Lessened insulin hypophosphatemia following N-sulfanilyl-N'-butylurea (BZ-55 or carbutamid).
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Hypophosphatemia↗
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Effects of sulfonylurea compounds on Pneumocystis carinii.
Two sulfonylurea compounds, carbutamide and tolbutamide, were studied for efficacy against Pneumocystis carinii pneumonitis in the corticosteroid-treated rat model and compared with trimethoprim-sulfamethoxazole (TMP-SMZ). The chemical structures of these sulfonylureas are identical except that an amino group in carbutamide is replaced with a methyl group in tolbutamide. Carbutamide was totally effective in the prevention and treatment of P. carinii pneumonitis in dosages of 100 and 200 mg/kg per day. The carbutamide dosage of 50 mg/kg per day prevented the infection in 90% of animals, whereas tolbutamide in the same dosage permitted infection in 100% of animals. This study shows that carbutamide is at least as effective as TMP-SMZ in the treatment and prevention of murine P. carinii pneumonitis. The presence of an amino group in the para position on the benezene ring is a determinant for this activity.
Administration, Oral↗
Electrophysiological effects of hypoglycaemic sulphonylureas on rabbit heart.
The hypoglycaemic sulphonylurea drugs glibenclamide and carbutamide were compared as to their influence on the electrical activity of isolated rabbit heart preparations. Carbutamide (10(-5)-10(-3) M) was found to depress slightly the nomotopic and junctional automaticity, while in Purkinje fibres it enhanced automaticity and conduction velocity. On the other hand, glibenclamide (10(-6)-10(-3) M) had no significant influence on the nomotopic and junctional automaticity, and markedly depressed automaticity and conduction velocity in the Purkinje fibres. The atrial conduction system was not much influenced by the sulphonylureas tested. Carbutamide depressed the electrical threshold in Purkinje fibres. It follows that the hypoglycaemic sulphonylurea compounds carbutamide and glibenclamide differ considerably with respect to their influences on cardiac electrical activity.
Action Potentials↗
Effects of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides.
In diabetic patients it has been shown that tolbutamide and carbutamide enhanced and glibenclamide did not influence the incidence of digitalis intoxication, or that of multifocal ectopic beats or coupling due to premature ectopic ventricular beats during digitalis therapy. In rabbits glibenclamide decreased and tolbutamide and carbutamide increased strophanthidin toxicity in a dose dependent manner. It was concluded that glibenclamide should be preferred to tolbutamide or carbutamide in digitalis-treated diabetics, when satisfactorily metabolic control is not achieved with a dietary regime alone.
Aged↗
The effect of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides and arrhythmogenic activity due to myocardial ischaemia.
The effects of different sulphonylureas on the electrical cardiac activity were studied in 145 rabbits and in 103 rats as well as in 278 digitalis-treated, non-smoker non-insulin-dependent diabetics on the same therapy at least during the previous three months. In rabbits and rats glibenclamide (0.0032-100 mumol. kg-1) decreased, while tolbutamide and carbutamide (0.008-1000 mumol. kg-1) increased strophantidin toxicity and myocardial ischaemia induced transitory ventricular fibrillation dose-dependently. The differences between the dose-response curve of glibenclamide and those of tolbutamide or carbutamide were significant. In digitalized non-insulin-dependent diabetics, multifocal ectopic ventricular beats could be observed in none among the 80 glibenclamide-treated diabetics, while in 12 cases of the 71 tolbutamide and in 10 cases of the 61 carbutamide treated diabetics. Two of the 66 non-insulin-dependent diabetics receiving only diet and 7 of the 278 age and sex matched, non-smoker, metabolically healthy patients had multifocal ectopic ventricular beats. No significant difference could be found between the therapeutical groups. It was concluded that instead of tolbutamide, glibenclamide must be preferred in digitalis-treated diabetics, when metabolic control is not satisfactorily achieved by diet and regime alone.
Animals↗
Effect of diabetes therapy on the myocardium in experimental diabetes.
The effects of chronic antidiabetic treatment were examined in a clinically manifest, but non-ketotic diabetic animal model in which increased stabilization of steric structure in the cardiac connective tissue and left ventricular diastolic stiffness have been demonstrated. These changes accounted for decreased left ventricular performance during left ventricular afterload. Each of 8 diabetic dogs was given daily 8-16 IU of insulin, 250-750 mg carbutamide or 2-10 mg glibenclamide, respectively; doses were always adjusted to the actual metabolic requirements and findings were compared to those of 11 untreated diabetic and 6 healthy dogs. After three months, the hemodynamic and metabolic studies showed that the metabolically controlled diabetic dogs had less marked alterations in the connective cardiac tissue, left ventricular diastolic stiffness and performance. Apart from a considerable rise of arterial blood pressure during carbutamide treatment, no other difference was found in the cardiac actions of the three hypoglycemic agents tested.
Animals↗
Glibenclamide is exceptional among hypoglycaemic sulphonylureas in accumulating progressively in beta-cell-rich pancreatic islets.
Six hypoglycaemic sulphonylurea compounds were compared with regard to their ability to bind to beta-cell-rich pancreatic islets microdissected from ob/ob-mice. Glibenclamide differed from carbutamide, tolbutamide, chlorpropamide, glibornuride and glipizide in not being rapidly bound to an equilibrium, but accumulating progressively in amounts far exceeding the water space. An inhibitor of the anion channels in the beta-cell membrane, 4-acetamido-4'-isothiocyanate-stilbene-2,2'-disulphonic acid (SITS), suppressed the islet uptake of glibenclamide and to some extent also that of carbutamide and glibornuride. The unusual uptake characteristics of glibenclamide had their counterpart in a retardation of its maximal action in promoting the entry of Ca2+ into the beta-cells.
Animals↗
Direct effect of hypoglycemic sulphonylureas on the cardiovascular system of dogs.
The effects of first generation sulphonylurea compounds carbutamide, gliclazide and tolbutamide as well as second generation compounds glibenclamide and glipizide on the cardiovascular system were investigated in dogs. Six dogs received each compound intravenously at cumulative dose levels of 74, 296, 1184 mumol/kg of carbutamide and tolbutamide, 0.4, 2.0, 10.0 mumol/kg of glibenclamide and glipizide, and 16, 48 and 144 mumol/kg of gliclazide. Mean arterial blood pressure, myocardial contractile force, cardiac output and heart rate were measured. The rate of change of myocardial contractile force development (positive dF/dt), as well as of myocardial relaxation (negative dF/dt) were measured. The first generation sulphonylureas were found, in dogs, to exert a positive inotropic effect in contrast to second generation compounds. The clinical importance of our findings may be in the potential for the malfunction of the cardiovascular system (based on cardiopathy, neuropathy, atherosclerosis, and obesity), developing in diabetes, to be further impaired by the first generation sulphonylureas. Therefore, second generation sulphonylureas should be preferred in the therapy of type 2 diabetics, if satisfactory metabolic control cannot be achieved by dietary management alone and sulphonylurea treatment becomes necessary.
Animals↗
Identification and quantification of 8 sulfonylureas with clinical toxicology interest by liquid chromatography-ion-trap tandem mass spectrometry and library searching.
BACKGROUND: Identification of sulfonylureas in blood may be useful in the evaluation of hypoglycemic crises of unknown origin. The aim of the present study was to develop a highly selective liquid chromatography-electrospray tandem mass spectrometry (MS-MS) method using an ion-trap detector for rapid screening, identification, and quantification of sulfonylureas in human plasma. METHODS: After standard liquid-liquid extraction with glisoxepide as an internal standard, 8 sulfonylureas (glibenclamide, glipizide, gliclazide, glibornuride, glimepiride, carbutamide, chlorpropamide, and tolbutamide) were eluted from a C18 column within 10 min with an isocratic mobile phase. Drugs were identified and quantified in full-scan MS-MS mode by use of a homemade MS-MS library. We used the assay in 134 cases of hypoglycemic crises of unknown origin. RESULTS: No ion suppression effect was noted for the analytes at their specific retention-time windows. For all drugs, assay validation showed good linearity (r2>0.990) and acceptable imprecision and recovery based on commonly used criteria of acceptance. The mean extraction recoveries were 63%-87% for 5 sulfonylureas but <45% for 3 (carbutamide, chlorpropamide, and tolbutamide). Nevertheless, the high sensitivity of the MS instrument made possible detection and quantification of all 8 drugs at subtherapeutic to toxic concentrations with good precision. Sulfonylureas were found in 9 hypoglycemic patients. CONCLUSION: The described assay method allows accurate, rapid identification and quantification of 8 sulfonylureas in human plasma and can be used for specific diagnosis of factitious hypoglycemia caused by ingestion of these drugs.
Chromatography, Liquid↗
[Trends in prescribing oral antidiabetic drugs. An analysis of the Berlin diabetes register covering 28 years].
On the basis of the data collected by the (East) Berlin diabetes register, the prevalence of diabetes and trends in the prescription of oral antidiabetic agents over almost three decades were analysed. Between 1961 and 1989, the diabetic registration rate increased threefold, from 13,700 to 49,000. This corresponds to an increase in prevalence from 1.3% to 3.8%. At the beginning of the nineteen-sixties, only carbutamide and tolbutamide were prescribed, the respective percentages being 29% and 71%. From 1969 onward, the percentage of carbutamide decreased drastically and was no longer prescribed after 1973. With the introduction of the sulfonylureas ureas of second generation in 1969, the prescription of tolbutamide and glibenclamide showed an inverse evolution. In 1989, the prescription rate of tolbutamide was only 10% of all oral antidiabetics, while 88% of the patient group received glibenclamide. Since 1965, biguanides have been increasingly prescribed, reaching a peak of 32% of all prescriptions of oral diabetics by 1975. Thereafter, prescription of biguanides decreased. In 1979, biguanides accounted for only about 5% of all oral antidiabetics prescribed, and in 1989, for only 0.3%. The introduction of structured dietary teaching programs for type 2 diabetics resulted in a drastic change in the prescription of oral diabetics in the case of newly diagnosed patients: in 1968, primary management with oral antidiabetics peaked, accounting for 43.2% of the cases (newly diagnosed diabetics 3.049). This percentage decreased progressively and, in 1985, reached a figure of 17.5% in new cases of diabetes (total number of newly diagnosed cases 3.936). Since 1975, the percent of cases managed primarily with insulin has remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)
Berlin↗
In vitro antidiabetics-antacid interactions.
The adsorption of the oral antidiabetics metformin hydrochloride, glibenclamide, acetohexamide, tolbutamide, carbutamide, tolazamide and glymidine on various antacids or adsorbents was studied at 37 degrees C. The antacids or adsorbents used were magnesium trisilicate, aluminium hydroxide, calcium carbonate, magnesium oxide, bismuth oxycarbonate, talc, kaolin as well as charcoal. None of the substances tested, with the exception of charcoal, exhibited superior adsorptive properties for all the drugs. Magnesium trisilicate and calcium carbonate were the best adsorbents for metformin hydrochloride. Acetohexamide and glibenclamide were adsorbed to an appreciable extent on most antacids. Tolbutamide showed an adsorption tendency towards talc. Most antacids slightly adsorbed carbutamide, while magnesium trisilicate showed a higher adsorption capacity for tolazamide and glymidine. The dissolution rate of acetohexamide in magnesium oxide suspension (5:400) increased about 40-fold after 10 min, whle in magnesium trisilicate suspension (5:400) it increased about 7-fold. On the other hand, magnesium trisilicate did not influence the dissolution rate of metformin hydrochloride. The probable variation in the bioavailability of orally administered antidiabetics when coadministered with antacids was discussed. However, further in vivo studies are needed before a final assessment for such drug-antacid interaction can be confirmed.
Adsorption↗
The direct effect of hypoglycaemic sulphonylureas on myocardial contractile force and arterial blood pressure.
The cardiovascular effects of glibenclamide, gliclazide and carbutamide were studied on myocardial contractile force, cardiac output, mean arterial pressure and heart rate in 43 intact, 14 pancreatectomized and 18 adrenalectomized dogs. It is shown that a positive inotropic and hypertensive effect of hypoglycaemic sulphonylureas develops without the mediation of glucagon, insulin or adrenaline. Contrary to the other investigated sulphonylureas, glibenclamide reduced myocardial contractile force and arterial blood pressure.
Adrenalectomy↗
Comparison of the effects of leucines, non-metabolizable leucine analogues and other insulin secretagogues on the activity of glutamate dehydrogenase.
Glutamate dehydrogenase (GLDH) from bovine liver was employed in model system for testing a possible role of GLDH in insulin release. The ability of different insulin secretagogues to stimulate the activity of the diethylstilbestrol-inhibited enzyme was tested. The two insulin-releasing amino acids, L-leucine and its non-metabolizable analogue 2-aminobicyclo(2, 2, 1)heptane-2-carboxylic acid [b(--)-BCH], were the best stimulators of GLDH activity. The non-secreting stereoisomers, D-leucine and b(+)-BCH, were less effective. Glucose, L-arginine and the leucine metabolite alpha-ketoisocaproic acid lacked significant effects on GLDH activity. Small and diverging effects were obtained with sulfonvlurea compounds: whereas carbutamide caused slight stimulation, tolbutamide and glipizide had no effect, and glibenclamide was an inhibitor. The specificity of the insulin-releasing amino acids L-leucine and b(--)-BCH in stimulating GLDH activity makes it tempting to speculate about a connection between allosteric regulation of pyridine nucleotide-dependent enzymes and insulin release.
Amino Acids↗
Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds.
The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.
Animals↗
Interaction of N-benzoyl-D-phenylalanine and related compounds with the sulphonylurea receptor of beta-cells.
1. The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic beta-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for K(ATP)-channel inhibition. In addition, the effects of cytosolic nucleotides on K(ATP)-channel inhibition by NBDP were investigated. 2. NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (K(D) value) of 11 microM and half-maximally effective concentrations of K(ATP)-channel inhibition (EC50 values) between 2 and 4 microM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP). 3. In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1-1 mM) reduced K(ATP)-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), K(ATP)-channel activity was completely suppressed by 0.1 mM NBDP. 4. The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer. 5. Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold. 6. Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative. 7. Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the K(D) and EC50 values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency. 8. This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic beta-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of K(ATP)-channel activity in the absence of inhibitory cytosolic nucleotides.
ATP-Binding Cassette Transporters↗
Mechanism of action of oral antidiabetic drugs.
The fall in blood sugar with carbutamide (BZ55) 24 hr. after the maintenance dose of insulin (28.1%+/-2.9 s.e) in rabbits made severely diabetic with alloxan was significantly different from the change in the blood sugar with the same drug given 72 hr. (6.8%+/-2.0) or distilled water given 24 hr. (7.7%+/-1.3) respectively after the last dose of insulin. It is postulated that the drug acts by liberating bound insulin in the plasma.
Alloxan↗
Photohemolytic potency of oral antidiabetic drugs in vitro: effects of antioxidants and a nitrogen atmosphere.
The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10(-3) mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10(-4) mol/l, no hemolytic effects were seen in the concentration of 10(-4) mol/l or 10(-5) mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.
Antioxidants↗
[The course of asymptomatic diabetes under varying preventive therapy--concluding report of a 5-year prospective study].
During a prospective study the course of asymptomatic diabetes in different preventive treatment (diet, additionally tolbutamide, carbutamide or buformin) was observed concerning the frequency of manifestation and the behaviour of the oral glucose tolerance. Among the 100 protodiabetics after 5 years 38 clinical manifestations could be established, which finally nearly equally were distributed to all 4 groups of treatment. Only under the influence of buformin an effect preventing manifestation limited to 2 years appeared. Patients with persisting full or partial remissions continuously and more decreased in weight than cases of manifestation. Furthermore, the course was determined by the initially existing degree of hyperglycaemia as well as by the improvement of the glucose tolerance achieved in the first year. On account of the results of the examinations and the existing literature a preventive use of oral antidiabetics cannot be recommended.
Buformin↗