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PubMed1978

Intramuscular or intravenous glucagon for sulphonylurea hypoglycaemia?

Because of the differing opinions on the value of glucagon and the best way of administering it in severe hypoglycaemia induced by sulphonylurea drugs, experiments were conducted on normal subjects, and in diabetic patients before and during treatment with chlorpropamide. In all subjects glucagon raised blood sugar concentrations, and produced a greater and more prolonged increase in blood glucose concentrations when given intramuscularly than when given intravenously. Hypoglycaemia did not occur in any subject.

Adult↗
PubMed1978

Early arterial lesions in maturity onset diabetes mellitus detected by an ultrasonic technique.

Using an ultrasonic technique preclinical atheroma was studied in maturity onset diabetics. The elasticity of the leg arteries was measured as the elastic modulus in 32 patients and a normal range was established in 13 controls. The elastic modulus was higher (i.e. the arteries were stiffer) in diabetics than controls and this was associated with a higher mean blood pressure in the diabetics. Nine phenformin and 10 chlorpropamide treated diabetics had evidence of more severe arterial disease than 13 diet treated patients. This could not be accounted for by other factors known to influence arterial disease.

Arteriosclerosis↗
PubMed1976

Effects of sulfonylurea therapy on insulin binding to mononuclear leukocytes of diabetic patients.

We have studied insulin binding to circulating mononuclear cells obtained from 31 untreated, adult, nonobese, nonketotic diabetic subjects with fasting hyperglycemia, 40 normal subjects and four patients with fasting hyperglycemia secondary to chronic pancreatitis. Our results show that the mononuclear cells of untreated adult diabetic patients have a decreased ability to bind insulin when they are compared to cells obtained from normal subjects. The binding affinity for insulin was the same for both groups of cells, and the decreased binding could be accounted for by a 45 per cent decrease in the number of available insulin receptor sites per cell. Treatment with chlorpropamide (one to three months, average dose equals 375 mg/day) was associated with a marked reduction in hyperglycemia and an increase toward normal in insulin binding to mononuclear cells. In conclusion, (1) mononuclear cells from nonobese, nonketotic, untreated adult diabetic patients with fasting hyperglycemia demonstrate a decreased ability to bind insulin due to decreased numbers of insulin receptors per cell; (2) treatment with an oral hypoglycemic agent is associated with a diminution in hyperglycemia and a return toward normal of insulin binding.

Adult↗
PubMed1983

Clinical pharmacology of glipizide.

The clinical pharmacology of glipizide and other sulfonylureas is briefly reviewed. Reevaluation of the University Group Diabetes Program data suggests that sulfonylureas do not increase cardiovascular mortality. Instead, a long-term study of subjects with impaired glucose tolerance indicates that sulfonylureas reduce the frequency of cardiovascular morbidity and can postpone or even prevent the development of impaired glucose tolerance to manifest diabetes. It is likely that all sulfonylureas have the same principal mechanism(s) of action but that they differ in potency and pharmacokinetics, resulting in considerable clinical differences. Thus, glipizide and glibenclamide (glyburide) are much more potent than tolbutamide and chlorpropamide. Glipizide has the most rapid absorption and onset of action, as well as the shortest half-life and effect-duration; hence the risk of long-lasting hypoglycemia is minute. Glipizide has complete bioavailability, and its blood glucose-lowering effect is improved when it is given before breakfast. Glipizide may be administered once daily without loss of therapeutic efficacy.

Biological Availability↗
PubMed1994

Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer.

OBJECTIVE: This study compares the human placental transport of glyburide, glipizide, chlorpropamide, and tolbutamide. STUDY DESIGN: The recirculating single cotyledon human placenta model tested maternal-to-fetal transport in term placentas perfused immediately after delivery. Drug levels were measured by high-performance liquid chromatography and liquid scintillation spectrometry, and transport rates were calculated by comparing maternal and fetal concentrations. RESULTS: The transport of these substances differed significantly over a tenfold range (analysis of variance, p < 0.0008). A significant association exists by multiple linear regression between drug transfer and molecular weight, dissociation constant, and the octanol-water partition coefficient (R2 = 0.91, p < 0.0001). CONCLUSIONS: There is significant variability in human placental transfer rates of the oral hypoglycemics, which strongly correlates with molecular properties. These data suggest that less fetal exposure may occur with second-generation sulfonylureas and anticipate that regression models may be useful in selecting agents that minimize placental transport to the fetus.

Administration, Oral↗
PubMed1988

Opiate-prostaglandin interactions in the regulation of insulin secretion from rat islets of Langerhans in vitro.

The inadequate insulin secretory response to glucose stimulation in non-insulin dependent diabetes has been attributed to many factors including high PGE2 levels blunting the secretory response, and to the existence of inhibitory opiate activity in vivo. The purpose of the present work was to see if there was a connection between these two independent theories. Radioimmunoassayable PGE2 in islets of Langerhans was found to be proportional to islet number and protein content and was typically 4 to 5pg/micrograms islet protein. Indomethacin (2.8 X 10(-5) M), sodium salicylate (1.25 X 10(-3) M) and chlorpropamide (7.2 X 10(-5) M) all lowered islet PGE2 levels and stimulated insulin release in vitro. Dynorphin (1-13), stimulated insulin release at a concentration of 6 X 10(-9) M, while lowering islet PGE2. Conversely, at a higher concentration, (6 X 10(-7) M), dynorphin had no stimulatory effect on insulin secretion and did not lower PGE2 levels in islets or in the incubation media. The stimulatory effects of dynorphin and sodium salicylate on insulin secretion were blocked by exogenous PGE2 (10(-5) M). PGE2 at a lower concentration (10(-9) M) did not exert any inhibitory effect on dynorphin- or sodium salicylate-induced insulin release. This concentration of exogenous PGE2 stimulated insulin release in the presence of 6mM glucose. Results from these experiments suggest that since an opioid peptide can lower endogenous PGE2 production in islets and since the stimulatory effects of the opioid peptide are reversed by exogenous PGE2 there may be interactions between these two modulators of insulin secretion.

Animals↗
PubMed1976

In vivo cytogenetic activity of sulphonylurea drugs in man.

A cytogenetic investigation of diabetic patients undergoing treatment with sulphonylurea drugs, particularly chlorpropamide, shows that significantly more chromatid aberrations and chromosome exchange aberrations are present in the lymphocytes of these patients compared with controls. This is taken as evidence of possible mutagenic activity by these drugs, although the possibility cannot be ruled out that the diabetic state itself is a contributory factor.

Adult↗
PubMed1991

Efficacy of gliclazide in comparison with other sulphonylureas in the treatment of NIDDM.

Three studies were performed to assess the efficacy of various sulphonylureas in the management of diet-failed NIDDM patients. In the first study, 224 patients inadequately controlled by diet alone or with oral hypoglycaemics received gliclazide in addition to diet or in place of existing drugs for three months. The dosage was adjusted to obtain adequate control or up to the maximum recommended dosage. Good glycaemic control was achieved in 65% of patients. Conversion from other oral hypoglycaemics to gliclazide led to an improvement in control except in cases previously treated with glibenclamide. In the second study, diabetic control was compared in 112 NIDDM patients treated concurrently for one year with chlorpropamide, glipizide, gliquidone, glibenclamide or gliclazide. On the basis of HbA1 levels, the best results were obtained with glibenclamide and gliclazide, leading to normal HbA1 levels in 74% and 80% of patients, respectively. In the third study, secondary failure rates were assessed in 248 NIDDM patients treated for five years with gliclazide, glibenclamide or glipizide. Gliclazide had the lowest secondary failure rate (7%) and was significantly better than glipizide (25.6% failures in five years), but the difference relative to glibenclamide (17.9%) just failed to reach the threshold of significance. The results of these studies show that gliclazide is a potent hypoglycaemic agent which compares favourably with others of its type. It has a low incidence of side effects, few problems with hypoglycaemia, and retains its efficacy longer than other sulphonylureas. Gliclazide may therefore be considered a first choice for the therapy of diet-failed NIDDM patients.

Blood Glucose↗
PubMed1983

Prostaglandins in alcohol intolerance and hangover.

The effects of alcohol on the formation of prostaglandins (PGs) and the blockade of some actions of alcohol by PG-inhibitors suggest that PGs may be involved in the action of ethyl alcohol. Regulation of lipid peroxidation and synthesis and release of precursor fatty acids may affect the overall formation of PGs. The effect of alcohol may be qualitative for several reasons: (i) the possible preferred formation of 1-series of PGs would mean an important qualitative change in PG-impact in some tissues; (ii) inhibition of PG-metabolism in the lung might affect mostly the plasma levels of PGE; (iii) a selective blockade of certain PG-effects and a potentiation of some others gives rise to qualitative changes in the actions of PGs. PGs may be involved in several acute or short-term reactions caused by alcohol. Chlorpropamide-alcohol flush, alcohol intolerance and hangover are effectively alleviated by a prophylactic use of PG-inhibitors. Speculatively PGs might also be involved in migraine attacks provoked by alcohol and in antabuse in reaction. The roles of PGs in the regulation of vascular tone, water and electrolyte balance as well as in certain secretory and metabolic processes may be important in the generation of alcohol related reactions.

Alcoholic Intoxication↗
PubMed1986

Urinary diluting capacity in elderly diabetic subjects.

Urinary concentrating ability declines with normal human aging but diluting capacity has been less well studied as a function of age. We studied free water clearance (CH2O) in a group of Type II diabetic patients, aged 47 to 70 years. Conventional water load testing in sulfonylurea-treated diabetic patients revealed preservation of diluting capacity (ability to achieve Uosm less than 100 mOsm/kg) in subjects greater than 60 years of age. Tolazamide permitted expression of normal CH2O; chlorpropamide administration predictably reduced CH2O relative to tolazamide by 58% in subjects greater than 60 years. Free water clearance (CH2O) and glomerular filtration rate (GFR) were comparable in elderly subjects (greater than 60 years) and those less than or equal to 60 years. Normal CH2O in these diabetic patients was explained by persistently normal GFR in the study group. Osmolar clearance (Cosm) was insignificantly lower in diabetics greater than 60 years. Thus, a fall in CH2O in elderly diabetic patients is not a factor contributing to clinical hypoosmolar states encountered in this population.

Aged↗
PubMed1990

The individual over time: time series applications in health care research.

This paper presents a summary and a brief theoretical introduction to time series ARIMA modeling of single subject data. Time series, a statistical technique that may be appropriate when data are measured repeatedly and at nearly equal intervals of time, has potential research applications in the study of chronic diseases such as diabetes, hypertension, and herpes simplex. Both intervention models and multivariate models are covered, with examples illustrating the utility of time series techniques in chronic disease research. Time series modeling of a subject with diabetes before and after being placed on a regimen of chlorpropamide is used to demonstrate the potential of intervention analysis. Multivariate time series techniques are illustrated by modeling the relationship between exercise and blood glucose, and by modelling the relationship between psychosocial distress and lymphocyte subsets of the cellular immune system.

Blood Glucose↗
PubMed2005

Utilization of pure nuclear quadrupole resonance spectroscopy for the study of pharmaceutical crystal forms.

Solid-state physical characterization of a pharmaceutical substance is necessary for successful development and approval of the final product. Different physical analytical techniques are available to do so: X-ray diffraction (XRD), IR, Raman, DSC, TG and NMR. Moreover, all of them detect the presence of excipients perturbing the analysis of the pure substance in low doses. In order to study polymorphism and pseudo polymorphism of drug, this paper introduces possible applications of pure nuclear quadrupole resonance, as a non-destructive technique in qualitative and quantitative approaches. Chlorpropamide and diclofenac sodium were used as examples. Unlike the mentioned techniques, the nuclear quadrupole resonance (NQR) signal of pharmaceutical compounds is not perturbed by the presence of solid excipient or other substances unless they possess resonance frequencies in the same frequency range of the compound studied.

Chlorpropamide↗
PubMed1985

Review of glyburide after one year on the market.

After one year on the American market, glyburide, a second-generation sulfonylurea, seems well accepted by physicians. If the hyperglycemia of patients with type II diabetes mellitus is not corrected by diet and exercise, glyburide can be used as adjunctive therapy. The drug is comparable in efficacy to the first-generation sulfonylurea chlorpropamide, but it has fewer reported side effects. Additionally, glyburide does not appear to interact with other medications and is well absorbed from the gastrointestinal tract. Although the drug had been reported to produce hypoglycemia, increased clinical experience--along with use of judicious dosages in appropriate patients--has decreased the incidence of hypoglycemia. Although still in the investigational stage, combination insulin/glyburide therapy may also benefit subgroups of type II diabetic patients. Glyburide is a useful and rational addition to therapy in properly selected patients with type II diabetes mellitus.

Chlorpropamide↗
PubMed1982

Radioimmunoassay of vasopressin in familial cental diabetes insipidus.

We examined plasma arginine-vasopressin concentrations by radioimmunoassay in two brothers, aged 6 and 7.5 years, with familial central diabetes insipidus inherited as an autosomal dominant trait. Plasma AVP was measured in relation to increasing plasma osmolality induced by water deprivation and hypertonic saline infusion. The brother with the more severe urinary concentrating defect had no detectable AVP when his plasma osmolality was as high as 306 mOsm/kg; the other brother had detectable but clearly subnormal AVP concentrations. The one brother tested had an apparently normal end-organ response to exogenous vasopressin. Chlorpropamide had a significant antidiuretic effect in the brother with detectable AVP levels, and a lesser effect in the other brother . Our findings suggest that intrafamilial variation in the severity of congenital DI is related to the degree of vasopressin deficiency.

Arginine Vasopressin↗
PubMed1985

Sulfonylurea stimulates liver fructose-2,6-bisphosphate formation in proportion to its hypoglycemic action.

The effects of 5 sulfonylureas on fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated perfused rat liver were examined. All sulfonylureas examined stimulated dose-dependent formation of the activator in a limited range of the concentration. A maximum effect on F-2,6-P2 formation was observed at the concentration of 10(-3) M of tolbutamide or chlorpropamide, at 10(-4) M of gliclazide or acetohexamide and at 10(-6) M of glibenclamide. These concentrations of sulfonylurea correspond with those in blood when therapeutical doses of the drug are administered orally. Sulfonamide and biguanide did not show any stimulatory effect on F-2,6-P2 level. The results demonstrate that stimulation of liver F-2,6-P2 formation is a common characteristic of sulfonylureas and suggest strongly that one of the extrapancreatic actions of sulfonylurea is stimulation of F-2,6-P2 formation followed by enhancement of glycolysis and inhibition of gluconeogenesis in the liver.

Acetohexamide↗
PubMed2003

Effect of the aqueous extract of Chrysanthellum indicum on calcium mobilization and activation of rat portal vein.

The effects of the aqueous extract of Chrysanthellum indicum (CI) on calcium activation and mobilization were studied using the rat portal vein. The extract caused a concentration-dependent contraction of the portal vein. KCl (80 mM), norepinephrine (NA, 10(-6)M) and CI (4 mg/ml) evoked sustained contraction of the portal vein. In Ca-free medium (with EGTA) the contractions evoked by these agents were reduced significantly. The times-to-peak of KCl, NA and CI were similar -in normal PSS, but in Ca-free medium the times-to-peak for KCl and CI were greatly increased. The contractions induced by CI were not inhibited by chlorpropamide and prazosin, but were blocked by verapamil. The data obtained suggest that the aqueous extract of CI utilizes extracellular calcium pools to bring about contractile response and this effect might be mediated through the activation of potential-sensitive channels.

Animals↗
PubMed1997

Rates of hypoglycemia in users of sulfonylureas.

OBJECTIVE: To identify the demographic and clinical characteristics of sulfonylurea users. To assess the risk of hypoglycemia in patients treated with sulfonylureas in clinical practice, and to characterize the risk in relation to the different drugs used. RESEARCH DESIGN AND METHODS: A cohort of 33,243 sulfonylurea users chosen from 719 clinical practices in the United Kingdom were identified through the VAMP-Research database. Information on demographic characteristics, medical diagnoses and use of medical services was obtained through the computerized records. For a stratified sample of 500 patients, general practioners completed a structured questionnaire on the duration, treatment, and complications of diabetes mellitus, obesity, alcohol use, and smoking history. Patients with a diagnosis of hypoglycemia, as recorded in the database within a time-window of a sulfonylurea prescription, were identified. Incidence rates per person-year of sulfonylurea therapy were estimated. RESULTS: Other than a longer duration of diabetes in users of chlorpropamide, no differences were observed among users of different sulfonylurea agents with respect to diabetic complications, adequacy of diabetic control, obesity, smoking, and excessive alcohol consumption. A diagnosis of hypoglycemia during sulfonylurea therapy was recorded in 605 people over 34,052 person-years of sulfonylurea therapy, which converted into an annual risk of 1.8%. The risk in glibenclamide users was higher than in users of other types of sulfonylureas uses. Duration of therapy, concomitant use of insulin, sulfonylurea-potentiating or antagonizing and concomitant use of beta-blockers were predictive of the risk of developing hypoglycemia. DISCUSSION: Drug use patterns showed comparability among users of different sulfonylurea agents. Our findings suggest that the rate of diagnosis of hypoglycemia made by physicians is higher for glibenclamide than for other sulfonylureas. An epidemiological study with objectively diagnosed hypoglycemia should be undertaken to confirm these results.

Adult↗