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PubMed1982

Chlorpropamide and glibenclamide serum concentrations in hospitalized patients.

The relationships between the daily doses of the drugs and the steady state serum concentration was studied in 51 patients on chlorpropamide and in 27 patients on glibenclamide. All the patients were hospitalized during the study. A wide interindividual variation in chlorpropamide levels was observed and thus, the prediction of drug concentration was difficult from the dosage alone, despite a statistically significant correlation between the dose per body weight and the serum drug level. The differences could not be explained on the serum creatinine levels, age, sex, liver diseases or other drugs used concomitantly. In the case of glibenclamide, a wide interindividual variation in serum concentration of the drug also occurred.

Aged↗
PubMed1982

In vitro testing of chlorpropamide with human lymphocyte cultures in the presence of liver microsome fraction S9 mix of rats.

The oral hypoglycaemic drug 1-(p-chloroben-zenesulfonyl)-3-propylurea (chlorpropamide) was examined for clastogenic properties using human lymphocytes with a microsomal (S9 mix) activation system. Lymphocytes, exposed to the S9 mix only as well as to the solvent DMSO, yielded chromosome aberration levels within the background range. The sensitivity of the S9 mix could be demonstrated using 2-[bis(2-chloroethyl)amino]tetrahydro(2H)-1,3,2-oxazaphosphorine 2-oxide (cyclophosphamide) as a positive control, which only displays clastogenic properties after metabolic activation. Chlorpropamide, however, did not induce structural chromosome aberrations under the in vivo conditions tested in this study.

Animals↗
PubMed1982

Chlorpropamide-induced optic neuropathy.

A 65-year-old woman with adult-onset diabetes treated with chlorpropamide (Diabenese) had a toxic optic neuropathy that resolved with discontinuation of chlorpropamide therapy. Visual loss occurs in diabetics for a variety of reasons, and accurate diagnosis is necessary to institute appropriate therapy. The possibility of a drug-induced optic neuropathy should be considered in the differential diagnosis of visual loss in diabetics.

Aged↗
PubMed1981

Chlorpropamide bioavailability and pharmacokinetics.

The pharmacokinetics of chlorproamide was studied in eight healthy volunteers after intravenous and oral dosage. A long elimination half-life with considerable variations between subjects was recorded. The normalized areas under the curve were in close agreement between the subjects, suggesting that they had all absorbed the same magnitude of chlorpropamide. The AUCs after i.v. and p.o. administration did not differ significantly from each other. Thus, the differences in the bioavailability do not seem to be a critical factor in the previously reported large interindividual variations in chlorpropamide steady-state concentrations.

Administration, Oral↗
PubMed1980

Hypoglycemic coma, jaundice, and pure RBC aplasia following chlorpropamide therapy.

Five weeks following the initiation of chlorpropamide therapy for diabetes mellitus, hypoglycemic coma, cholestatic jaundice, and RBC aplasia developed in a 41-year-old woman. Within 40 days of stopping the drug, she had made a complete recovery. To our knowledge, this is the first case in which these three complications of chlorpropamide have occurred simultaneously.

Adult↗
PubMed1980

Chlorpropamide-induced pure RBC aplasia.

A 70-year-old man experienced pure RBC aplasia after high-dose chlorpropamide therapy. This is the second reported case of pure RBC aplasia associated with chlorpropamide. Cessation of the drug therapy was followed by rapid and sustained complete return to a normal hemoglobin level. A brief review of pure RBC aplasia is presented.

Aged↗
PubMed1995

Effect of compression temperature on the consolidation mechanism of chlorpropamide polymorphs.

The effect of environmental temperature on the compression mechanism of chlorpropamide (CPM) polymorph, forms A and C, was investigated with an eccentric type tabletting machine with two load cells and a noncontact displacement transducer. The temperature of the die was controlled at 0 and 45 degrees C by a thermocontroller. Sample powders (200 mg), which were also controlled at 0 and 45 degrees C by a thermocontroller, were compressed at almost 230 MPa. The tabletting dynamic processes of CPM forms A and C at 0 and 45 degrees C were evaluated by Cooper and modified Heckel analyses. The results suggest that particle brittleness or plasticity was affected by compression at different temperatures. The higher tablet hardness of form A at 45 degrees C was thought to be caused by the increased plasticity of primary particles, whereas that of form C at 45 degrees C was ascribed to the decreased size of the secondary particles.

Chemistry, Pharmaceutical↗
PubMed1980

Wide variation in serum chlorpropamide concentration in outpatients.

Serum chlorpropamide concentrations (s-CPA) were determined and related to clinical findings in 83 outpatients with maturity onset diabetes. The daily doses of CPA (mg/kg) varied six-fold, but s-CPA ranged 18-fold between the patients. There was a significant correlation between dose and s-CPA (r = 0.61), which rose to 0.75 in the 30 patients who had prescribed no other drugs. Patients given other drugs concomitantly were over-represented amongst subjects with extreme values of apparent plasma clearance of CPA. There was no correlation either between serum creatinine or age and s-CPA. Of the 83 patients 40 (48%) had acceptable blood and urinary glucose values according to our criteria; but as 17 were overweight, only 23 patients (28%) had acceptable clinical control. Of the remaining 60 patients, too low a dose was being given to only 12, and dietary failure was the most probable explanation in the others. Thirteen patients (16%) probably did not need CPA. It is likely that this is a partial explanation for the high utilisation of oral antidiabetic drugs in Sweden. There was no general correlation between dose or s-CPA and blood glucose values, but analysis of s-CPA may still be of value in explaining unexpected changes in clinical control.

Adult↗
PubMed1977

Chlorpropamide-induced hypoglycemia: successful treatment with diazoxide.

A healthy adolescent boy was treated on two occasions for an overdose of chlorpropamide (Diabinese). Glucose therapy alone was not sufficient to control the hypoglycemia, but the administration of glucose plus diazoxide raised the blood sugar to supranormal levels. A bolus of intravenous glucagon briefly raised the blood sugar level to within normal limits, increased the blood ketones but also augmented insulin secretion. An overdose of sulfonylurea may cause prolonged and fatal hypoglycemia. Rational therapy, both in diabetic and normal persons, is glucose plus an "insulin antagonist." The administration of diazoxide was effective in our patient, substantially reducing the plasma insulin level; this agent may be the "insulin-antagonist" of choice for use in sulfonylurea-induced hypoglycemia.

Adolescent↗
PubMed1983

Nephrotic syndrome and immune complex glomerulonephritis associated with chlorpropamide therapy.

Therapeutic drugs are well-recognized as a cause of the nephrotic syndrome in humans. However, documentation of the renal histopathologic features is lacking or incomplete in many cases. Even when accurate histopathologic information is available, there is little evidence to support a specific pathogenetic mechanism of renal injury in the vast majority of cases. We describe a patient with diabetes who had hepatitis and dermatitis in association with the use of chlorpropamide. In addition to these well-described toxic reactions to this drug, the nephrotic syndrome developed. Renal biopsy revealed the presence of a proliferative glomerulonephritis that was shown to be of an immune complex nature on immunofluorescence and electronmicroscopic study. Serial serum complement levels and circulating immune complex levels were consistent with an immunologically mediated reaction. Repeated renal biopsy documented resolution of the renal changes. Thus, in this patient, a drug-induced nephrotic syndrome was associated with a proliferative glomerulonephritis, probably due to the formation of immune complexes.

Chlorpropamide↗
PubMed1992

Failure of glutathione and cysteine prodrugs to block the chlorpropamide-induced inhibition of aldehyde dehydrogenase in vivo.

Augmentation of cellular L-cysteine or glutathione (GSH) levels in vivo by the administration of prodrugs of L-cysteine or GSH, viz. 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA), 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-car boxylic acid (RibCys) and GSH monoethyl ester (GSH-OEt), did not block the inhibition of aldehyde dehydrogenase (AlDH) by chlorpropamide (CP) or N1-ethylchlorpropamide (N1-EtCP), as shown by their inability to protect AlDH and thereby prevent the elevation of blood acetaldehyde (AcH) in ethanol-treated rats. Since the formation of an alkylcarbamoylating species by conjugation of n-propylisocyanate, a potential metabolite of CP or N1-EtCP, with GSH or L-cysteine is possible, intervention by GSH or cysteine may not produce a detoxified product. Evaluation of the two products that could theoretically be produced in vivo, viz. S-(n-propylcarbamoyl)-L-cysteine and S-(n-propylcarbamoyl)-GSH, indicated that these compounds inhibit rather than spare AlDH in rats. Indeed, the latter were as effective as N1-EtCP, a direct acting inhibitor of AlDH, and all three were better inhibitors of AlDH in vivo than CP itself. Thus, formation of S-conjugates of the active CP metabolite produced in vivo may not be a detoxication process, but may in fact represent redistribution of a transportable form of this highly reactive metabolite.

Acetaldehyde↗
PubMed1977

Effect of chlorpropamide and phenformin on rat liver: the effect on plasma membrane-bound enzymes and cyclic AMP content of hepatocytes in vitro.

Chlorpropamide and phenformin inhibited (Na+ - K+)-ATPase and stimulated a high affinity cyclic AMP-phosphodiesterase of isolated liver plasma membrane when tested in vitro. In addition, the two drugs decreased the intracellular cyclic AMP content of isolated hepatocytes without being effective on plasma membrane-bound adenylate cyclase. The results suggest that the plasma membrane plays an important role in the mechanism of action of the two hypoglycemic drugs, but do not exclude the presence of intracellular targets.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Basal normoglycemia attained with chlorpropamide in mild diabetes.

Sixteen adult-onset diabetics, who were thought by current criteria to be well controlled on diet alone, had substantially elevated overnight, basal plasma glucose concentrations. Chlorpropamide had a sufficiently prolonged stimulatory effect on the beta cells such that normal basal plasma glucose levels were obtained in 13 patients. Both basal plasma C-peptide levels and the C-peptide response to meals became normal, with improved postprandial glycemia. Diurnal plasma triglyceride levels were reduced. Plasma growth hormone levels were normal both before and after therapy. When diet alone is insufficient to maintain basal normoglycemia in mild diabetes, chlorporpamide is as effective as basal insulin supplements in producing normal basal plasma glucose levels.

Blood Glucose↗
PubMed1982

Chlorpropamide-alcohol flushing, malar thermal circulation index, and baseline malar temperature.

Chlorpropamide-alcohol flushing (CPAF) has been advanced and challenged as a specific marker for familial noninsulin dependent diabetes mellitus. The previous studies assay flushing reactions employing arbitrarily defined critical threshold values of rise and rate of rise in facial temperature. Since these methods ignore the curvilinear relationship between skin temperature and cutaneous blood flow, errors of analysis obtained, Further, the role of baseline facial temperature is obfuscated. The method of malar thermal circulation index derived from the relationship between skin temperature and cutaneous blood flow provides a more accurate assay method and permits the characterization of the role of baseline facial temperature. Baseline facial temperature is less in subjects with CPAF and noninsulin dependent diabetes than in normal subjects. The lower baseline facial temperature alone may account for the reported differences in the parameters of the CPAF test.

Body Temperature↗
PubMed1984

Effect of chlorpropamide and gliclazide on plasminogen activator activity in vascular walls in patients with maturity onset diabetes.

The components of the fibrinolytic system were studied in patients with maturity onset diabetes, treated with chlorpropamide for three years or more. Half of the patients (7/15) were shown to have abnormally low plasminogen activator activity of the vascular walls. The patients were then shifted to gliclazide, a new sulfonylurea, and after six months all patients had a normal vascular plasminogen activator activity. At follow up after 24 and 48 months the results remained the same. The normalization of the vascular fibrinolytic defence system could not be explained by improvement of glucose control.

Aged↗
PubMed1985

Chromosomal studies in diabetic patients treated with chlorpropamide.

Chromosome studies were carried out on the peripheral blood of nine diabetic patients treated with chlorpropamide, on nine healthy controls and on nine untreated diabetic controls. Data from each treated individual were compared with the mean of the pooled data from the two control groups. There was a statistically significant increase in the individual numbers of sister chromatid exchanges per metaphase in each of the patients treated with the drug compared with the mean of the pooled control values. There was no significant increase in the numbers of structural chromosomal aberrations in the treated patients compared with the controls.

Adult↗
PubMed1998

Inhibition of human class 3 aldehyde dehydrogenase, and sensitization of tumor cells that express significant amounts of this enzyme to oxazaphosphorines, by chlorpropamide analogues.

In some cases, acquired as well as constitutive tumor cell resistance to a group of otherwise clinically useful antineoplastic agents collectively referred to as oxazaphosphorines, e.g. cyclophosphamide and mafosfamide, can be accounted for by relatively elevated cellular levels of an enzyme, viz. cytosolic class 3 aldehyde dehydrogenase (ALDH-3), that catalyzes their detoxification. Ergo, inhibitors of ALDH-3 could be of clinical value since their inclusion in the therapeutic protocol would be expected to sensitize such cells to these agents. Identified in the present investigation were two chlorpropamide analogues showing promise in that regard, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2) and 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2). Each inhibited NAD-linked benzaldehyde oxidation catalyzed by ALDH-3s purified from human breast adenocarcinoma MCF-7/0/CAT cells (IC50 values were 16 and 0.75 microM, respectively) and human normal stomach mucosa (IC50 values were 202 and 5 microM, respectively). The differential sensitivities of stomach mucosa ALDH-3 and breast tumor ALDH-3 to each of the two inhibitors can be viewed as further evidence that the latter is a subtle variant of the former. Human class 1 (ALDH-1) and class 2 (ALDH-2) aldehyde dehydrogenases were much less sensitive to NPI-2; IC50 values were >300 microM in each case. API-2, however, did not exhibit a similar degree of specificity; IC50 values for ALDH-1 and ALDH-2 were 7.5 and 0.08 microM, respectively. Each sensitized MCF-7/0/CAT cells to mafosfamide; the LC90 value decreased from >2 mM to 175 and 200 microM, respectively. Thus, the therapeutic potential of combining NPI-2 or API-2 with oxazaphosphorines is established.

Aldehyde Dehydrogenase↗