Clinical Experience with the Oral Antidiabetic Compound,Tolazamide

In clinical experience totalling 82 patient-years with the sulfonylurea tolazamide, satisfactory control of glycemia was obtained in 70% of diabetics. The preponderance of elderly and newly diagnosed diabetics in the group probably increased the percentage of successes, because when tolazamide was compared with tolbutamide in the same patients the frequency of clinical effectiveness was similar. The ratio of effectiveness by weight for tolbutamide/tolazamide was 6.6/1.0. No toxic effects were detected, side effects were minimal and there appeared to be little tendency to induce unwarranted hypoglycemia.     

A Comparative Study of Some Brands of Tolbutamide Available in Canada: Part I. Clinical Aspects

Two lots of brand-name and three lots of non-proprietary tolbutamide products, the latter having been reported to be clinically ineffective, were compared in a double-blind study in 22 diabetic patients. Every patient took each of the five brands for two weeks. The dose range was 1 to 2 g. per day and the dose was kept constant in each patient throughout the five test periods. Statistical analyses of fasting, mid-morning and mid-afternoon blood sugar levels, mid-morning and mid-afternoon blood tolbutamide levels and levels of tolbutamide and its metabolite in 24-hour urine did not show any significant differences among the five products except for better control of fasting blood-sugar levels by one brand, nor did clinical observations reveal any differences.     

A Comparison of the Effects of Tolazamide and Tolbutamide Upon Blood Glucose and Serum Insulin and Lipid Levels in Diabetic Subjects

The effects of tolazamide (300 mg. daily), a new oral hypoglycemic sulfonylurea, and tolbutamide on the blood glucose, serum insulin, cholesterol and triglyceride levels were compared in 14 subjects with maturity-onset diabetes of varying severity. The mean effects of the two drugs in the pharmacologically equivalent doses were the same. In particular, the mean reduction of the blood glucose level was 19% and of the serum triglyceride level was 17% with both agents. However, an individual subject might respond to one agent and not to the other; neither the blood glucose nor the serum lipid response could be predicted from the pretreatment blood glucose level or the per cent of ideal body weight.     

Glucose and Insulin Secretory Response Patterns Following Diet and Tolazamide Therapy in Diabetes

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.     

Diabetes Mellitus: Distinguishing Between Patients Receiving Insulin and Those Requiring Insulin Therapy

Fifteen patients with maturity onset type diabetes, all of whom had received insulin for periods of one to thirty-five years, were admitted to hospital and insulin treatment was discontinued. Within 24 to 48 hours each patient was given an intravenous tolbutamide test, following which all were given either diet therapy alone or diet therapy plus oral agents. If significant hyperglycemia or ketonemia resulted, insulin therapy was reinstituted.Approximately 50 percent (8 of 15) of the patients showed improvement in fasting blood sugar levels following discontinuation of insulin. It was not possible to distinguish the insulin independent from the insulin dependent group using such criteria as age, sex, degree of overweight, insulin dosage, duration of diabetes or duration of insulin therapy. However, using the intravenous tolbutamide test it was possible to differentiate between the two groups. Those who did not require insulin responded to intravenous tolbutamide with a glucose decrease greater than 10 percent from the initial value. The insulin dependent group had either no glucose decrease or a rise in blood glucose following intravenous administration of tolbutamide.     

The Effects of Dextrothyroxine in Diabetes

Eighteen diabetic patients were treated with dextrothyroxine (from 2 mg to 8 mg daily) for varying periods up to six months. This produced a decided reduction of serum cholesterol levels. Statistically valid comparisons were made of their fasting blood sugar levels before and after two weeks of dextrothyroxine treatment. Administration of this drug was associated with a significant elevation of fasting blood sugar levels. Good diabetic control did not preclude this adverse effect.After more prolonged treatment with the drug, 8 of the 18 patients experienced progressive deterioration of their diabetic control, necessitating increased amounts of insulin or oral drugs. Despite close observation, one patient developed acidosis.When dextrothyroxine was discontinued, there was a significant drop in blood sugar levels in these patients. Two patients had hypoglycemic reaction.When the fasting blood sugar values of the 18 patients, studied while they were receiving significant doses of dextrothyroxine, are compared with a control series of blood sugar determinations obtained on these same patients before dextrothyroxine administration was begun, the diabetogenic effect of this drug is confirmed by the highly significant difference demonstrated.Four patients were given dextrothyroxine a second time, and again experienced deterioration of diabetic control.     

Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus

The effect of 1 week clofibrate administration on glucose and insulin responses to oral glucose and to intravenous tolbutamide was evaluated in 21 patients with mild maturity-onset diabetes (fasting plasma glucose 108-152 mg/100 ml). After treatment, oral glucose tolerance and hypoglycaemic effect of tolbutamide were significantly improved; plasma insulin response was reduced after glucose and unmodified after tolbutamide; fasting plasma glucose was also significantly reduced. These findings did not correlate with the observed fall in serum lipids. Short-term clofibrate improves glucose metabolism in mild diabetes irrespective of its effects on lipid metabolism. It is suggested that the drug's action may be mediated by reduced insulin resistance.     

Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 μmol/l (100 μg/ml)), yet the variation in dosage was only sixfold (0·5-3·9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 μmol/l (244 μg/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5·4%) of the tolbutamide-treated patients and 10 (16·7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5·5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8·0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.     

Effectiveness of hypoglycemic agents in guinea pigs exposed to mixed gamma-neutron radiations

The effect of 200, 1000, and 5000 rads of mixed gamma-neutron radiations on total blood reducing sugar and blood glucose levels in guinea pigs was investigated 2 and 24 hours, and 9, 22, and 60 days postirradiation. In addition, the effectiveness of insulin and tolbutamide in these animals was evaluated before and after irradiation. Glucose increased to a lesser degree and later than did the nonglucose fraction of the blood sugar. Insulin and tolbutamide were at least as effective in irradiated animals as in unirradiated ones except after 5000 rads, when tolbutamide was significantly less effective. These results suggest that: (1) insufficient insulin is released by the pancreas in response to elevated blood sugar levels following irradiation; (2) the pancreas does produce insulin at these times and is able to release it in response to tolbutamide; and (3) a decrease in insulin production occurs following supralethal doses of radiation.     

Characterization of the sulfonylurea receptor on beta cell membranes

Specific, high affinity sulfonylurea receptors were characterized on membranes of an insulin-secreting hamster beta cell line (HIT cells). Saturable binding of the sulfonylurea, [3H]glyburide, was linear up to 0.8 mg/ml membrane protein. Scatchard analysis of equilibrium binding data at room temperature indicated the presence of a single class of saturable, high affinity binding sites with a Kd of 0.76 +/- 0.04 nM and a Bmax of 1.09 +/- 0.13 pmol/mg protein, n = 9. The insulin secretory potency of glyburide, glipizide, tolbutamide, tolazamide, and carboxytolbutamide was compared to the ability of these ligands to displace [3H]glyburide from the sulfonylurea receptor. Tolbutamide, tolazamide, and glipizide demonstrated reasonable agreement with ED50 values of 15 microM, 3 microM, and 30 nM and Ki values of 25.3 microM, 7.2 microM, and 45 nM, respectively. The inactive tolbutamide metabolite, carboxytolbutamide, at the highest concentration tested, only partially displaced [3H]glyburide from the receptor and was a very poor secretagogue. At 37 degrees C the affinity of [3H]glyburide binding, Kd = 2.0 nM, was similar to the ED50 of 5.5 nM when the free glyburide concentrations were corrected for binding of the drug to albumin. These studies suggest that sulfonylureas initiate their biologic effect through a high affinity, specific interaction with sulfonylurea receptors on the beta cell membrane.     

Hypoglycemic effects of the wood of Taxus yunnanensis on streptozotocin-induced diabetic rats and its active components

Hypoglycemic effects of the H(2)O and MeOH extracts of the wood of Taxus yunnanensis were examined in streptozotocin (STZ)-induced diabetic rats. The H(2)O extract significantly lowered the fasting blood glucose level by 33.7% at a 100mg/kg dose on intraperitoneal administration. From the active H(2)O extract of the wood, three lignans, i.e., isotaxiresinol (1), secoisolariciresinol (2) and taxiresinol (3), were isolated as major components. These lignans were further tested for their hypoglycemic effects on the same experimental model. At a dose of 100mg/kg (i.p.), isotaxiresinol (1) reduced the fasting blood glucose level of diabetic rats by 34.5%, while secoisolariciresinol (2) and taxiresinol (3) reduced by 33.4% and 20.9%, respectively. The blood glucose lowering effects of 1 and 2 were stronger than the mixture of tolbutamide (200mg/kg) and buformin (1mg/kg) used as a positive control, which lowered fasting blood glucose level by 24.0%.     

Blood Glucose Measurement with Dextrostix and New Reflectance Meter

A new instrument, Eyetone, has been produced for use with a Dextrostix reagent strip for estimating blood sugar levels. It differs from the Dextrostix Reflectance Meter in having only one meter scale, a two-point calibration, and a range of measurement limited to 10-400 mg/100 ml. Results with the manufacturers'' original calibration were unsatisfactory, but when recalibrated the performance of the instrument gave a regression equation line close to the ideal. The three Eyetone instruments tested were comparable in their accuracy and functional stability. Packed cell volumes in the blood samples in the range of 30-50% had a negligible effect on the results. The Dextrostix-Eyetone method represents a quick and reliable alternative to conventional laboratory methods for blood sugar estimation. It is especially useful for patients outside hospital.     

Tolbutamide inhibits gastrin release in man

Tolbutamide significantly decreased fasting plasma gastrin after 5 min of intravenous infusion in patients with atrophic gastritis, duodenal ulcer, or insulin-dependent diabetes mellitus (IDDM) as well as in healthy volunteers. Increased plasma insulin and decreased blood glucose were observed in patients with atrophic gastritis, duodenal ulcer and healthy volunteers, but not in patients with IDDM. Suppression of plasma gastrin in healthy volunteers was also observed following oral administration of tolbutamide. Despite the observed decrease in plasma gastrin, neither basal nor tetragastrin-stimulated acid output was changed for 30 min following tolbutamide infusion in healthy volunteers. Thus, our data suggest that tolbutamide inhibits gastrin release in man via mechanisms independent of changes in plasma insulin, blood glucose or acid secretion.     

74 例急性脑卒中合并糖代谢异常患者治疗及预后的前瞻性研究

目的:探讨急性脑卒中患者血糖代谢异常的治疗方法及其对预后的影响。方法:抽取我院于2010年1月-2011年10月收治的74例急性脑卒中血糖代谢异常患者,按照入院时间先后将其分为对照组和实验组,其中对照组34例给予常规溶栓抗凝和抗血小板治疗,实验组40例行给予胰岛素联合溶栓抗凝和抗血小板综合治疗。对所有患者进行1-2个月的随访,对比两组患者的临床疗效和空腹血糖变化。结果:两组间治疗前相比,空腹血糖值差异无统计学意义(P>0.05);两组间治疗后相比,实验组患者的空腹血糖值(5.76±1.09)低于对照组(9.36±1.66),比较差异有统计学意义(P<0.05)。两组间相比,实验组患者的总有效率为97.5%,高于对照组的88.2%,统计学差异有意义(P<0.05)。实验组患者神经功能缺损评分(NDS)为39.4±2.4、格拉斯哥昏迷评分(GCS)为9.2±1.6和日常生活活动能力(ADL)为5.4±1.2均高于对照组(27.7±1.4、6.4±1.2、3.8±1.3),比较差异有统计学意义(P<0.05)。结论:运用诺和灵、血栓通、奥扎格雷联合治疗急性脑卒中合并血糖代谢异常,可有效地改善患者的血糖变化和脑部功能。     

Adjunctive use of tolazamide in newly-diagnosed diabetic children

Recent data suggests that one of the major actions of sulfonylureas is to potentiate the anabolic cellular effects of insulin. This is the first study to examine the use of sulfonylureas as adjunctive therapy in newly-diagnosed type I diabetic children. A random, prospective, double blind study over 15 months, stratified by age at diagnosis, was conducted. The treatment group (n = 13) received daily oral weight-adjusted tolazamide whereas the control group (n = 11) received placebo. Monthly comparison of the HbA1 values between groups revealed no statistical difference; likewise, the fasting serum C-peptide values were not dissimilar. The mean daily insulin dose per kilogram, however, was less in the tolazamide group (P less than 0.001). The data suggests that the addition of tolazamide may not be of therapeutic benefit in newly diagnosed juvenile diabetics, although insulin requirements may be reduced.     

Oral administration of orinase (tolbutamide); clinical observations of effect on nondiabetic and diabetic humans

Ingestion of tolbutamide (Orinase(R)) by nondiabetic humans brought about a maximum reduction in blood sugar within one to two hours. In diabetic persons taking large doses of insulin, or who needed insulin for control, hyperglycemia, ketosis, and increased excretion of glucose in the urine developed when tolbutamide was substituted for insulin or was used before insulin therapy was begun. The only serious toxic manifestation observed was a skin rash in two patients. Successful control of diabetes with tolbutamide was limited to cases in which the disease was of mild, stable type and the patient was 40 or more years of age, of normal weight, and with a previous insulin requirement of 5 to 30 units per day. It was of benefit in 43.5 per cent of all diabetic patients in the series studied and in about 75 per cent of the group that might be referred to as selected. The duration of the disease and the duration of insulin therapy were unimportant in predicting effectiveness for tolbutamide therapy.     

Modulatory effect of butyric acid-a product of dietary fiber fermentation in experimentally induced diabetic rats

The effect of feeding of butyric acid on alleviation of diabetic status was studied. Diabetes was induced in rats using streptozotocin. Rats were fed with basal diet containing wheat bran (5%) as a source of insoluble dietary fiber and guar gum (2.5%) as a source of soluble dietary fiber. The experimental group received butyric acid at 250, 500 and 750 mg/kg body weight/day. The diabetic animals lost weight in spite of high diet consumption. The levels of water intake, urine output, urine sugar, fasting blood sugar increased during diabetic condition compared to control and these were reduced by nearly 20% in the fiber-fed diabetic group. Further supplementation of butyric acid at 500 mg/kg body weight/day ameliorated the diabetic status by nearly 40%. Urine sugar level during the diabetic state was reduced from 7.2 g/day to 3.6 g/day and fasting blood glucose from 270 mg/dl to 180 mg/dl. Butyric acid feeding at 500 mg/kg body weight/day was most effective in controlling the diabetic status.     

Anti-diabetic effect of ginsenoside Re in ob/ob mice

We evaluated the anti-diabetic effects of ginsenoside Re in adult male C57BL/6J ob/ob mice. Diabetic ob/ob mice with fasting blood glucose levels of approximately 230 mg/dl received daily intraperitoneal injections of 7, 20 and 60 mg/kg ginsenoside Re for 12 consecutive days. Dose-related effects of ginsenoside Re on fasting blood glucose levels were observed. After the 20 mg/kg treatment, fasting blood glucose levels were reduced to 188+/-9.2 and 180+/-10.8 mg/dl on Day 5 and Day 12, respectively (both P<0.01 compared to vehicle group, 229+/-9.5 and 235+/-13.4 mg/dl, respectively). The EC(70) of ginsenoside Re was calculated to be 10.3 mg/kg and was used for subsequent studies. Consistent with the reduction in blood glucose, there were significant decreases in both fed and fasting serum insulin levels in mice treated with ginsenoside Re. With 12 days of ginsenoside treatment, glucose tolerance of ob/ob mice increased significantly, and the area under the curve for glucose decreased by 17.8% (P<0.05 compared to vehicle treatment). The hypoglycemic effect of the ginsenoside persisted even at 3 days of treatment cessation (blood glucose levels: 198+/-13.1 with ginsenoside treatment vs. 253+/-20.3 mg/dl with vehicle, P<0.01). There were no significant changes in body weight or body temperature. Preliminary microarray analysis revealed differential expression of skeletal muscle genes associated with lipid metabolism and muscle function. The results suggest that ginsenoside Re may prove to be useful in treating type 2 diabetes.     

Hypoglycemic effect of Hibiscus rosa sinensis L. leaf extract in glucose and streptozotocin induced hyperglycemic rats

Investigations were carried out to evaluate the effect of aqueous extract of H. rosa sinensis leaves on blood glucose level and glucose tolerance using Wistar rats. Repeated administration of the extract (once a day for seven consecutive days), at an oral dose equivalent to 250 mg kg(-1), significantly improved glucose tolerance in rats. The peak blood glucose level was obtained at 30 min of glucose load (2 g kg(-1)), thereafter a decreasing trend was recorded up to 120 min. The data exhibit that repeated ingestion of the reference drug tolbutamide, a sulphonylurea and the extract brings about 2-3 fold decrease in blood glucose concentration as compared to single oral treatment. The results clearly indicate that tolbutamide improves the glucose tolerance by 91% and extract does so only by 47%. At 250 mg kg(-1), the efficacy of the extract was 51.5% of tolbutamide (100mg kg(-1)). In streptozotocin diabetic rats, no significant effect was observed with the extract, while glibenclamide significantly lowered the glucose level up to 7 hr. These data suggest that hypoglycemic activity of H. rosa sinensis leaf extract is comparable to tolbutamide and not to glibenclamide treatment.     

冠心病患者血清HN、CTRP3与血脂及病情严重程度的关系研究

摘要 目的：分析血清抗凋亡多肽（HN）、补体C1q肿瘤坏死因子相关蛋白因子3（CTRP3）与冠心病（CHD）患者血脂及病情严重程度的关系。方法：选取2017年1月至2018年12月期间西安医学院第二附属医院收治的CHD患者360例（CHD组）,另选取同期健康体检者100例作为对照组（NC组）,比较两组血清HN、CTRP3、血脂水平及基线资料;根据CHD患者病变支数分为单支病变组（n=131）、双支病变组（n=119）、多支病变组（n=110）,根据冠状动脉造影结果测定Gensini积分,采用Pearson相关分析HN、CTRP3与血脂及Gensini积分的相关性。结果：CHD组患者吸烟史比例、收缩压、空腹血糖、总胆固醇（TC）、甘油三酯（TG）及低密度脂蛋白（LDL-C）水平均高于NC组（P<0.05）,血清HN、CTRP3和高密度脂蛋白（HDL-C）均低于NC组（P<0.05）;CHD双支病变组和多支病变组患者吸烟史、空腹血糖、TC水平以及Gensini积分均高于单支病变组,CTRP3和HDL-C水平均低于单支病变组,多支病变组收缩压高于单支病变组,多支病变组吸烟史、空腹血糖和Gensini积分均高于双支病变组,且多支病变组CTRP3低于双支病变组（均P<0.05）;Pearson相关分析结果显示：CHD患者血清HN水平与HDL-C水平呈正相关性,CHD患者血清CTRP3水平与Gensini积分呈负相关（P<0.05）。结论：CHD患者血清中HN、CTRP3水平均显著降低,HN与HDL-C水平呈正相关,CTRP3降低程度与CHD患者病情严重程度有关,临床可考虑将其作为评估CHD患者病情严重程度的辅助血清学指标。