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PubMed1999

Sulfonylureas stimulate renin secretion from the perfused kidney of the rat.

To elucidate whether sulfonylureas directly influence renin secretion, the effect of tolbutamide, glibenclamide, or chlorpropamide on renin secretion was investigated by using the perfused kidney of the rat. The isolated kidneys of male Wistar rats (200-250 g) were perfused with a medium containing 2 microM tolbutamide, 2 microM glibenclamide, and 2 microM chlorpropamide, respectively. Renin activity significantly increased from a basal value of 11.7 +/- 3.6 to a peak value of 20.6 +/- 5.5 ng/Ang I/ml/h with tolbutamide, from 14.4 +/- 4.6 to 32.7 +/- 6.5 ng/Ang I/ml/h with glibenclamide, and from 15.0 +/- 4.9 to 30.4 +/- 6.1 ng/Ang I/ml/h with chlorpropamide. The cAMP concentration in the effluent was not changed by the addition of the sulfonylureas. In kidneys perfused with a calcium-free medium, glibenclamide produced a significant increase in renin activity from a basal value of 13.4 +/- 2.1 to a peak value of 30.6 +/- 3.4 ng Ang I/ml/h. These results suggest that sulfonylureas stimulate renin secretion from perfused rat kidneys.

Animals↗

PubMed1985

Comparison of diabetic control in type 2 (non-insulin dependent) diabetic patients treated with different sulphonylureas.

Diabetic control was compared in groups of Type 2 (non-insulin dependent) diabetic patients treated concurrently for 1 year with five different sulphonylurea drugs: chlorpropamide (21), glipizide (24), gliquidone (22), gliclazide (22) and glibenclamide (23). Glycosylated haemoglobin (HbA1) levels decreased in all groups over the first 2 months, but tended to level off or increase thereafter. In a total of 96 patients assessed after 1 year, gliclazide produced normal HbA1 levels in a significantly greater number of patients than chlorpropamide (p = 0.01) and gliquidone (p = 0.038), and glibenclamide was also significantly better than chlorpropamide (p = 0.02). Significant improvements in HbA1 were produced overall in the gliquidone (p less than 0.01), gliclazide (p less than 0.01) and glibenclamide (p less than 0.02) groups and the gliquidone and gliclazide groups were significantly better than the glipizide group (p less than 0.01 in both cases). Only the glibenclamide group had a significant change in weight (p less than 0.05). There may be differences between different sulphonylureas which could be of clinical advantage in certain patients.

Aged↗

PubMed1977

The effects of long-term therapy with oral hypoglycemic agents on the oral glucose tolerance test dynamics in male chemical diabetics.

The effect of fixed doses of oral hypoglycemic agents and placebo (diet alone) on the blood glucose, serum insulin, triglyceride, and cholesterol responses during oral glucose tolerance tests done annually for up to four years' follow-up was studied, in a double-blind manner, in five groups of mild male chemical diabetics. The drugs used were chlorpropamide (100 mg. O.D.), tolbutamide (500 mg. b.i.d.), phenformin (50 mg. O.D.), acetohexamide (250 mg. O.D.), and placebo. Each subject was given an individualized diet aimed at attaining and maintaining ideal weight. Comparison by chi-square analysis between the placebo group and each of the drug groups showed (a) no significant differences with regard to the number of subjects with normal glucose tolerance in each of the tests and (b) no change in the insulin secretion dynamics. Comparison between the initial test and each of the subsequent tests within each group showed (a) a greater number of subjects with normal glucose tolerance in the first follow-up test in the chlorpropamide group only, (b) no change in the insulin secretion dynamics except in the chlorpropamide group, where there was an increased insulin/glucose ratio in the first follow-up test, and (c) no change in the fasting serum triglyceride and cholesterol levels.

Acetohexamide↗

PubMed1982

Sulfonylureas do not affect insulin binding or glycemic control in insulin-dependent diabetics.

Sulfonylureas alone are ineffective in the therapy of insulin-independent diabetes mellitus (IDDM). These agents, however, might serve as an adjunct to insulin treatment if they directly affect insulin binding to its receptor. We studied 11 patients with IDDM to determine whether chlorpropamide acts directly on the insulin receptor and whether it could augment the effect of insulin on glycemic control. Mean tracer insulin binding to both peripheral monocytes and erythrocytes in 11 poorly controlled patients was normal. Optimization of glucose control by continuous subcutaneous insulin infusion for 7--10 days did not alter insulin binding to either cell type. Addition of chlorpropamide, 250--500 mg/day for another 7--10 days did not affect any aspect of insulin binding (tracer binding, number of receptor sites, insulin sensitivity, or affinity) in either cell type. Insulin binding was not changed in one patient after 3 days of 250 mg/day of the drug and in another after 500 mg/day over 3 mo. The sulfonylurea, in addition, provides no additive effect with insulin on blood glucose levels or insulin doses required to maintain euglycemia. We conclude that short-term use of chlorpropamide in addition to insulin in IDDM does not alter insulin binding to circulating monocytes or erythrocytes. In addition, we were unable to show that this agent is a clinically useful adjunct to insulin in IDDM.

Adult↗

PubMed1982

The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes.

In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P less than 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3-6 mo. During therapy, FPG was lower (133 +/- 9 vs. 216 +/- 20 mg/dl, mean +/- SEM; P less than 0.001), glucose production was lower (59.5 +/- 2.0 vs 77.6 +/- 4.9 mg/m2/min; P less than 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P less than 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 +/- 2, treated 21 +/- 2 muU/ml; P= NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P less than 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 +/- 8.1 vs. 7.8 +/- 2.4 mg/m2/min; P less than 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.

Adult↗

PubMed1995

United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.

OBJECTIVE: To assess the relative efficacy of treatments for non-insulin dependent diabetes over three years from diagnosis. DESIGN: Multicentre, randomised, controlled trial allocating patients to treatment with diet alone or additional chlorpropamide, glibenclamide, insulin, or metformin (if obese) to achieve fasting plasma glucose concentrations < or = 6 mmol/l. SETTING: Outpatient diabetic clinics in 15 British hospitals. SUBJECTS: 2520 subjects who, after a three month dietary run in period, had fasting plasma glucose concentrations of 6.1-14.9 mmol/l but no hyperglycaemic symptoms. MAIN OUTCOME MEASURES: Fasting plasma glucose, glycated haemoglobin, and fasting plasma insulin concentrations; body weight; compliance; and hypoglycaemia. RESULTS: Median fasting plasma glucose concentrations were significantly lower at three years in patients allocated to chlorpropamide, glibenclamide, or insulin rather than diet alone (7.0, 7.6, 7.4, and 9.0 mmol/l respectively; P < 0.001) with lower mean glycated haemoglobin values (6.8%, 6.9%, 7.0%, and 7.6%, respectively; P < 0.001). Mean body weight increased significantly with chlorpropamide, glibenclamide, and insulin but not diet (by 3.5, 4.8, 4.8, and 1.7 kg; P < 0.001). A similar pattern was seen for mean fasting plasma insulin concentration (by 0.9, 1.2, 2.4, and -0.1 mU/l; P < 0.001). In obese subjects metformin was as effective as the other drugs with no change in mean body weight and significant reduction in mean fasting plasma insulin concentration (-2.5 mU/l; P < 0.001). More hypoglycaemic episodes occurred with sulphonylurea or insulin than with diet or metformin. CONCLUSION: The drugs had similar glucose lowering efficacy, although most patients remained hyperglycaemic. Long term follow up is required to determine the risk-benefit ratio of the glycaemic improvement, side effects, changes in body weight, and plasma insulin concentration.

Adult↗

PubMed2004

Evaluation of the analgesic, anti-inflammatory and anti-diabetic properties of Sclerocarya birrea (A. Rich.) Hochst. stem-bark aqueous extract in mice and rats.

In order to appraise some of the ethnomedical uses of Sclerocarya birrea (A. Rich.) Hochst., subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae], the present study was undertaken to investigate the analgesic, anti-inflammatory and anti-diabetic properties of the plant's stem-bark aqueous extract in experimental models of pain, inflammation and diabetes mellitus. The analgesic effect of Sclerocarya birrea stem-bark aqueous extract was evaluated in mice, while its anti-inflammatory and anti-diabetic effects were investigated in rats. Diclofenac (DIC, 100 mg/kg p. o.) and chlorpropamide (250 mg/kg p. o.) were used respectively as reference analgesic, anti-inflammatory and anti-diabetic agents for comparison. Like diclofenac (DIC, 100 mg/kg p. o.), Sclerocarya birrea stem-bark aqueous extract (SBE, 100-800 mg/kg p. o.) produced dose-dependent, significant protection (p < 0.05-0.001) against electrical heat-induced pain. The plant extract (SBE, 25-800 mg/kg p. o.) also produced dose- and time-related, sustained and significant reductions (p < 0.05-0.001) in the fresh egg albumin-induced acute inflammation of the rat hind paw oedema. However, the analgesic and anti-inflammatory effects of the plant's extract were found to be approximately 10-15 times less than that of diclofenac. In one set of experiments involving hypoglycaemic/antidiabetic evaluation of the plant's extract, graded doses of Sclerocarya birrea stem-bark aqueous extract (SBE, 25-800 mg/kg p. o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant's aqueous extract (SBE, 800 mg/kg p. o.) was used. The hypoglycaemic effect of this single dose of Sclerocarya birrea stem-bark aqueous extract (SBE, 800 mg/kg p. o.) was compared with that of chlorpropamide (250 mg/kg p. o.) in both fasted normal and fasted streptozotocin (STZ)-treated diabetic rats. Following acute treatment, relatively moderate to high doses of Sclerocarya birrea stem-bark aqueous extract (SBE, 25-800 mg/kg p. o.) produced dose-dependent, significant reductions (p < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p. o.) also produced significant reductions (p < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administration of the single dose of Sclerocarya birrea stem-bark aqueous extract (SBE, 800 mg/kg p. o.) significantly reduced (p < 0.01-0.001) the blood glucose levels of both fasted normal (normoglycaemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that Sclerocarya birrea stem-bark aqueous extract possesses analgesic, anti-inflammatory and hypoglycaemic properties. These experimental findings lend pharmacological support to the suggested folkloric uses of the plant's stem-bark in the management and/or control of pain, inflammatory conditions, and adult-onset, type-2 diabetes mellitus in some communities of South Africa.

Anacardiaceae↗

PubMed1994

Latent alkyl isocyanates as inhibitors of aldehyde dehydrogenase in vivo.

On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allylchlorpropamide 3 was, as expected, a potent inhibitor of hepatic AlDH in rats, as indicated by the 4-fold increase in the levels of ethanol-derived blood acetaldehyde relative to that elicited by chlorpropamide itself. Closely following in activity in decreasing order were N3-(n-propylcarbamoyl)uracil (7),N-(n-propylcarbamoyl)saccharin (6), and the S-(n-propylcarbamoyl) derivative (9) of benzyl mercaptan. However, two hydantoin derivatives, 5 and 8, were totally inactive in inhibiting AlDH in vivo. A prodrug of N1-ethylchlorpropamide, viz., its N3-trifluoroacetyl derivative (4b), was a good in vivo inhibitor of AlDH, mimicking the activity of the parent N1-ethylchlorpropamide. These results suggest that latent alkyl isocyanates are inhibitors of AlDH, giving further support to the hypothesis that the inhibition of AlDH in vivo by the hypoglycemic agent chlorpropamide may be due to the release of n-propyl isocyanate following metabolic bioactivation.

Aldehyde Dehydrogenase↗

PubMed2004

ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes.

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.

Adolescent↗

PubMed1996

Individual sulfonylureas and serious hypoglycemia in older people.

OBJECTIVE: To compare the risk of serious hypoglycemia associated with the use of individual sulfonylureas in older people. DESIGN: A retrospective cohort study. SETTING: The Tennessee Medicaid Program. PATIENTS: A total of 13,963 Medicaid enrollees, aged 65 years or older, who were prescribed one of six sulfonylureas from 1985 to 1989. MAIN OUTCOME MEASURE: Hospitalization, emergency room admission, or death associated with neuroglycopenic or autonomic symptoms, myocardial infarction, stroke, or injury, with a concomitant blood glucose determination of less than 2.8 mmol/L (50 mg/dL). RESULTS: We identified 255 persons with a first episode of serious hypoglycemia during 20,715 person-years of sulfonylurea use. The crude rate (per 1000 person-years) of serious hypoglycemia was highest in glyburide users, 16.6 (95% confidence interval [CI], 13.2 to 19.9 and lowest among users of tolbutamide, 3.5 (95% CI, 1.2 to 5.9). Users of tolbutamide, tolazamide, and glipizide had lower risks of serious hypoglycemia than users of chlorpropamide, whereas the risk of serious hypoglycemia among glyburide users did not differ from that of chlorpropamide users. Among second generation sulfonylureas, the adjusted relative risk of severe hypoglycemia among glyburide users, compared with glipizide users, was 1.9 (95% CI, 1.2 to 2.9). An increased risk of serious hypoglycemia associated with use of glyburide compared with glipizide occurred in all strata, including those defined by gender, race, nursing home residence, dose, and duration of use. CONCLUSIONS: Significant differences in risk of serious hypoglycemia were observed among users of individual agents. This may be explained by duration, timing, or potency of hypoglycemic action. These data confirm previous findings that chlorpropamide use is associated with high risk of hypoglycemia and indicate that among second generation sulfonylureas, glipizide is less associated with hypoglycemia than is glyburide. More information comparing the effectiveness of glycemic control among individual sulfonylureas is needed to assist prescribers in selecting a specific agent for use in clinical practice.

Aged↗

PubMed2000

Comparative tolerability of sulphonylureas in diabetes mellitus.

The sulphonylurea drugs have been the mainstay of oral treatment for patients with diabetes mellitus since they were introduced. In general, they are well tolerated, with a low incidence of adverse effects, although there are some differences between the drugs in the incidence of hypoglycaemia. Over the years, the drugs causing the most problems with hypoglycaemia have been chlorpropamide and glibenclamide (glyburide), although this is a potential problem with all sulphonylureas because of their action on the pancreatic beta cell, stimulating insulin release. Other specific problems have been reported with chlorpropamide that occur only rarely, if at all, with other sulphonylureas. Hyponatraemia secondary to inappropriate antidiuretic hormone activity, and increased flushing following the ingestion of alcohol, have been well described. The progressive beta cell failure with time results in eventual loss of efficacy, as these agents depend on a functioning beta cell and are ineffective in the absence of insulin-producing capacity. Differences in this secondary failure rate have been reported, with chlorpropamide and gliclazide having lower failure rates than glibenclamide or glipizide. The reasons for this are unclear, but the more abnormal pattern of insulin release produced by glibenclamide may be partly responsible and, indeed, may explain the increased risk of hypoglycaemia with this agent. Previously reported increased mortality associated with tolbutamide therapy has not been substantiated, and more recent data have shown no increased mortality from sulphonylurea treatment. Indeed, benefit from glycaemic control, regardless of the agent used--insulin or sulphonylurea--was reported by the United Kingdom Prospective Diabetes Study. Nevertheless, there is still ongoing controversy in view of the experimental evidence, mainly from animal studies, of potential adverse effects on the heart from sulphonylureas, but these are difficult to extrapolate into clinical situations. Most of these studies have been carried out with glibenclamide, which makes comparison of possible risk difficult. Other cardiovascular risk factors may be modified by gliclazide, which seems unique among the sulphonylureas in this respect. Its reported haemobiological and free radical scavenging activity probably resides in the azabicyclo-octyl ring structure in the side chain. Reduced progression or improvement in retinopathy has been reported in comparative trials with other sulphonylureas, and the effect is unrelated to improvements in glycaemia. There are differences between the sulphonylureas in some adverse effects, risk of hypoglycaemia, failure rates and actions on vascular risk factors. As a group of drugs, they are very well tolerated, but differences in overall tolerability can be identified.

Diabetes Mellitus↗

PubMed2002

Trends in oral antihyperglycemic and insulin use in the Nova Scotia senior population (1993-1999).

Trends in prescribing patterns of insulin and oral antihyperglycemic drugs for Nova Scotia seniors pharmacare beneficiaries were examined from April 1, 1993 to March 31, 2000 and evaluated relative to published guidelines. The number of patients, prescriptions, and drug costs for oral antihyperglycemic drugs and insulins were calculated. The source of insulin was examined subsequent to the marketing of human insulin in 1993. The percentage of patients using human insulin increased from 66% in 1993 to 96% in 1995, and beef and pork insulin use decreased from 38% in 1993 to 19% in 1995. First generation sulfonylureas decreased between 1993 and 1999; chlorpropamide decreased from 23% to 7% of antihyperglycemic users, and tolbutamide decreased from 4% to 1%. Among second-generation sulfonyl-ureas, glyburide remained frequently used with 59% of antihyperglycemic users in 1999, while gliclazide increased in use from 2% to 22% between 1993 and 1999. Metformin, a biguanide, increased in use from 29% to 37% of antihyperglycemic users. Acarabose having been introduced to the market later, increased in use from 1% to 5% between 1996 and 1999. Once human insulin became available, patients were rapidly transferred from animal to human insulin. Chlorpropamide remained widely used despite safety concerns for use in the elderly. Glyburide was the most frequently prescribed oral antihyperglycemic agent. Recently raised concerns about its safety in patients with renal disease require follow-up. Further work is needed to determine the reasons for slow uptake of recommendations related to chlorpropamide and the effect of switches to human insulin and newer oral antihyperglycemics on patient outcomes and health care costs.

Administration, Oral↗

PubMed1986

[The relatively frequent incidence of severe sulfonylurea-induced hypoglycemia in the last 25 years in Switzerland. Results of 2 surveys in Switzerland in 1969 and 1984].

In 1969 and 1984 all emergency wards in Switzerland were asked to report on the incidence of severe episodes of hypoglycemia (HE) during treatment with sulfonylureas. Each of the two surveys referred to a ten-year period (period A 1960-1969, period B 1975-1984). The number of HE reported was 78 for period A and 116 for period B. The number of diabetics treated with sulfonylurea preparations was established on the basis of tablet consumption, which amounted to 35,000 in period A and 47,500 in period B. The incidence of hypoglycemia in each period was comparable (period A 0.22, and period B 0.24 per 1000 patient years), but differed with regard to the sulfonylurea preparations used. In period A hypoglycemic episodes occurred more frequently under chlorpropamide than under tolbutamide and carbutamide. In period B the incidence of episodes under chlorpropamide and glibenclamide was comparable, but was significantly higher than under tolbutamide and glibornuride. The risk of hypoglycemia occurring is thus significantly higher under glibenclamide and chlorpropamide than under glibornuride and tolbutamide. 6.5% of HE were fatal in period A, compared with 4.3% in period B. Advanced age proved to be a risk factor in HE: 77% of patients with HE were over 69 years of age, whereas only 50% of all diabetics treated with sulfonylurea preparations were in this age group. Further risk factors were impaired renal function (21%) and possible drug interactions (27%). There was less likelihood of recurrence of a hypoglycemic episode in period B than in period A.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Alcohol tolerance in patients with non-insulin-dependent (type 2) diabetes treated with sulphonylurea derivatives.

The oral ethanol loading test (0.5 g/kg body mass given as 40% solution) was carried out in 5 groups, each of 10 out-patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide (CAS 64-77-7) 0.5 t.i.d., chlorpropamide (CAS 94-20-2) 0.5 once daily morning, glibornuride (CAS 26944-48-9) 0.025 t.i.d., glibenclamide (CAS 10238-21-8) 0.005 t.i.d. and glipizide (CAS 29094-61-9) 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentrations of ethanol, acetaldehyde, pyruvate, lactate, hydrocarbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗

PubMed1993

[Alcohol tolerance in patients with non-insulin-dependent diabetes (type 2) treated orally with drugs--derivatives of sulphonylurea].

The oral ethanol loading test (0.5 g per kg b.m. given as 40% solution) was carried out in 5 groups, each of 10 patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide 0.5 t.i.d., chlorpropamide 0.5 once daily morning, glibornuride 0.025 t.i.d, glibenclamide 0.005 t.i.d. and glipizide 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentration of ethanol, acetaldehyde, pyruvate, lactate, carbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism. All studied drugs intensified to a similar degree the alcohol-induced hypoglycaemia, but had no significant effect on the decrease of blood pyruvate level neither on the increase of blood lactate level. They didn't change the post-alcohol decrease of blood bicarbonate and pH, and didn't modify the behaviour of partial gas pressure. There was also no difference between pooled groups of patients with positive and negative thermographic reaction with respect to family history of diabetes and frequency and intensity of vascular complications. It is concluded that in patients with non-insulin-dependent (type 2) diabetes the second generation sulphonylurea derivatives are associated with lower risk of alcohol intolerance in case of its incidental ingestion in small amounts. The hypothesis of association of positive thermographic reaction to alcohol during treatment with sulphonylurea derivatives with more frequent occurrence of diabetes in family members and lower tendency to vascular complications was not confirmed.

Adult↗

PubMed1980

Acute lymphoblastic leukemia. Association with vasopressin-responsive diabetes insipidus.

A rare case of acute lymphoblastic leukemia presenting with vasopressin-responsive diabetes insipidus (DI) is reported. The patient presented with polydypsia and polyuria of 9 L/day. Findings from special investigations of the CNS, including brain scan, computerized tomographic scan, EEG, and lumbar puncture were within normal limits. The patient's condition improved substantially after receiving vasopressin injections and later chlorpropamide. The incidence and underlying mechanism of this rare complication of acute leukemia are reviewed, and the response of DI to chlorpropamide is discussed briefly. In this patient it is presumed that the DI was caused by leukemic infiltration of the supraopticohypophyseal tract, posterior pituitary, or hypothalamus.

Adult↗

PubMed1976

Assay of sulfonylureas in human plasma by high-performance liquid chromatography.

A sensitive and specific high-performance liquid chromatographic procedure for the determination of chlorpropamide or tolbutamide in plasma in the presence of their metabolites is described. The ether extract of acidified plasma is redissolved in the mobile phase, 17% acetonitrile in 0.05 M aqueous ammonium formate, and chromatographed on a reverse-phase column on a high-performance liquid chromatograph fitted with a UV absorbance detector. Quantitation of plasma samples containing less than 0.5 mug/ml of chlorpropamide and 5 mug/ml of tolbutamide is reported, using these drugs as mutual internal standards. The retention times of the metabolites are such that they do not interfere in the procedure. The assay method was tested in a human volunteer with both drugs and found suitable for single-dose pharmacokinetic studies.

Chlorpropamide↗

PubMed2005

Experimental antihyperglycemic effect of diterpenoids of llareta Azorella compacta (Umbelliferae) Phil in rats.

Aqueous or ethanol infusions of Azorella compacta (llareta) in common with many other plants have been used as antidiabetic in the popular medicine in the altiplanic region of Chile. In order to determine if the diterpenic compounds chemically elucidated and isolated from this plant are responsible for this effect, streptozotocin diabetic rats (507 +/- 67 mg/mL glucose) were injected with two injections of diterpenic compounds mulinolic acid, azorellanol, and mulin-11,13-dien-20-oic acid at 180 mg/mL. Glycemia of animals treated with mulinolic acid and azorellanol was decreased to 243 +/- 2 and 247 +/- 14 mg/mL respectively, values very close to those reached by chlorpropamide injection used in controls. After 3 h treatment with mulin-11,13-dien-20-oic acid no effect was detected. The blood serum insulin in diabetic rats (146 +/- 58 pg/mL) was lower than in control rats. After injection of azorellanol, insulin was elevated to 247 +/- 23 pg/mL but with mulinolic acid, insulin was not changed. The antihyperglycemic effect of these compounds may explain the effectiveness of llareta in popular medicine. Because of the similarity to the hypoglycemic medication chlorpropamide, azorellanol could be acting on the beta cells of pancreatic islets, while mulinolic acid may act upon glucose utilization or production in the liver.

Animals↗