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PubMed1980

Comparison of polyethylene glycol and polyoxyethylene stearate as excipients for solid dispersion systems of griseofulvin and tolbutamide II: dissolution and solubility studies.

The effects of joining a long-chain ester group with the polyethylene glycol molecule were studied in solid dispersion systems by comparing the dissolution and solution properties of such systems prepared from polyethylene glycol 2000 with those prepared from the nontoxic, water-soluble, solid excipient polyoxyethylene 40 stearate. Solid dispersion systems of griseofulvin and tolbutamide were prepared by physical mixing, fusion, or coprecipitation from ethanol. The compacted dispersion systems dissolved by progressive erosion, releasing floccules of microcrystals. The released microcrystals of tolbutamide (3--10 micrometer) were smaller than the original drug particles (approximately 20 micrometer), but those of griseofulvin were of similar size to the original particles. In general, the rate of and extent of release of each drug were greater from polyoxyethylene 40 stearate than from polyethylene glycol 2000 dispersions. The aqueous solubility and dissolution rate of nondisintegrating disks of each pure drug increased only slightly in the presence of polyethylene glycol 2000 but increased considerably with increasing concentration of polyoxyethylene 40 stearate due to micellar solubilization. Thus, polyoxyethylene 40 stearate generally is superior to polyethylene glycol 2000 in promoting the dispersion of the drugs in solids, disintegration of the compacted solids, and solubilization of the drug during dissolution.

Chemical Precipitation↗
PubMed1982

Extended Hildebrand solubility approach: solubility of tolbutamide, acetohexamide, and sulfisomidine in binary solvent mixtures.

The extended Hildebrand approach for predicting solubilities of crystalline compounds in solvent mixtures was tested using tolbutamide, acetohexamide, and sulfisomidine in mixed solvents consisting of hexane-absolute ethanol and 95% (v/v) ethyl alcohol-aqueous buffer. The solubility of these drugs was determined at 25 +/- 0.2 degrees and then back-calculated using the adhesive energy term, W, to account for solute-solvent interaction. Solubilities were predicted within 13% for tolbutamide, 31% for acetohexamide, and 43% for sulfisomidine, and with considerably better accuracy in most solvent mixtures.

Acetohexamide↗
PubMed1988

Concentration-dependent effects of tolbutamide, meglitinide, glipizide, glibenclamide and diazoxide on ATP-regulated K+ currents in pancreatic B-cells.

The influence of the hypoglycemic drugs tolbutamide, meglitinide, glipizide and glibenclamide on ATP-dependent K+ currents of mouse pancreatic B-cells was studied using the whole-cell configuration of the patch-clamp technique. In the absence of albumin, tolbutamide blocked the currents half maximally at 4.1 mumol/l. In the presence of 2 mg/ml albumin half maximal inhibition of the currents was observed at 2.1 mumol/l meglitinide, 6.4 nmol/l glipizide and 4.0 nmol/l glibenclamide. The hyperglycemic sulfonamide diazoxide opened ATP-dependent K+ channels. Half maximally effective concentrations of diazoxide were 20 mumol/l with 0.3 mmol/l ATP and 102 mumol/l with 1 mmol/l ATP in the recording pipette. Thus, the action of diazoxide was dependent on the presence of ATP in the recording pipette. The free concentrations of the drugs which influenced ATP-dependent K+ currents were comparable with the free plasma concentrations in humans and the free concentrations which affected insulin secretion in vitro. The results support the view that the target for the actions of sulfonylureas and of diazoxide is the ATP-dependent K+ channel of the pancreatic B-cell or a structure closely related to this channel.

Adenosine Triphosphate↗
PubMed1996

Blockade of dopamine storage, but not of dopamine synthesis, prevents activation of a tolbutamide-sensitive K+ channel in the guinea-pig substantia nigra.

The substantia nigra has one of the highest levels of ATP-sensitive K+ channel in the brain. Since this channel is controlled by cell metabolism, the aim of this study was to see how closely it is associated with nigral dopamine systems, which are decreased in Parkinson's disease. In a sub-population of neurons within the rostral substantia nigra pars compacta of the guinea-pig, a brief period of hypoxia resulted in a tolbutamide (100-500 microM) sensitive hyperpolarisation [input resistance (IR) decrease from 144.88 +/- 14.04 M omega pre-hypoxia to 105.91 +/- 13.25 M omega during hypoxia]. Maximal blockade of this decrease was seen in presence of 500 microns tolbutamide [IR decrease only from 161.35 +/- 32.82 M omega to 155.02 +/- 34.29 M omega]. Reserpine (which depletes dopamine stores) but not alpha-methyl-para-tyrosine (which decreases de novo synthesis of dopamine) caused a marked attenuation of this hyperpolarisation [IR decrease only from 163.32 +/- 44.42 M omega pre-hypoxia to 154.42 +/- 50.97 M omega during hypoxia]. This observation suggests that blockade of dopamine storage, but not of de novo synthesis, leads to a loss of responsiveness of certain mid-brain neurons to hypoxia, rendering them potentially more susceptible to subsequent degeneration. The possible link between nigral dopamine systems and ATP-sensitive K+ channels is discussed.

Animals↗
PubMed1987

The permissive effect of glucose, tolbutamide and high K+ on arginine stimulation of insulin release in isolated mouse islets.

Mouse islets were used to study how glucose modulates arginine stimulation of insulin release. At 3 mmol/l glucose, arginine (20 mmol/l) decreased the resting membrane potential of B cells by about 10 mV, but did not evoke electrical activity. This depolarisation was accompanied by a slight but rapid acceleration of 86Rb+ efflux and 45Ca2+ influx. However, 45Ca2+ efflux and insulin release increased only weakly and belatedly. When the membrane was depolarised by threshold (7 mmol/l) or stimulatory (10-15 mmol/l) concentrations of glucose, arginine rapidly induced or augmented electrical activity, markedly accelerated 86Rb+ efflux, 45Ca2+ influx and efflux, and triggered a strong and fast increase in insulin release. When glucose-induced depolarisation of the B-cell membrane was prevented by diazoxide, arginine lost all effects but those produced at low glucose. However, the delayed increase in release still exhibited some glucose-dependency. In contrast, depolarisation by tolbutamide, at low glucose, largely mimicked the permissive effect of high glucose. Depolarisation by high K+ also amplified arginine stimulation of insulin release, but did not accelerate it as did glucose or tolbutamide. Omission of extracellular Ca2+ abolished the releasing effect of arginine under all conditions. The results thus show that the permissive action of glucose mainly results from its ability to depolarise the B-cell membrane. It enables the small depolarisation by arginine itself to activate Ca channels more rapidly and efficiently. Changes in the metabolic state of B cells may also contribute to this permissive action by increasing the efficacy of the initiating signal triggered by arginine.

Animals↗
PubMed1993

The effect of tolbutamide on cerebral blood flow during hypoxia and hypercapnia in the anaesthetized rat.

The increase in blood flow in the cerebral cortex of the anaesthetized rat during hypoxia and hypercapnia was investigated. Cerebral blood flow (CBF) was measured using the hydrogen clearance method with acutely implanted platinum electrodes. Hypoxia (PaO2 35.3 +/- 2.4 Torr) and hypercapnia (PaCO2 68.1 +/- 5.1 Torr) increased basal CBF from 76.3 +/- 9.0 ml/100g/min to 168.1 +/- 20.1 ml/100g/min and 162.4 +/- 31.9 ml/100g/min respectively. The sulphonylurea tolbutamide (1mM in 1%DMSO) had no significant effect on CBF in hyperoxia or in hypercapnia. However, it attenuated the increase of CBF during hypoxia by 66 +/- 11% (p < 0.01). This suggests that opening of tolbutamide-sensitive potassium channels may be involved in the process of hypoxic vasodilation in the rat cerebral cortex.

Anesthesia↗
PubMed1981

Effect of tolbutamide on the protein secretion of the rat salivary glands.

Protein and amylase content as well as the distribution of isoamylases were determined in the parotid and the submandibular glands of the rat following treatment with tolbutamide for 3-21 days. Significant changes were only observed in the submandibular glands in which, compared with the controls, the amylase activity decreased distinctly after 3 days but had increased 7-fold after 21 days of tolbutamide. These findings could be explained by secretion of epinephrine from the adrenal medulla supposed to take place independently of the effect of insulin and by the possible inhibition of a protein kinase involved in the process of protein secretion from the submandibular gland.

Amylases↗
PubMed1989

ATP-sensitive potassium channels in adult mouse skeletal muscle: different modes of blockage by internal cations, ATP and tolbutamide.

Single ATP-sensitive K channels were studied in membrane patches excised from enzymatically dissociated mouse toe muscle. The channel conductance is 74 pS in symmetrical 160 mM KCl solutions. Replacement of K+ by Na+ in the internal solution or 2 mM internal Ca2+ or Mg2+ induced a rectification of the current-voltage curve at positive potentials. No change of the current-voltage curve was observed by adding small amounts of the channel blockers ATP (20-100 microM) or tolbutamide (0.5 mM) to internal 160 mM KCl solutions. The openings of the channel occurred in bursts. Open (tau o), closed (tau c) times within bursts and pauses (tau p) between bursts were determined over a wide range of positive and negative membrane potentials. At increasing potentials tau o increases, tau c reaches a minimum near 0 mV and tau p decreases. According to the voltage dependence and the time scale of channel blockage three types of blocking agents could be distinguished: (i) small internal cations (Na+, Ca2+, Mg2+) are "fast" blockers at positive voltages; at negative voltages they decrease tau o and increase tau c. (ii) Internal ATP anions produce a voltage-dependent decline of the open-state probability and strongly decrease tau o. (iii) Tolbutamide causes a voltage-independent decrease of the open-probability and its main effect is an increase of tau p. The results suggest that the ATP-sensitive K channel has an internal gate like those of other voltage-gated cation channels and that different blockers interfere with different transitions in channel gating.

Action Potentials↗
PubMed1987

Changes of membrane currents in cardiac cells induced by long whole-cell recordings and tolbutamide.

Single isolated myocytes were obtained from the ventricles of adult guinea pig hearts. The whole-cell recording configuration of the patch-clamp technique was used to measure membrane currents. A decrease (run-down) of the Ca2+ inward current and an increase of a time-independent K+ outward current were observed during long lasting (1-3h) recordings. The time at which the outward current developed depended on the intracellular ATP concentration in the pipette, suggesting that this current is identical to the ATP-dependent K+ current described by Noma and Shibasaki (1985). However, the maximum outward current reached in the experiments was independent of the ATP concentration indicating a limited diffusion of ATP in the cell interior. In single-channel experiments on isolated patches of cell membrane and in whole-cell recordings the ATP-dependent K+ current could be blocked by the hypoglycaemic sulphonylurea tolbutamide. The IC50 of 0.38 mM was about 50 times higher than that reported for pancreatic beta-cells (Trube et al. 1986). The Ca2+ inward current and the inwardly rectifying K+ current were not affected by tolbutamide (3 mM).

Action Potentials↗
PubMed1975

A dissolution rate apparatus for the prediction of initial drug absorption patterns in beagles: tolbutamide tablets.

An apparatus utilizing liquid turbulence to simulate hydrodynamic conditions generated by gastrointestinal peristalsis was designed to estimate drug release from solid oral dosage forms; This turbulence was achieved through special arrangements of a pipetting pump to a dissolution chamber. By adjusting the flow rate of the pump to deliver and withdraw a fixed volume of dissolution medium per minute, a correlation was developed between dissolution rates and absorption patterns in beagles of two commerical tolbutamide tablets, A and B, and a micronized tolbutamide suspensionmon the basis of this relationship, it was possible to predict the initial absorption patterns of two misformulated tablets, C and D.

Animals↗
PubMed1975

[Clinical investigations of the effect of tolbutamide and glibenclamide on pancreatic glucagon secretion (author's transl)].

The effects of tolbutamide, glibenclamide, arginine and arginine in combination with glibenclamide upon insulin, glucagon and glucose serum levels have been studied in healthy young men. Sulphonylurea-induced hypoglycemia is followed by a reactive hyperglucagonemia. Arginine-induced hyperglucagonemia is not suppressed by sulphonylureas. While there exists no difference between tolbutamide and glibenclamide-stimulated glucagon secretion, there is one with regard to insulin secretion.

Adult↗
PubMed1978

Uptake of tolbutamide by islets of Langerhans and other tissues.

3-H-tolbutamide was distributed in a volume exceeding the space occupied by 14-C-sucrose in islets as well as in liver, kidney, muscle, and fat. In contrast to previous reports, the findings suggest that tolbutamide is not restricted to the extracellular space of islets.

Adipose Tissue↗
PubMedDate not supplied

The effect of the acute administration of tolbutamide on left ventricular function in insulin-dependent diabetics.

Despite better control of diabetic patients with morbidity and mortality from heart disease is significantly higher than in non-diabetics. While this may be a result of premature atherosclerosis or primary diabetic cardiopathy, the possibility of oral hypoglycemic agents have adverse cardiac effects must be considered. Using nuclear angiography the effect of the acute administration of 1 g tolbutamide on left ventricular ejection fraction (EF) in a group of 10 Type-1 diabetics was investigated. There was no difference in the response of the EF when compared to the response in 10 diabetic controls given i.v. saline. While i.v. tolbutamide may have adverse cardiac effects when administered to animals or in vitro this does not necessarily apply to human diabetics.

Adult↗
PubMed1990

Excretion of tolbutamide metabolites in young and old subjects.

Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.

Adult↗
PubMed1981

Effect of diethyldithiocarbamate on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons.

The present study describes the inhibitory effects of diethyldithiocarbamate (dithiocarb) on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons. The plasma half-life for the beta-slopes of hexobarbital (25 mg/kg, i.v.) and phenazone (50 mg/kg, i.v.) were increased 2.5 and 3.5 fold respectively, when dithiocarb (100 mg/kg, i.p.) was administered simultaneously. The plasma half-life of tolbutamide was 2.27 h, when administered alone to rats; and 4.04 h, when administered with dithiocarb. Metabolic elimination of halothane, trichloroethylene, dichloroethane, and carbon tetrachloride, from the atmosphere of a closed exposure system was studied in rats. Treatment with dithiocarb (100 mg/kg, i.p.) immediately before exposure, prolonged the elimination half-life of: halothane (103 parts/10(6)) by a factor of 7.6, of trichloroethylene (25 parts/10(6)) by a factor of 5.3; dichloroethane (69 parts/10(6)) by 4.6; and carbon tetrachloride (38 parts/10(6)) by 2.4, respectively. The inhibitory actions of dithiocarb on the metabolism of the tested drugs and chemicals are explained as the consequences of a depressed microsomal mono-oxygenase activity due to a decrease in the cytochrome P 450 content.

Animals↗
PubMedDate not supplied

p-Hydroxymercuribenzoate-induced hyperglycemia: influence of pre- and post-treatment with L-leucine, tolbutamide, D-mannoheptulose, insulin and alloxan.

The aims were to see whether p-hydroxymercuribenzoate (PMB) administration affects the serum insulin concentration in mice in vivo, whether the transitory hyperglycemia induced in fed mice by treatment with PMB is affected by L-leucine, tolbutamide, D-mannoheptulose or insulin, and whether PMB affects the B-cell toxicity of alloxan. A significant decrease in the serum insulin concentration was found 1 and 2 h following PMB injection in fed and starved mice. PMB-induced hyperglycemia was abolished by pre-treatment with L-leucine and tolbutamide, but not by pre-treatment with D-mannoheptulose, or by post-treatment with insulin. Pre-treatment of fed mice with PMB caused potentiation of the initial hyperglycemia following alloxan, but inhibited the second hyperglycemic phase. These findings indicate that PMB treatment of mice has a transient inhibitory influence upon insulin secretion, and protects against the development of alloxan diabetes.

Alloxan↗
PubMed1989

Free and bound sodium in pancreatic beta-cells exposed to glucose and tolbutamide.

The effects of glucose and tolbutamide on the sodium handling of the pancreatic beta-cells were evaluated by measuring the total sodium content in intact islets from ob/ob-mice by integrating flame photometry and the free ion in individual beta-cells by dual wavelength fluorometry. Whereas increasing the glucose concentration from 3 to 20 mM resulted in a lowering of sodium, the addition of 100 microM tolbutamide caused a rise. The above-mentioned effects were most marked (about 50%) for the physiologically significant free sodium. The data indicate a more important role for Na+ in the regulation of insulin release than so far acknowledged. Increase of Na+ may contribute to the secretory response to hypoglycemic sulfonylureas by providing an additional rise of cytoplasmic Ca2+.

Animals↗
PubMed1979

Influence of acetylsalicylic acid on plasma glucose, insulin, glucagon, and growth hormone levels following tolbutamide stimulation in man.

The effects of acetylsalicylic acid (ASA), a known inhibitor of prostaglandin (PG) synthesis, on plasma glucose, insulin, glucagon and growth hormone (GH) responses to tolbutamide were examined in ten normal volunteers. Treatment with 3.2 g ASA daily for 3 days caused a significant reduction in basal plasma glucose levels (p less than 0.05); by contrast, basal insulin rose from 23 +/- 2 to 31 +/- 2 microU/ml (p less than 0.01). No significant changes in the basal concentrations of glucagon and GH were found after ASA. Insulin response to tolbutamide was significantly augmented after ASA (p less than 0.01) while GH response to hypoglycemia was reduced (p less than 0.05). The pattern of plasma glucose and glucagon was not significantly modified by the treatment. Since ASA seems to have an action opposite to PGE on insulin and GH secretion, it is possible that the ASA may work through inhibition of PG synthesis.

Adult↗