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A series of N-[[(dialkylamino)alkoxyl]phenyl]benzamidines was synthesized and evaluated for hypoglycemic activity in the glucose-primed rat. Structure-activity relationship indicated that N'-phenyl-N-[4-[2(diisopropylamino)-ethoxy]phenyl]benzamidine dihydrobromide (7), N'-(4-chlorophenyl)-N-[4-[2-(diisopropylamino)ethoxy]phenyl]-benzamidine dihydrochloride (31), and N'-phenyl-N-[4-[(diisopropylamino)propoxy]phenyl]benzamidine dihydrobromide (11) are some of the more interesting compounds. A comparison of these hypoglycemic agents with classical standards (tolazamide, phenformin, and buformin) in several experimental models showed that the benzamidines seem to combine in one molecule some of the biological activities of the beta-cytotrophic sulfonylureas and some of the activities of the biguanides.

Insulin requirements, C-peptide levels, and serum lipids have been assessed in 12 obese, insulin-requiring (greater than 60 U/day) patients with type II diabetes mellitus, in a randomized crossover fashion with two treatment regimens: NPH alone and combined NPH and tolazamide, over a period of 3 months each, with maintenance of weight and glycemic control (HgA1, 2hpp and mean 24h glucose profile) at comparable levels. Serum cholesterol improved in both groups compared to their respective baseline values (p less than 0.05). In addition, serum triglyceride was lower (p less than 0.05) in the combined therapy as compared with NPH alone therapy. Insulin requirements were decreased by 23% (p less than 0.002) in the combined therapy group, without significant change in weight, glycemic control, or C-peptide levels. However, C-peptide increments in the combined therapy group were significantly higher than the baseline by 70% (p less than 0.02). NPH plus tolazamide therapy as compared with NPH alone lowers insulin requirement in obese, type II diabetic women without significant alteration in glycemic control, possibly by an increased tissue sensitivity to insulin, and decreases serum triglyceride levels.

The extraction of drugs from small blood samples (1 ml or less) for subsequent quantitative determination is described. Isolation was carried out by adsorption of the drugs to Amberlite XAD-2 resin utilizing a batch procedure that enabled the simultaneous extraction of up to 200 samples in approx. 5 hours. A new desorption technique yielded extracts of high purity that could be used directly for gas chromatographic or radioimmunological determinations, even if hemolyzed or putrid blood was to be examined. The following 26 substances were quantitated after addition to postmortem blood speciments at concentrations of 1-10 microgram/ml: tilidine, diphenhydramine, dibenzepine, imipramine, chlorpromazine, amphetamine, pentazocine, phenacetin, methaqualone, meprobamate, parathion, diazepam, digoxin, beta-methyldigoxin, carbromal, glutethimide, amobarbital, pentobarbital, cyclobarbital, phenobarbital, diphenylhydantoin, carbutamide, tolbutamide, glycodiazin, tolazamide and chlorpropamide. Thereby recoveries of 60-100% could be achieved. The reproducibility of the procedure was satisfactory as demonstrated by coefficients of variation of 3.7-8%.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other β-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess β-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 ± 11 μU/ml when not receiving tolazamide (0.14 ± 1 . 3 μU/ ml) with tolazamide (P < .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 ± 22 (μU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5–10 min after intravenous tolbutamide were undetectable (−0.5 (μU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic pcells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue. This phenomenon has features in common with the effect of sustained hyperglycemia on desensitization of the β-cell response to intravenous glucose with implications regarding the pathogenesis of NIDDM. More over, it suggests that the insulinotropic effect of sulfonylureas might be more effective, particularly in cases of NIDDM with “secondary failure” to sulfonylureas, if these drugs are administered either on an intermittent schedule or as “pulse” therapy, using a form with a shorter duration of action.

A series of benzimidoylpyrazoles was synthesized and evaluated as hypoglycemic agents. Methyl 1-(N-cyclohexylbenzimidoyl)-5-methyl-3-pyrazolecarboxylate (13) and methyl 1-[N-(4-methoxyphenyl)benzimidoyl]-5-methyl-3-pyrazolecarboxylate (33) are two of the more interesting compounds. A comparison of these benzimidoylpyrazoles with classical standards (tolazamide, phenformin, and buformin) in several experimental models show that these compounds seem to combine in one molecule some of the biological activities of the beta-cytotrophic sulfonylureas and some of the activities of the biguanides. A synthetic scheme for the preparation of the benzimidolypyrazoles and a preliminary structure-activity relationship are presented.

The described pharmacokinetic analysis involved two separate studies on nine dogs randomly assigned to three groups of three dogs each. In the first study, the effect of varying the dosage of tolazamide was examined. The second study concerned the effect of varying the dosage of oxyphenbutazone on tolazamide. A 3 x 3 Latin square was used to study both effects. Each group received each treatment, with a minimum of 1 week separating each session. THe pharmacokinetics of tolazamide followed a two-compartment open model. The hybrid rate constants, alpha and beta, were not significantly different at the three dosages when measured by a three-way analysis of variance. The only significant difference at the three dosage levels of tolazamide was in the apparent volume of distribution. In the pharmacokinetic interaction associated with intravenous administration of one dose of tolazamide and three doses of oxyphenbutazone, the apparent volume of distribution and the hybrid rate constant alpha did not change significantly while the hybrid rate constant for tolazamide, beta, seemed to decrease with increasing oxyphenbutazone.

The effect of sulfonylureas on long-term regulation of glucose uptake by insulin and insulin-like growth factors has been studied in the L6 line of cultured skeletal muscle cells. These cells have previously been shown to possess many characteristics of differentiated skeletal muscle and to bind and respond to physiological concentrations of insulin and insulin-like growth factors I and II. Tolazamide (half-maximal at 0.2 mg/ml) augments the effects of insulin, insulin-like growth factor I, and insulin-like growth factor II on glucose uptake, increasing both sensitivity and maximal efficacy of the hormones. In the absence of added hormone, tolazamide has no effect on glucose uptake. A similar increase in insulin-stimulated glucose uptake with unaltered basal uptake occurs with glyburide (half-maximal at 0.5 microgram/ml). The action of tolazamide requires long-term exposure to the sulfonylurea (22 h) and is inhibited by cycloheximide, suggesting a process that involves new protein synthesis. In contrast to glucose uptake, amino acid uptake in L6 cells is increased by tolazamide in the absence of hormones. Insulin and the insulin-like growth factors also stimulate amino acid uptake, but this effect is not further augmented by tolazamide. Thus, sulfonylureas appear to directly modulate amino acid uptake, but to indirectly augment glucose uptake through an effect on insulin and insulin-like growth factor stimulated pathways. Neither insulin binding nor insulin degradation is altered by tolazamide, indicating a post-binding mechanism of action. The L6 cultured skeletal muscle cell line should be useful in future studies on the mechanism of the extrapancreatic actions of sulfonylureas.

The effects of sulfonylureas on the production of plasminogen activator (PA) and antiactivator (PAI) were investigated using bovine aortic endothelial cells. All compounds studied stimulated PA release (1.3- to 5.2-fold), with glipizide being the most potent, followed by tolazamide, chlorpropamide, and tolbutamide, in that order, while glyburide was the least effective. Both tissue-type and urokinase-type PA production was enhanced. Studies using metabolic inhibitors indicated that both RNA and protein syntheses are required for the sulfonylurea-mediated stimulation of PA release. In addition to continuous release of the two PAs, there was also a continuous release of a single PAI, which did not show an increase after the sulfonylureas. These results suggest that, in addition to their beneficial effects in the treatment of diabetes mellitus, some sulfonylurea compounds may also have significant thrombolytic effects. These results also suggest that pharmacological enhancement of PA production by vascular endothelial cells may be a promising antithrombotic mechanism.

A 67-year-old thin diabetic man went into remission four months after onset of diabetes mellitus and initiation of therapy with an oral hypoglycemic agent. Eighteen months later the patient was still in remission. During this period, he experienced the severe stress of a modified jaw resection for carcinoma.

Chlorpropamide inhibited by 35 to 65% the increase in the urinary excretion of adenosine 3',5'-monophosphate (cyclic AMP) following a large dose (250 U) of parathyroid hormone (PTH) in normal subjects and patients with hypoparathyroidism and pseudohypoparathyroidism. By contrast, in normal subjects, the response of urinary cyclic AMP excretion to smaller amounts of PTH (15 and 30 U) was not decreased by chlorpropamide. Chlorpropamide did not decrease the phosphaturic response to any dose of PTH. The probable explanation for the discrepant effects of chlorpropamide on urinary cyclic AMP and phosphate excretions is that phosphaturia results from a minimal elevation of cyclic AMP and that chlorpropamide does not decrease cyclic AMP production to such a low level. Chlorpropamide decreased the accumulation of renal cyclic AMP in response to PTH in the parathyroidectomized rat, suggesting that this may be the mechanism of action for this drug in decreasing the urinary excretion of cyclic AMP in response to PTH in man. Tolazamide, another sulfonylurea, did not inhibit the elevation of urinary cyclic AMP excretion after PTH. Therefore, the sulfonylurea part of the molecule is probably not involved in the inhibition produced by chlorpropamide.

The sulfonylureas, tolbutamide, tolazamide and acetohexamide significantly diminish uptake of insulin by the isolated perfused rat liver, whereas the nonhypoglycemic metabolite of tolbutamide, carboxytolbutamide, has no such effect. These results suggest that the sustained action of the sulfonylureas may in part be due to reduced hepatic uptake of endogenously secreted insulin.

The blood sugar lowering sulphonylureas chlorpropamide, tolazamide and tolbutamide showed competitive inhibition of diphenylhydantoin hydroxylation by the 9000 g-supernatant of rat liver homogenates. Tolbutamide was the strongest inhibitor and chlorpropamide the weakest. The enzyme kinetics could not be presented satisfactory by Lineweaver-Burk plots; therefore log-dose response curves were used and the potency of the inhibitors was calculated according to the method of Arunlakshana and Schild. The relative inhibitory potency of the three sulphonylureas chlorpropamide-tolazamide-tolbutamide was 1:2·5:4·3.

Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone.

An analysis was made of the records of 1,840 patients in whom diabetes started after the age of 35 and before the age of 70, and who were under the authors' care for from one to fifteen years. According to the predictions of life-insurance tables, these patients lived longer than non-diabetic patients. There was a significant decrease in longevity in those who had persistent hyperglycemia. The greatest increase in longevity occurred in those whose disease could be controlled by diet alone or with sulfonylurea drugs. There was less apparent benefit from phenformin or insulin in this respect. In comparison, the findings of the University Group Diabetes Program are discussed in some detail. The authors' data indicate that, in the treatment of diabetes, sulfonylurea drugs have a beneficial effect upon longevity when they are used properly.

Tolazamide, a new oral hypoglycemic agent, was compared with tolbutamide, a related chemical compound, for stability of control of 12 patients suffering from maturity-onset diabetes mellitus. A short 12-week study was conducted which incorporated a cross-over design and the results were examined by variance analysis after dosage was individualized to the patient's requirements. Greater stability of fasting blood sugar was found on tolazamide; patients also had less glycosuria and lower fasting blood sugar on tolazamide. Tolazamide appeared to be between five and six times as potent as tolbutamide, mg. for mg.No hepatic, renal, hematologic or symptomatic toxic reactions were observed during the total of 72 person-weeks of tolazamide therapy.

Tolazamide and tolbutamide were found to interfere with the determination of blood glucose by the method of Boehringer GOD-PERID and a glucose oxidase, peroxidase method using O -dianisidine as the oxygen acceptor chromogen. Tolazamide produced falsely low blood glucose results and the decrease was significant at tolazamide levels of 5 mg/100 ml if the sample was not processed through a protein precipitation procedure employing either a heavy metal or alkaline zinc salts. Dialysis did not remove the drug on the Auto-Analyser. Tolbutamide produced a false increase in blood glucose but at the expected blood levels of this drug its effect would be minimal. Attempts have been made to establish where in the reaction sequence, tolazamide interfered. Evidence was found that this substance is a competitor for the oxygen liberated by peroxidase.

Interference by certain compounds with the glucose oxidase-peroxidase system used in blood glucose estimations appears to be a function of the oxygen affinity of the oxygen acceptor chromogen or the oxidative coupling system. It has been shown 1 that tolazamide interferes seriously with the Boehringer GOD-PERID blood glucose method. By utilising other compounds with similar chemical groups, it was found possibleto identify the group in the tolazamide molecule that caused interference and consequently to predict the effects of other compounds on such blood glucose methods. A comparison of three chromogenic systems was also performed. These were guaiacum 2 , phenol-4-aminophenazone 3 and the Boehringer 2'2-diazo-di(3-ethyl benzthiazoline-6-sulphonic acid) (ABTS). Some of the advantages and disadvantages of these three systems are discussed.

The dissolution behavior of the acid and the sodium salt of this drug in phosphate buffers has been investigated. Data have been analyzed by relationships derived from the diffusion controlled model for dissolution of solids in reactive media. The results of this study show that surface conversion of the sodium salt to the acid occurs in the lower pH range of these studies. Calculations suggest that appreciable conversion takes place only after initial surface supersaturation ratios of about 20 or greater are achieved. Under conditions of much greater initial surface supersaturation ratios, a relatively impermeable acid surface coating is formed, and the dissolution rate is governed by this acid phase.