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PubMedDate not supplied

[Oral antidiabetics of the sulfonylurea group and their problems in therapy].

By the abolition of biguanids as oral antidiabetics the importance of derivatives of sulfonylcarbamids became prominent in the treatment of diabetic elderly patients. Because of the properties of that group, there are a number of problems by the therapy with these derivatives. There is the mostly existing multimorbidity in geriatric patients with the risk of incompatibilities of drugs in cause of multitherapy and there is the influence of morbid states on the pharmacokinetics. Some of the various questions will be shortly described in this article. There are then given also practical advices for the relations with the derivatives of sulfonylcarbamids in treating diabetic patients.

Administration, Oral↗
PubMed1995

Antidiabetic and hypolipidemic effects of S-methyl cysteine sulfoxide isolated from Allium cepa Linn.

S-methyl cysteine sulphoxide (SMCS), a sulphur containing amino acid isolated from onion (Allium cepa Linn) showed antidiabetic and antihyperlipidemic effects. Oral administration of SMCS daily at a dose of 200 mg/kg body weight for a period of 45 days to alloxan diabetic rats controlled significantly their blood glucose and lipids in serum and tissues and altered the activities of liver hexokinase, glucose 6-phosphatase and HMG CoA reductase towards normal. The above effects of SMCS were comparable to those of glibenclamide and insulin.

Allium↗
PubMed1993

Analytical investigations of Glipolamid--a new antidiabetic drug.

A qualitative and quantitative analysis of an antidiabetic drug Glipolamid was developed. The qualitative analysis included the determination of the physical-chemical properties (UV-VIS, IR, NMR spectra, hRf) and characteristic reactions. The quantitative assay included the following methods of the determination of Glipolamid in substance as well as in tablets: alkalimetric in non-aqueous medium, acidimetric and spectrophotometric.

Hydrogen-Ion Concentration↗
PubMed1975

Histopathology of the endocrine pancreas of a fresh-water fish, Clarias batrachus (L.) IX: Effect of the new antidiabetic drug, glibenclamide (HB 419).

Oral administration of glibenclamide, the new antidiabetic drug, caused hypoglycemia in Clarias batrachus. The effect was maximal at 15 hours, when some fish had practically no sugar in their plasma. The hypoglycemic effect was insignificant in partially-pancreatectomized fish, indicating that the drug potentiated the effect of insulin in such animals. In fasting normal fish, the drug provoked an increase in the liver glycogen contents while in the diabetic animals, a reverse condition occurred. Significant beta-cell degranulation and vacuolisation was noted in the Langerhans' islets, the effect being synchronous with hypoglycemia. In a few cases, the alpha-cells had also undergone degenerative changes. No significant side effects and discerneable toxicity was observed in the treated-fish. It is stipulated that the drug is endowed with the beta cytotropic property.

Animals↗
PubMed1993

Sex difference in pharmacokinetics of the novel sulfonylurea antidiabetic glimepiride in rats.

Glimepiride (Hoe 490, CAS 93479-97-1), a novel sulfonylurea antidiabetic agent, was studied for the cause of sex-related difference in the elimination clearance of the unchanged drug in rats. After intravenous and oral administration, the serum level of the unchanged drug was higher in female rats and AUC and t1/2 (beta) values were about 1.7- and 1.4-fold those for males, while Vss and oral bioavailability were nearly equal. The excretion clearance of the unchanged drug was quite small in both male and female animals, and most of the administered drug was excreted into the bile as a hydroxymethyl derivative, M1. In the in vitro metabolism study, M1 was found to be formed mainly in the liver microsomal fraction, and its hydroxylation activity was significantly higher in males. This metabolic activity was dependent on NADPH and was inhibited by proadifen. On the other hand, formation of M2, a carboxyl derivative, from M1 was observed in the cytosol fraction and showed no sex difference. Its metabolic activity depended on NAD and was inhibited by pyrazole. These results suggest that the sex difference observed in rat pharmacokinetics is mainly due to different hydroxylation activities of the side chain methyl group based on the participation of sex dependent cytochrome P-450 in liver microsomes.

Administration, Oral↗
PubMed1993

[The glycemic response to a test breakfast of an enteral diet with fiber and a high starch content in diabetics treated with insulin and oral antidiabetics].

An enteral nutrition preparation appeared recently on the Spanish market specifically for diabetic patients. It is a normocaloric and normoproteic formula of low osmolarity, rich in soluble fibre and slow-absorption carbohydrates such as fructose and starch, following the classic norms of the American Diabetics Association. The glycemic response was examined at 0, 30, 60 and 120 minutes following the ingestion of 250 cc of Precitene Diabet as breakfast for 40 diabetic patients, half treated with oral antidiabetic substances (DMado) and the other half with insulin (DMins). In both groups, the greatest glycemic increase was at 60 minutes. In the DMado patients, the increase at 60 minutes (70 mg/dl) was not significantly different from that considered by Skyler as acceptable. The same occurred at 120 minutes (40 mg/dl). In the DMins patients, the glycemic increase at 60 minutes was 27 +/- 29 mg/dl, more than that considered acceptable by Skyler (p 0.0006). After 120 minutes this difference was also greater than the acceptable level, by 41 +/- 38 mg/dl (p 0.0002). In conclusion, it may be considered that, for DMado patients, glycemic control remains within the postprandial limits considered to be "acceptable" so that no treatment modification is felt necessary in the administration of enteral nutrition with Precitene Diabet. The glycemic response in the DMins patients was higher than "acceptable", calling for rapid insulin supplements to their habitual NPH insulin doses.

Administration, Oral↗
PubMed1993

[Differential therapy with oral antidiabetic drugs].

The more than 3 million type II diabetics in Germany constitute a true therapeutic challenge. Type II diabetes mellitus is part of the so-called metabolic syndrome characterized by the problem of insulin resistance/hyperinsulinemia. Treatment of type II diabetes aims at reducing insulin resistance. Oral antidiabetic management must be based on diabetic diet, in conjunction--if needed--with monotherapy with acarbose or metformin. Only after exhausting these principles of management, acarbose or metformin may be combined with sulfonylurea. Primary monotherapy with insulinotropically acting sulfonylureas is, in most cases, no longer appropriate as we are learning more about the pathophysiology of metabolic syndrome.

Blood Glucose↗
PubMed1993

[Combination therapy of oral antidiabetic drugs with insulin].

The treatment of type II diabetes should not only concentrate on blood glucose levels but also should take symptoms like insulin resistance, hyperinsulinemia, low HDL-cholesterol, high VLDL, and systemic hypertension into consideration. These symptoms are well described by the metabolic syndrome and are known to be risk factors of macroangiopathy. In obese type II diabetic patients weight loss by caloric restriction is the most essential therapeutic step. Retarding intestinal carbohydrate uptake glucosidase-inhibitors are able to lower postprandial blood glucose levels without stimulating insulin secretion. The biguanide metformin is suitable to diminish peripheral insulin resistance, gluconeogenesis, and intestinal glucose absorption on cellular mechanisms others than betacytotropic effects. In non obese type II diabetic patients sulfonylureas are advantageous because of meal related stimulation of endogenous insulin which runs the physiological way with first pass through the liver. Therefore, sulfonylurea treatment should be continued when secondary failure indicates the need for exogenous insulin. In accordance with the course of type II diabetes in secondary failure insulin should be added to sulfonylureas in as small amounts as possible to ameliorate poor metabolic control. Thus iatrogenic hyperinsulinemia and resulting insulin resistance can be largely avoided. If there is any long term benefit when different oral antidiabetic agents are administered together with insulin has to be evaluated in further clinical studies.

Blood Glucose↗
PubMed1995

Influence of food on the disposition of the antidiabetic drug metformin in diabetic patients at steady-state.

The effect of food on the bioavailability of the antidiabetic drug metformin (Glucophage, Lipha Laboratories) was investigated in patients at steady-state. Seventeen diabetic patients (5 males and 12 females) treated with a long-term metformin therapy received their morning dose after an overnight fasting or after each of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the Cmax (Tmax) were calculated. Compared to fasting conditions, AUC and Cmax for metformin were bioequivalent after the four types of breakfast except the low fat (high carbohydrate) diet which had results slightly reduced (90% CI = [0.76-0.90]). The intraindividual variability was calculated and found to be lower than the interindividual variability.

Adult↗
PubMed1995

Photodegradation and in vitro phototoxicity of the antidiabetic drug chlorpropamide.

Methanolic solutions of the phototoxic antidiabetic drug chlorpropamide (CAS 94-20-2, 1) are photolabile towards UVB light under aerobic conditions. Irradiation of 1 produces the formation of the stable compounds p-chlorobenzenesulfonamide (2), N-(p-chlorophenylsulfonyl)formamide (3) and the dimer 4. A radical intermediate was evidenced by thiobarbituric acid that was used as a radical sonde, as well as by the dimerization of cysteine. The compound 1 showed moderate lytic activity upon the photohemolysis in vitro test on human erythrocytes which was increased with the addition of traces of its aggregate excipient. Inhibition of this process on addition of reduced glutathione (GSH), superoxide dismutase (SOD) or ascorbic acid suggests the involvement of radicals and superoxide ion in the photohemolysis process. The absence of inhibition with 1,4-diazabicyclo[2.2.2]octane (DABCO) and sodium azide (NaN3), and the lack of formation of singlet oxygen during the photolysis (confirmed with 2,5-dimethylfuran) rule out the possibility of participation of 1O2 in this process. Glutathione depletion was also observed. No photohemolysis was detected in the presence of the isolated photoproduct.

Antioxidants↗
PubMed1995

Dose proportionality studies of novel thiazolidinedione derivatives as potent antidiabetic agents in mice.

The determination of the plasma concentrations of the new oral antidiabetic agents BM 13.1246 ((+/-)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] benzyl]-2,4-thiazolidinedione), [sequence: see text] BM 13.1215 ((+/-)-5-[(5-methyl-2-phenyl-4-oxazolyl)-methyl-2- benzofuranyl-5-methyl]-2,4-oxazolidinedione), [sequence: see text] and BM 50.1050 ((+/-)-5[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] naphthalyl]methyl-2,4-thiazolidinedione) [sequence: see text] in ob/ob mice plasma was performed by using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet (270 nm) detection. The analytical procedures have recoveries of more than 80%, and a between-run precision of less than 4% for all analysed compounds. The pharmacokinetic behaviour, especially the dose proportionality, was investigated in ob/ob mice after repeated oral doses of 1 and 10 mg/kg, respectively. All compounds were absorbed quickly and attained maximum plasma concentrations within 2-5 h after administration. In the examined interval of dosing, an approximately proportional increase of the plasma levels for BM 13.1246 and BM 50.1050 was observed. After repeated oral doses the terminal half-lives are about 4 h for BM 13.1246, 8 h for BM 13.1215, and 6 h for BM 50.1050.

Animals↗
PubMed1996

Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach.

We have attempted to predict the human pharmacokinetics of troglitazone after oral administration based on animal data. Troglitazone is a new antidiabetic agent that exhibits a high-metabolic clearance and is metabolized mainly in the liver to sulfate and glucuronide conjugates. The prediction of the area under the plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans after oral administration was initially attempted by use of allometric equations involving the oral plasma clearance of total (CLp.o.) or unbound drug (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and animal body weight. The exponents in the allometric equations between the clearances and body weights were 0.63 to 0.82 with high correlation coefficients (r > .98), and there was no marked difference in predictability by the three methods. Next, the prediction of the range of plasma profiles after oral administration to humans was attempted by the following series of steps: (1) calculation of the exponent and coefficients in the allometric relationships between body weight and parameters, such as total body plasma clearance (CLi.v.) and various distribution volumes (Vss, V beta and Vc) based on animal data; (2) estimation of the absorption rate constant (ka) from allometric relationship to body weight, and estimation of F value from the predicted AUCp.o. (3) description of the plasma concentration-time profiles after oral administration by an equation involving the allometric exponents and coefficients, ka, F and body weight. The observed and simulated plasma profiles were similar and the predicted AUCp.o. values were 60 to 120% of those observed. These methodologies will be useful for predicting the human pharmacokinetics after oral dosing from animal data.

Administration, Oral↗
PubMed1996

Oral antidiabetic drugs: an overview.

Chronic hyperglycaemia, i.e. impaired glucose tolerance (IGT) and NIDDM, conveys a great risk of macrovascular disease. Both insulin resistance and impaired insulin secretion seem necessary to establish chronic hyperglycaemia, and untreated it appears to promote and worsen both insulin resistance and impaired insulin secretion. The prevention and treatment of chronic hyperglycaemia should include measures directed at both derangements, and the therapeutic goal should be normoglycaemia. As this is rarely achieved by non-pharmacologic treatment alone, addition of oral antidiabetic drugs are often indicated. Their ability to attain euglycaemia is greater the earlier they are employed, but they should never be introduced until after optimization of non-pharmacologic measures. Delayed early insulin response to glucose or a meal always accompanies chronic hyperglycaemia and is not normalized by non-pharmacologic treatment. This justifies the use of insulin-releasing drugs with a rapid onset of action, e.g. the sulphonylurea glipizide. The non-sulphonylureas, repaglinide and A-4166, are even more rapid- and also short-acting, representing a reduced risk of long-lasting, and hence dangerous, hypoglycaemia. Continuous exposure to high concentrations of sulphonylureas may downregulate beta-cell sensitivity. Maximum doses are much lower than previously assumed. The most effective improvers of insulin action seem to be the thiazolidinediones, but they are not yet marketed. Metformin is the only globally available drug for improving insulin action. It is as antihyperglycaemic as sulphonylureas but does not cause hyperinsulinaemia, weight increase or hypoglycaemia. The risk of lactic acidosis can be minimized by avoiding metformin in subjects with renal impairment. Combined treatment with sulphonylurea and metformin can be highly effective even in advanced NIDDM.

Biguanides↗
PubMed1997

Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data.

Sulfation and glucuronidation, the major routes of metabolism of troglitazone, an antidiabetic agent, were examined in vitro using hepatic cytosol and microsomes prepared from KK mice, an animal model of non-insulin-dependent diabetes mellitus. Stereoselectivity was observed for both conjugation reactions, and the metabolic intrinsic clearance of glucuronidation was about 3- to 100-fold higher than that of sulfation for each stereoisomer. In addition, the metabolic intrinsic clearance of glucuronidation exhibited an 8-fold difference among stereoisomers. The predicted metabolic clearance for each stereoisomer, calculated from the in vitro data based on a dispersion model, was comparable to the measured metabolic clearance in vivo, ranging from 27 to 93%. We also attempted to predict the in vivo metabolic clearance from in vitro metabolism data, to investigate species differences in the stereoselectivity of the conjugation reactions in normal animals, i.e., ddY mice and rats. For ddY mice the in vivo hepatic glucuronidation clearance was 170-fold higher than the corresponding sulfation clearance, whereas for rats the sulfation clearance was 6-fold higher than the glucuronidation clearance. The hepatic sulfation clearance in mice and rats predicted from in vitro metabolism data was 5.3- and 1.1-fold higher, respectively, than that in vivo, calculated from the plasma disposition of parent drug and biliary excretion of metabolites. For glucuronidation, the predicted values in mice and rats were 1.0- and 0.33-fold higher, respectively. These results suggest that semiquantitative extrapolation of in vitro stereoselective metabolism of troglitazone, by conjugation, to the in vivo situation is possible.

Animals↗
PubMedDate not supplied

Phototoxicity to sulphonamide derived oral antidiabetics and diuretics. Comparative in vitro and in vivo investigations.

The oral antidiabetics chlorpropamide, glibenclamide, glipizide, gliquiudone, glymidine, tolazamide and tolbutamide, and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide, and xipamide were investigated for potential phototoxicity in vitro using a cell culture model, and in vivo in hairless mice. After exposure to broad band UVA, the majority of the substances tested in vitro yielded a phototoxic action leading to loss of culture forming ability. In vivo, all tested substances induced edema or ulceration, and lead to a significantly increase in skin fold thickness of the mouse skin. In all, a number of substances not described to induce clinical photosensitivity nor phototoxicity in vitro or in vivo were detected in our testing. When determining potential photosensitizers, it seems important to utilize different test methods, as not all substances will exhibit action in a given assay.

Administration, Oral↗
PubMed1997

Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus.

The duration of action and the pharmacokinetics of gliquidone (1-cyclohexyl-3-[[4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2(1H)-isochinolyl)ethyl]phenyl]-sulfonyl]-urea, AR-DF 26 SE, CAS 33342-05-1, Glurenorm, Beglynor) were investigated in 32 patients with non-insulin-dependent (type 2) diabetes mellitus over 16 h. In a single-blinded cross-over design vs. placebo, one 30 mg tablet gliquidone was administered 15 min before breakfast. Concomitant to the measurement of glucose and insulin, the gliquidone plasma levels of 20 subjects were determined by a new specific liquid chromatographic (HPLC) assay method with fluorescence detection, and the pharmacokinetic parameters calculated. Following the gliquidone administration, the mean plasma glucose profiles of the responders were up to 15% lower than with placebo (p < 0.005) between 8 a.m. and 6 p.m., representing a duration of the blood sugar-lowering effect of 8 to 10 h. Insulin values were raised, with peaks over 40% higher, during or shortly after meals. Subsequently, the insulin levels returned to approximately the same levels obtained with placebo during the postprandial phase. Plasma concentrations of gliquidone showed pronounced interindividual variability. The mean maximum concentration in plasma Cmax was 0.65 microgram/ml, (range: 0.12-2.14 micrograms/ml, coefficient of variation (CV): 82%). The median time to reach maximum plasma concentrations tmax was 2.25 h (range: 1.25-4.75 h). The areas under the plasma concentration-time curve from zero time to infinity (AUC0-infinity) and the mean terminal elimination half-lives (t1/2 beta) were computed from those patients (N = 8) who exhibited at least five plasma levels above the limit of quantitation in the terminal log-linear phase using a two-compartment model: the mean AUC0-infinity was 5.1 micrograms.h/ml (range: 1.5-10.1 micrograms.h/ml, CV 56%). The dominant half-life t1/2 alpha derived from therapeutically relevant plasma levels of gliquidone (> 80 ng/ml) was approximately 1.2 h (range: 0.4-3.0 h. CV: 71%) and the mean terminal half-life t1/2 beta was approximately 8 h (range: 5.7-9.4 h, CV: 17%). From the pharmacodynamic behavior as well as from the pharmacokinetic parameters it can be deduced that gliquidone belongs to the class of short-acting sulfonylureas used in antidiabetic therapy.

Aged↗
PubMed1997

Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs.

The pharmacokinetics of troglitazone (CAS 97322-87-7, CS-045), a new oral antidiabetic drug for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), were investigated in rats, mice and dogs following oral and intravenous administration of 14C-labeled troglitazone at doses of 5 mg/kg. The absorption rates, calculated from the AUC ratios of total radioactivity after oral and intravenous administration, or from the biliary excretion rate after intraduodenal administration in rats were both as high as 75%. High uptake by the liver, one of the pharmacological target organs, was demonstrated in both rats and mice. Furthermore, in the KK mouse, an obese NIDDM model animal, the radioactivity was incorporated selectively as troglitazone itself to muscle, the peripheral target organ. Troglitazone reversibly bound to serum albumin with a high ratio (> 99%). Troglitazone was mostly metabolized to the conjugates: sulfate (M 1) and glucuronide (M 2). The oxidized metabolite, a quinone-type metabolite (M 3), was found to be further metabolized to the sulfate (U 2). The biliary excretion rates of these conjugates were high in each animal, and the occurrence of enterohepatic circulation of the conjugates was also suggested. Sex differences in pharmacokinetics were observed in rats; i.e. females showed a higher plasma concentration of troglitazone, and a lower concentration of M 1, than males, and they excreted the sex-related metabolite, a hydroxylated M 1 (U 1), in the bile.

Administration, Oral↗
PubMed1997

Evaluation of antidiabetic effect of an ayurvedic drug, 'tarakeswara rasa' in rats.

Administration of tarakeswara rasa--an ayurvedic drug--to alloxan induced diabetic rats resulted in a significant decrease in the blood glucose. Its antidiabetic effect was also evident from the tissue parameters estimated. The drug administration to diabetic rats also resulted in the reduction of cholesterol, triglyceride and phospholipid content.

Animals↗