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Bovine lens aldehyde dehydrogenase. Purification and preliminary characterization.

Cytoplasmic aldehyde dehydrogenase from bovine lens was purified to apparent homogeneity by using ion-exchange and affinity chromatography. Sedimentation-equilibrium ultracentrifugation, gel-filtration chromatography and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis show that the enzyme is a dimer of Mr 114000, with subunits of Mr 57000. The enzyme does not dissociate into monomers in the presence of Ca2+ or Mg2+. The enzyme has a pI of 5.0, an activation energy of 35.1kJ/mmol and a pK value of 8.6 with acetaldehyde as substrate. The enzyme is a prolate ellipsoid with a Stokes radius of 4nm. Progesterone, deoxycorticosterone and chlorpropamide inhibited enzyme activity, and this inhibition may play a role in cataract formation in patients maintained on systemic corticosteroids and in tablet-dependent diabetics.

Aldehyde Dehydrogenase↗

Case report. Computed tomography of the brain in severe hypoglycaemia.

Computed tomographic (CT) findings in a case of extreme hypoglycaemia induced by an overdose of chlorpropamide are described. Brain lesions tend to be preferentially localized along the boundary zones ("watersheds") between the territories of the main cerebral arteries. In our case, generalized brain damage occurred during severe hypoglycaemic coma. Neuropathological changes in this condition have been the subject of previous studies in experimental animals. Computed tomography allows follow-up studies of the human brain damaged by hypoglycaemic coma. Abnormalities revealed by CT probably represent reparative tissue reactions that indirectly reflect the extent of neuronal destruction.

Adolescent↗

A screening test for detecting sulfonylureas in plasma.

Hypoglycemia induced by surreptitious sulfonylurea ingestion can be difficult to distinguish from an insulin-secreting tumor. We describe a technique for detecting most of the common sulfonylurea drugs in plasma. After preliminary acidification, and extraction in ether, the residue is reconstituted and injected onto a Versapack high-performance liquid chromatography column. Detection is at 230 nm. This procedure gives good separation of chlorpropamide, glibenclamide, gliclazide, glipizide, and tolbutamide. Results are semiquantitative but the sensitivity of the assay is sufficient to detect and identify clinically active concentrations of all five drugs. It is a rapid and reliable screening test. Four representative case histories are reported in which the screen proved to be of diagnostic value.

Aged↗

Erythrocyte aldehyde dehydrogenase and disulfiram-like side effects of hypoglycemics and antianginals.

Disulfiram-like responses to various drug therapies are caused by elevated ethnol-derived blood acetaldehyde concentrations resulting from drug-induced inhibition of aldehyde dehydrogenase enzymes. We have found that the nitrate ester antianginal drugs, isosorbide dinitrate and nitroglycerin, are potent inhibitors of human erythrocyte aldehyde dehydrogenase. To further characterize this drug-induced enzyme inhibition, erythrocyte aldehyde dehydrogenase activities were measured in patients undergoing therapy with nitrate ester antianginals (isosorbide dinitrate and nitroglycerin) and sulfonylurea hypoglycemics (chlorpropamide and tolazamide). The erythrocyte enzyme was decreased by approximately 25% in sulfonylurea-treated patients, whereas in the nitrate ester-treated patients, an 88% inhibition was observed. The minimal enzyme inhibition in the sulfonylurea-treated group was unexpected because these therapies have well-documented disulfiram-like side effects. This weak inhibition contrasted with the severe inhibition observed in the nitrate ester-treated group where the disulfiram-like side effects are not considered a serious clinical problem. This apparent anomaly was attributed to differences in inhibition of the erythrocyte and liver aldehyde dehydrogenase by the parent drugs and their hepatic metabolites.

Aldehyde Dehydrogenase↗

Transient neonatal diabetes mellitus in a pair of twins.

The occurrence of transient neonatal diabetes mellitus in male twins with almost identical courses of illness is reported. A trial with chlorpropamide treatment of twin A had no obvious influence on the insulin consumption or on duration of treatment. Very low values of plasma C-peptide and serum proinsulin with no detectable insulin antibodies supports the theory of delayed maturation of the beta-cell.

Chlorpropamide↗

Idiopathic neurogenic diabetes insipidus in a cat.

A 5-year-old, domestic long-haired cat was presented for examination because of polydipsia, polyuria and inappropriate urination of 3 months' duration. Neurogenic diabetes insipidus was diagnosed, based on hyposthenuria with failure to concentrate urine in response to water deprivation and positive response to antidiuretic hormone administration. Treatment with hydrochlorothiazide or chlorpropamide orally gave inadequate antidiuresis, but response to injections of vasopressin tannate in oil was sufficient for satisfactory management.

Administration, Oral↗

Glibenclamide therapy in diabetes mellitus.

In an initial trial of glibenclamide in the treatment of maturity onset diabetes mellitus 28 patients were treated for up to one year and no toxic effects or side-effects were encountered. The hypoglycaemic potency of this drug is such that 5 mg. of glibenclamide corresponds to about 1,500 mg. of tolbutamide and 375 mg. of chlorpropamide.

Adult↗

Long-term infusion of growth hormone release inhibiting hormone in acromegaly: effects on pituitary and pancreatic hormones.

Growth hormone release inhibiting hormone (GH-RIH) was infused at a rate of 1.3 mug/min for 28 hours into four patients with acromegaly, two of whom also had clinical diabetes mellitus. Growth hormone and glucagon were suppressed throughout the infusion though delayed secretion of insulin occurred in association with both meals and an oral glucose load. Glucose tolerance was improved in one diabetic patient who was taking chlorpropamide while the other required much less insulin than usual. Secretion of endogenous thyroid-stimulating hormone was lowered in one euthyroid patient on carbimazole. Luteinizing hormone, follicle-stimulating hormone, ACTH, and prolactin were not affected. Serum somatomedin levels were reduced in one patient. There was a rapid rebound of all the suppressed hormones when the infusions stopped. Longer-acting analogues of GH-RIH will be needed before long-term therapy of acromegaly or diabetes mellitus becomes possible, but such preparations should be available soon for clinical trial.

Acromegaly↗

Longitudinal study of untreated chemical diabetes.

More information is needed about the "natural history" of early diabetes mellitus. A report is presented of the progress over one to nine years of 72 patients who formed the control group of a clinical trial of chlorpropamide and placebo in the management of subclinical diabetes. Most patients showed no deterioration of carbohydrate tolerance, and only four (5.6%) progressed to overt diabetes. The findings of other published series are reviewed. Studies of the effect of treatment of early diabetes must be large scale and long term, and an untreated control group must be included to prevent apparent improvement in carbohydrate tolerance being wrongly attributed to the effect of therapy.

Adult↗

Lactic acidosis due to metformin therapy in a low risk patient.

A 55 year old diabetic women treated with chlorpropamide and metformin for three years presented with acute oliguric renal failure and lactic acidosis from which she died. The plasma metformin level was very high suggesting that the lactic acidosis was caused by the drug. There were no contraindications to metformin therapy and renal function was normal three months previously. This case demonstrates that lactic acidosis can occur as a result of metformin therapy in the absence of pre-existing risk factors.

Acidosis, Lactic↗

Opuntia streptacantha: a coadjutor in the treatment of diabetes mellitus.

This report describes the effect produced by the complementary daily administration of Opuntia streptacantha sap to a diabetic volunteer being under treatment with chlorpropamide. The plant product improved remarkably the general symptomatology of the patient as well as his insulin and glucose blood levels.

Blood Glucose↗

"Essential" hypernatremia due to ineffective osmotic and intact volume regulation of vasopressin secretion.

A physiological explanation for sustained hyperosmolality was sought in a patient with histiocytosis. During 23 days of observation with only sodium intake regulated at 100 mEq daily, elevation (mean 310 mOsm/kg of water) and fluctuation (range 298-323) of the fasting plasma osmolality were recorded. The presence of endogenous vasopressin was indicated by the patient's ability to concentrate the urine to as high as 710 mOsm/kg of water with a creatinine clearance of 84 cc/min, and by dilution of the urine in response to alcohol. The failure of increasing fluid intake to as high as 6.2 liters daily to lower the plasma osmolality indicated that deficient fluid intake was not solely responsible for the elevated plasma osmolality. Hypertonic saline infusion during water diuresis resulted in the excretion of an increased volume of dilute urine. The water diuresis continued despite a rise in plasma osmolality from 287 to 339. An isotonic saline infusion initiated during hydropenia resulted in a water diuresis which continued despite a rise in the plasma osmolality from 303 to 320. Stable water diuresis induced during recumbency by either oral ingestion of water or intravenous infusion of normal saline was terminated by orthostasis and resumed with the return to the recumbent position. Antecedent alcohol ingestion blocked the antidiuresis of orthostasis. The data are interpreted as indicating impairment of the osmoreceptor mechanism as the primary cause of the hyperosmolar syndrome. They also indicate that vasopressin secretion was regulated primarily by changes in effective blood volume. Chlorpropamide was found to be an effective treatment for the syndrome.

Adult↗

The effect of sulfonylurea drugs on rabbit myocardial contractility, canine purkinje fiber automaticity, and adenyl cyclase activity from rabbit and human hearts.

Long-term clinical studies have associated tolbutamide therapy with an increased incidence of cardiovascular deaths. The effects of this and other sulfonylurea drugs on contractility and rate of isolated rabbit atria, automaticity of isolated dog Purkinje fibers, and adenyl cyclase activity in particulate preparations of rabbit and human hearts were studied. At concentrations that are attained clinically, tolbutamide (10 mg/100 ml) increased contractility of driven rabbit atria to 124+/-5% of control, acetohexamide (3.9 mg/100 ml) to 140+/-5%, chlorpropamide (8.3 mg/100 ml) to 139+/-6%, and tolazamide (3.1 mg/100 ml) to 119+/-6%. These effects were accentuated in the presence of 2.5 x 10(-4) M theophylline and were not blocked by 1 x 10(-5) M propranolol. Adenyl cyclase was activated by each of these drugs at concentrations below those which increase contractility. The drugs also increased the rate and slope of phase 4 depolarization in spontaneously beating Purkinje fibers, but did not alter the spontaneous rate of isolated rabbit atria. Since inotropic and chronotropic stimulation can be deleterious in some clinical settings, these findings may be of significance in interpretation of cardiovascular mortality data.

Acetohexamide↗

On the mechanism of lithium-induced diabetes insipidus in man and the rat.

The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results in part from interference with the mediation of vasopressin at a step distal to the formation of 3',5' cyclic AMP.

Animals↗

A lipid and lipoprotein profile of treated and untreated diabetics.

A group of 149 diabetics and 98 healthy subjects without evidence of diabetes or ischaemic heart disease were studied. Untreated diabetics under 40 years old and 40 years of age and over showed statistically raised fasting serum turbidity, triglycerides, and raised beta and pre-beta lipoprotein levels but not raised cholesterol levels over the age and sex matched normal subjects. Further, some 63% of all diabetics showed a distinct split pre-beta lipoprotein pattern as seen on polyacrylamide disc electrolphoresis as compared with 17% in the control group. Raised lecithin and phosphatidylethanolamine (PE) levels were found in male diabetics and raised PE levels in young diabetic women. In patients under treatment with insulin, chlorpropamide, or phenformin the diabetes was well controlled in most cases, but these patients did not have significantly lower lipid levels. Diabetics on a low carbohydrate diet showed improvement in triglycerides and pre-beta lipoprotein levels, but beta lipoproteins were not lowered. It is suggested that diabetics may benefit by the inclusion of clofibrate in the treatment.

Adult↗

Sulphonylurea and hypothyroidism in Nigerian diabetic subjects.

Thyroid function has been assessed using the T3-Uptake test in 98 nigerian diabetic and 50 non-diabetic control subjects. Whilst abnormal tests suggestive of thyroidal hypofunctional state were commoner in the group on chlorpropamide alone, and in combination with metformin, these were unrelated to the duration of treatment. In addition, none had clinical hypothyroidism.

Adolescent↗

Crystal doping aided by rapid expansion of supercritical solutions.

The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction ranged from 45 to 100 degrees C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies revealed the formation of eutectic mixtures and solid solutions of CPD + urea. Formation of the solid solutions resulted in the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these results were the reductions in melting point (up to 9 degrees C) and in the DeltaH(f) values of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.

Calorimetry, Differential Scanning↗

Co-existent diabetes mellitus and diabetes insipidus, a familial disease.

Three male siblings with diabetes mellitus are described, two of whom also had coexistent diabetes insipidus. The co-existence of diabetes mellitus and insipidus appears to represent a single genetic abnormality and may or may not be accompanied by primary optic atrophy. Chlorpropamide was effective in controlling the symptoms of diabetes mellitus and diabetes insipidus.

Adult↗