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PubMed1989

Effects of low-concentration polymyxin B on insulin secretion induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), glucose, or tolbutamide from the isolated perfused rat pancreas.

To evaluate the role of protein kinase C on insulin secretion, we investigated the effects of low-concentration polymyxin B (100 mumol/L) on insulin secretion from the isolated perfused rat pancreas induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA, 10 nmol/L), a protein kinase C activator, glucose (10 mmol/L), or tolbutamide (738 mumol/L). Polymyxin B, a potent and relatively selective protein kinase C inhibitor at this low concentration, did significantly inhibit the gradual rise of insulin secretion induced by TPA (P less than .05). As for glucose or tolbutamide stimulation, polymyxin B significantly inhibited not only the second phase but also the first phase of insulin secretion (P less than .05) without changing the secretion patterns. Although the possibility of nonspecific effects of polymyxin B other than protein kinase C inhibition could not be excluded, the data suggest that protein kinase C might be involved in insulin secretion as a potentiating modulator.

Animals↗
PubMed1995

Tolbutamide causes a modest increase in insulin secretion in cystic fibrosis patients with impaired glucose tolerance.

We examined the effect of intravenous (i.v.) tolbutamide administration on glucose and hormone levels in cystic fibrosis (CF) patients with impaired first-phase insulin secretion and oral glucose tolerance (oral glucose tolerance test [OGTT]) and compared them with CF patients with only an impaired first-phase insulin secretion and healthy control subjects. Five CF patients with an impaired OGTT, ie, a serum glucose value of 7.8 mmol/L or greater 120 minutes after an oral glucose load (group I), five CF patients with a normal OGTT, ie, a serum glucose not exceeding 7.8 mmol/L 120 minutes after oral glucose (group II), and five healthy control (CON) subjects underwent IV glucose tolerance tests with glucose alone (IVGTT) and glucose administered in conjunction with tolbutamide ([IVTTT] 25 mg/kg; maximum dose, 1 g). Serum glucose levels were measured using the glucose oxidase method; insulin, C-peptide, and glucagon levels were measured by the double-antibody radioimmunoassay (RIA) technique. Serum immunoreactive trypsin (IRT) and hemoglobin A1 (HbA1) levels and height and weight were measured for each subject, and in addition, pulmonary function was assessed in those with CF. There were no significant differences in the area under the curve (AUC) for glucose or glucose or glucagon levels or the serum glucose disappearance rate (k value) between group I, group II, or CON subjects during the IVGTT. First-phase insulin and C-peptide secretion was abnormal during IVGTT and IVTTT in the CF groups: in group I it was severely impaired, whereas in group II it was between group I and CON values. During the IVTTT serum glucose levels and glucose k values were not significantly altered in any of the three groups as compared with the IVGTT.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic A- and B-cell function.

In the classical model of isolated perfused rat pancreas four commonly used sulfonylureas--tolbutamide, glibenclamide, gliquidone and gliclazide--were investigated at therapeutical concentrations at three different glucose levels (with 0, 2.22 and 5 mmol/l glucose surrounding) and in the presence of a metabolic stimulus with glucose at 8.33 mmol/l. All the sulfonylureas stimulated the B-cell function. Tolbutamide, gliquidone and gliclazide produced a prompt biphasic hormone release while glibenclamide induced a delayed monophasic insulin secretion. In all cases the amount of insulin released depended on the metabolic condition. As the environmental glucose levels fell, the sulfonylureas' stimulatory effect on the B-cell function decreased. At the therapeutical concentrations we tested, no sulfonylurea influenced A-cell activity whether directly or indirectly via an insulin-mediated paracrine inhibition of glucagon release.

Animals↗
PubMed1992

The effect of tolbutamide on burn hypermetabolism.

The effect of tolbutamide on improving burn hypermetabolism was studied prospectively in 31 burn adults with total body surface area burned > 40 per cent and 18 burned rabbits immediately after burn injury to postburn day 10. The results showed that burn hypermetabolism could be reduced using tolbutamide, which may be the result of the correction of relative insulin insufficiency, tissue insulin resistance and improving glucose utilization.

Adult↗
PubMed1996

General pharmacology of meloxicam--Part II: Effects on blood pressure, blood flow, heart rate, ECG, respiratory minute volume and interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide.

The pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), that go beyond those typical of an NSAID were examined. The extent to which meloxican shows NSAID-like interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide was also investigated. In the dose range studied, meloxicam had no influence on the blood pressure of the unanaesthetized rat, blood flow, heart rate, ECG and respiratory minute volume of the anaesthetized cat or on the blood pressure, heart rate and respiratory minute volume of the anaesthetized dog. The acute toxicity level of meloxicam after oral and parenteral administration to the rat and mouse proved considerably lower than that of indomethacin. Meloxicam showed excellent tissue tolerability following parenteral administration. The effects against inflammatory pain and acute antiexudative effects of meloxicam were enhanced by simultaneous low doses of paracetamol. Pirenzepine showed an antagonistic effect on the ulcerogenicity of meloxicam in the rat stomach. The diuretic effect of chlorthalidone in the rat was not influenced by high doses of meloxicam. The effect of phenprocoumon in the rat was enhanced by high doses of meloxicam. However, the hypoglycaemic effect of tolbutamide in the rabbit was not influenced by meloxicam.

Acetaminophen↗
PubMed1992

Opposing actions of tolbutamide and glibenclamide on hypoxic pulmonary vasoconstriction.

1. We show that cromakalin and diazoxide, drugs that activate ATP-sensitive potassium (KATP) channels, abolish hypoxic pulmonary vasoconstriction (HPV) of isolated, perfused rat lungs. 2. Glibenclamide, an inhibitor of these channels, does not affect HPV, but it reverses the relaxation caused by cromakalim and diazoxide. 3. Tolbutamide, which has effects similar to glibenclamide in other tissues, paradoxically abolishes HPV, an effect reversed by glibenclamide. 4. These results suggest that: (i) pulmonary vessels contain KATP channels which are normally closed and are not opened by levels of hypoxia that cause constriction, (ii) tolbutamide acts on the pulmonary vasculature by a mechanism which differs from that of glibenclamide.

Animals↗
PubMed2004

Crystal forms of tolbutamide from acetonitrile and 1-octanol: effect of solvent, humidity and compression pressure.

The possibility of obtaining tolbutamide polymorphs was investigated using the solvents acetonitrile and 1-octanol. Tolbutamide is an oral hypoglycemic agent that exists in four polymorphic forms. Characterization of the various polymorphs was carried out by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), infrared spectroscopy (FTIR), optical microscopy and dissolution studies. Form A, crystallized from acetonitrile, resembled the form I polymorph, while form O, crystallized from 1-octanol, resembled the form III polymorph. Tablets of both form A and form O were produced at compression pressures of 2500 lbs and 5000 lbs using cornstarch and talc and were exposed to 40%, 75% and 95% RH conditions. DSC and PXRD studies did not show any significant drug-excipient interaction. Moreover, the change in the crystalline state of either form upon exposure to humidity was not evident. Dissolution studies showed a significantly lower drug release rate from form O tablets compressed at 5000 lbs pressure and exposed to 95% RH. Pressure and humidity had no significant effect on the dissolution profiles on the form A tablets. It was concluded that form A was the robust choice for further formulation development.

1-Octanol↗
PubMed1987

Effect of age on the insulin secretory response of perfused rat pancreas to arginine and tolbutamide.

In this study we compared the ability of perfused pancreases from 2 1/2 month-old and 12 month-old rats to secrete insulin in response to arginine or tolbutamide. The results indicate that the insulin secretory response to either secretagogue was between 25-85% greater (two-way analysis of variance, P less than .01) by perfused pancreases of older rats. On the other hand, islet cell mass was approximately three-fold greater in the pancreases of the older rats. When this difference in mass of insulin secretory tissue was taken into consideration, it became apparent that insulin secretion per beta cell by perfused pancreases of the older rats was only half that of the younger rats in response to either arginine or tolbutamide (two-way analysis of variance, P less than 0.001). Thus, the decline with age in the ability of the beta cell to secrete insulin, previously noted in response to glucose, involves other insulin secretagogues as well.

Aging↗
PubMed1986

The comparative effects of tolbutamide and the non-hypoglycemic analog carboxytolbutamide on guanylate cyclase activity.

Tolbutamide and its non-hypoglycemic analog carboxytolbutamide increased soluble and particulate guanylate cyclase [E.C.4.6.1.2] activity twofold in liver, lung, colon, pancreas, kidney cortex, heart and spleen at a concentration of 1 microM. The ED50 for stimulation of guanylate cyclase activity was 50 nM for both agents. No stimulation of guanylate cyclase activity was observed with either agent when their concentrations were decreased to 1 nM. Maximal enhancement was at a concentration of 100 nM for both agents. Butylated hydroxytoluene, an antioxidant and hydroxyl radical scavenger, completely blocked any enhancement of guanylate cyclase by carboxytolbutamide, suggesting that its effect was due to a nonspecific oxidation reaction. Tolbutamide's augmentation of guanylate cyclase activity was not blocked by butylated hydroxytoluene. Varying the concentration of the guanylate cyclase co-factor manganese indicated that these sulfonylureas could not maximally activate guanylate cyclase without manganese being present. In addition to increased insulin receptors in monocytes and fibroblasts, the present findings, plus similar findings with the oral hypoglycemic agent glibenclamide, may help explain the mechanism of the extra-pancreatic effects of oral sulfonylurea agents at the cellular level.

Animals↗
PubMed1999

The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic beta cells is mediated by a 65-kDa mdr-like P-glycoprotein.

Intracellular application of the sulfonylurea tolbutamide during whole-cell patch-clamp recordings stimulated exocytosis >5-fold when applied at a cytoplasmic Ca2+ concentration of 0.17 microM. This effect was not detectable in the complete absence of cytoplasmic Ca2+ and when exocytosis was elicited by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS). The stimulatory action could be antagonized by the sulfonamide diazoxide, by the Cl--channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), by intracellular application of the antibody JSB1 [originally raised against a 170-kDa multidrug resistance (mdr) protein], and by tamoxifen (an inhibitor of the mdr- and volume-regulated Cl- channels). Immunocytochemistry and Western blot analyses revealed that JSB1 recognizes a 65-kDa protein in the secretory granules. This protein exhibited no detectable binding of sulfonylureas and is distinct from the 140-kDa sulfonylurea high-affinity sulfonylurea receptors also present in the granules. We conclude that (i) tolbutamide stimulates Ca2+-dependent exocytosis secondary to its binding to a 140-kDa high-affinity sulfonylurea receptor in the secretory granules; and (ii) a granular 65-kDa mdr-like protein mediates the action. The processes thus initiated culminate in the activation of a granular Cl- conductance. We speculate that the activation of granular Cl- fluxes promotes exocytosis (possibly by providing the energy required for membrane fusion) by inducing water uptake and an increased intragranular hydrostatic pressure.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Tolbutamide suppresses slow and medium afterhyperpolarization in hippocampal slices.

Afterhyperpolarizations (AHPs) were recorded (in whole-cell mode, with KMeSO4-containing electrodes) after multiple spikes evoked with 200 ms current pulses. Bath applications of tolbutamide (0.5-1 mM) to 12 CA1 neurones nearly abolished the medium and slow component of AHPs. Thus the AHPs generated by 7-8 spikes (mostly) were reduced by 82.6 +/- 5.2% (s.e.m.) at the initial peak (mAHP) and by 85.0 +/- 5.8% 1 s later (sAHP). Glibenclamide (10 microM) had no comparable blocking effect. The previous finding that tolbutamide (but not glibenclamide) selectively suppresses the anoxic hyperpolarization of CA1 neurones is therefore consistent with the idea that the anoxic hyperpolarization is mediated by Ca-dependent (especially AHP-type) K channels.

Animals↗
PubMed1993

Differences in K+ permeability between cultured adult and neonatal rat islets of Langerhans in response to glucose, tolbutamide, diazoxide, and theophylline.

The effects of glucose, tolbutamide, and diazoxide on K+ permeability in neonatal and adult rat pancreatic islets, maintained in culture 1 week, were investigated by measuring the 86Rb outflow rate from prelabeled islets. In the absence of glucose, the 86Rb efflux was significantly lower in neonatal than adult islets. Raising the glucose concentration to 2.8, 5.6, 8.3, and 11.1 mM produced a marked reduction in the 86Rb efflux in adult islets but only a minor reduction in neonatal islets. The effect of tolbutamide to reduce, and diazoxide to increase, the 86Rb efflux was also less in neonatal islets. These results are discussed with respect to previously reported differences in insulin secretion from neonatal and adult islets in culture.

Animals↗
PubMed1983

The effect of cimetidine on tolbutamide kinetics.

Although possible on theoretical grounds, no interaction between cimetidine and tolbutamide could be demonstrated in ten healthy volunteers. The plasma tolbutamide concentrations over 12 h following 0.5 g orally were essentially the same before and after 1 and 7 days cimetidine (400 mg twice daily).

Adult↗
PubMed1984

Failure of 'therapeutic' doses of beta-adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

The effects of separate 1 week pre-treatments with each of the beta-adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre-treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half-life, volume of distribution and plasma protein binding were not altered by the beta-adrenoceptor blocker pre-treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. 'Therapeutic' plasma concentrations of the beta-adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta-adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration-dependent.

Adrenergic beta-Antagonists↗
PubMed1984

Tolbutamide as a model drug for the study of enzyme induction and enzyme inhibition in the rat.

The effects of various drugs on the pharmacokinetics of tolbutamide have been examined in the rat. Phenobarbitone pretreatment caused a significant decrease in half life and area under the curve (AUC) and a significant increase in clearance and volume of distribution (Vd). Acute administration of primaquine significantly increased half life and AUC and decreased clearance. In contrast, the related animoquinolone chloroquine, was without effect. Acute administration of cimetidine produced similar changes to primaquine but of lesser magnitude. Formation of the major metabolite hydroxytolbutamide, was markedly enhanced by phenobarbitone and reduced by primaquine and cimetidine. We conclude that due to its single pathway of metabolism, tolbutamide is a good substrate to use when examining pharmacokinetic interactions involving hepatic enzyme induction and inhibition.

Animals↗
PubMed1985

Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure-activity relationship.

Tolbutamide has been used as a model drug for an examination of the effects of eleven substituted imidazole compounds on hepatic metabolism in vivo. The 1-substituted compounds 1-methylimidazole, miconazole, clotrimazole and ketoconazole produced marked alterations in tolbutamide kinetics (increased half-life, decreased clearance). However, if there was substitution in the 2- position, irrespective of a substituent on N-1, then the compound did not appear to inhibit metabolism (e.g. 2-methylimidazole, 1,2-dimethylimidazole, methimazole, metronidazole). The 4- substituted compounds, 4-methylimidazole and cimetidine were inhibitors. A structure-activity relationship for the inhibitory actions of the substituted imidazoles is thus evident in vivo.

Animals↗
PubMed1988

Different effects of bombesin on glucose- and tolbutamide-induced insulin release in man.

1. The effect of bombesin, a neurogastrointestinal peptide, on basal and stimulated insulin release was studied in man. 2. Two different stimuli were used, hyperglycaemic (20 g glucose) and hypoglycaemic (1 g tolbutamide). They were injected intravenously to two groups of male healthy volunteers during saline or bombesin (5 ng kg-1 min-1 for 60 min) infusion. 3. The peptide had no significant effect on basal levels of glucose and insulin. However, the insulin response to intravenous glucose was strongly potentiated by bombesin, the integrated insulin response being 2.23 +/- 0.59 mu ml-1 . 90 min and 0.98 +/- 0.19 mu ml-1 . 90 min during infusion of bombesin and saline, respectively (P less than 0.05). The behaviour of plasma glucose was not significantly modified by the peptide. Indeed, the glucose disappearance rate (K of Conard, mg min 10(-2)) changed from 2.5 +/- 0.3 during saline to 2.4 +/- 0.4 during bombesin infusion. 4. When the hypoglycaemic stimulus (i.e. tolbutamide) was used, no effect of the peptide on insulin release could be detected. Here again, the drop in plasma glucose (expressed as Marigo's coefficient) was not affected by the peptide, with a value of 92.8 +/- 12.6 and 84.0 +/- 10.9 during bombesin and saline administration. 5. These data therefore show that, at normal or low blood glucose levels, the dose of bombesin used is unable to modify insulin release and suggest that this peptide might be regarded as a glucose-dependent insulinotropic peptide.

Adult↗
PubMedDate not supplied

Few cultured rat primary sensory neurons express a tolbutamide-sensitive K+ current.

The response of dorsal root ganglion (DRG) neurons to metabolic inhibition is known to involve calcium-activated K+ channels; in most neuronal types ATP-sensitive K+ channels (K(ATP)) also contribute, but this is not yet established in the DRG. We have investigated the presence of a K(ATP) current using whole-cell recordings from rat DRG neurons, classifying the neurons functionally by their "current signature" (Petruska et al, J Neurophysiol 84:2365-2379, 2000). We clearly identified a K(ATP) current in only 1 out of 62 neurons, probably a nociceptor. The current was activated by cyanide (2 mM NaCN) and was sensitive to 100 microM tolbutamide; the relation between reversal potential and external K+ concentration indicated it was a K+ current. In a further two neurons, cyanide activated a K+ current that was only partially blocked by tolbutamide, which may also be an atypical K(ATP) current. We conclude that K(ATP) channels are expressed in normal DRG, but in very few neurons and only in nociceptors.

Action Potentials↗