chlorpropamide.

Aged↗

PubMed1981

Chlorpropamide-alcohol flushing and blood kinins.

In a pilot study six patients with noninsulin dependent diabetes, three positive and three negative to chlorpropamide-alcohol flushing (CPAF), were tested. The patients were tested both without and with chlorpropamide premedication. Blood kinin concentrations were determined before and after ingestion of small quantities of alcohol. No rise in blood kinin concentrations were found during the flush suggesting that kinins do not play a major part in chlorpropamide-alcohol flushing.

Alcohol Drinking↗

PubMed1991

Transepithelial water movement in response to carbamazepine, chlorpropamide and demeclocycline in toad urinary bladder.

1. Osmotic water movement across toad isolated hemibladders was measured by a gravimetric method. 2. The influence of carbamazepine, chlorpropamide and demeclocycline on the antidiuretic hormone (ADH)-induced water flow rate was examined. 3. No antidiuretic activity due to carbamazepine alone was observed but a slight inhibition due to ADH-induced water flow was observed in the presence of carbamazepine over a selected dose-range. This was unexpected and is inconsistent with data from in vivo studies in man. 4. Chlorpropamide potentiated ADH-induced water flow, in keeping with the hypothesis that chlorpropamide sensitizes the renal tubules to ADH-induced water flow. 5. Demeclocycline inhibited ADH-induced water flow. The mechanism of action remains unclear.

Animals↗

PubMed1978

Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes.

A simple test was devised to identify people susceptible to chlorpropamide-alcohol flushing (CPAF). Subjects were given a placebo tablet, followed by sherry 12 and 36 hours later. They then received a chlorpropamide tablet and sherry again after 12 and 36 hours. This single-dose challenge test was given to non-insulin-dependent diabetics, insulin-dependent diabetics, and normal subjects. CPAF was common in the non-insulin-dependent diabetics but rare in the other groups. When the test was used in identical twins and families of affected subjects CPAF appeared to be a dominantly inherited trait. We conclude that facial flushing after alcohol in people taking chlorpropamide is related to non-insulin-dependent diabetes, especially when there is a strong family history of diabetes, but not to insulin-dependent diabetes. It is a dominantly inherited trait.

Adolescent↗

PubMed1977

Inhibition of vasopressin-stimulated prostaglandin E biosynthesis by chlorpropamide in the toad urinary bladder. Mechanism of enhancement of vasopressin-stimulated water flow.

Chlorpropamide is known to enhance the water permeability response of the toad urinary bladder to vasopressin and to theophylline. In other studies, we have shown that prostaglandin E synthesis by the toad bladder inhibits the water permeability response to arginine vasopressin and to theophylline. In this study, the effect of chlorpropamide on vasopressin-, theophylline-, and cyclic AMP-stimulated water flow and on prostaglandin E biosynthesis was investigated in the toad urinary bladder in vitro. Chlorpropamide inhibited prostaglandin E biosynthesis during vasopressin-, theophylline- and cyclic AMP-stimulated water flow. Tolbutamide and glyburide, two other sulfonylurea compounds, also enhanced vasopressin-stimulated water flow and inhibited vasopressin-stimulated prostaglandin E biosynthesis. We conclude that the mechanism of enhancement on vasopressin-stimulated water flow by the sulfonylureas is the inhibition of prostaglandin E biosynthesis.

Animals↗

PubMed1983

Antithyroid effect of chlorpropamide?

1 The relationship between plasma chlorpropamide concentration and thyroid function was examined in 87 maturity onset diabetic patients receiving chronic therapy. 2 Although plasma chlorpropamide concentration was weakly negatively correlated with serum thyroxine (r = 0.33, P less than 0.01) the mean serum thyroxine and thyrotrophin (TSH) were not different from that of a matched control group of diabetics treated with diet alone. 3 Serum thyroxine was negatively correlated with the duration of diabetes in both groups. 4 These results suggest that chlorpropamide does not have a clinically significant antithyroid effect.

Adult↗

PubMed1983

Treatment of chlorpropamide overdose with diazoxide.

A patient who took a chlorpropamide overdose was treated for several hours with concentrated glucose solutions, with little success in maintaining adequate serum glucose concentrations. Intravenous diazoxide administration was begun with the hope of decreasing pancreatic insulin release. After diazoxide was begun, glucose requirements decreased dramatically, and serum glucose was supranormal for most of the period of diazoxide administration. The case was complicated by the fact that the patient had taken three agents that can cause hypoglycemia--chlorpropamide, alcohol, and aspirin. Drug interactions potentiating the hypoglycemic effect of the chlorpropamide were also possible. Glucose infusion is the mainstay of therapy for a sulfonylurea overdose. However, glucose acts as a further stimulus of insulin release from a sulfonylurea-primed pancreas. Administration of concentrated glucose solutions is technically difficult because of damage to veins. Metabolic consequences of high rates of glucose infusion to hyperinsulinemic patients include hypokalemia and hypophosphatemia. Diazoxide appeared to decrease the glucose requirement in this patient, as it did in three other reported cases. Diazoxide is approved for certain hypoglycemic, hyperinsulinemic conditions. Sulfonylurea overdose represents a hypoglycemic, hyperinsulinemic condition; diazoxide appears to be an effective treatment.

Adolescent↗