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PubMed1985

Genetic and environmental influence in the epidemiology of noninsulin-dependent diabetes mellitus: a global perspective.

Refinement of the classification of diabetes mellitus to include two major categories, insulin dependent (IDDM) and noninsulin-dependent (NIDDM) and the recent attention paid to the standardization of epidemiological techniques have led to much new information on the epidemiology of the disease. Support for the notion of genetic influence in the development of NIDDM has come from twin studies, but the search for specific genetic markers for NIDDM has been largely unproductive to date. There is increasing scepticism as to the utility of the chlorpropamide-alcohol flush as a genetic marker for NIDDM. The large disparity in the frequency of NIDDM between populations provides indirect support for the genetic hypothesis, as do recent studies of the association between NIDDM and ancestral genetic admixture. Obesity has long been considered a causal factor in the aetiology of NIDDM, though the strength and consistency of this relationship is now being questioned. The strength of the association between obesity and NIDDM has been shown to vary depending on the presence or absence of a family history of the disease. There is further preliminary evidence to suggest that association between obesity and NIDDM may vary in strength between populations, and between the sexes. Little evidence has so far emerged for a role of quantitative or qualitative aspects of diet in the aetiology of NIDDM. This may be due, in part, to the imprecision of current techniques for dietary estimation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1975

[Clinical-hematological demonstrations: aplastic anemia, acute leukemias, polyneuropathy in Waldenstrom's disease, acute porphyria].

Some cases are reviewed involving hematological diseases caused by exogenously or endogenously induced toxicity. First, 3 cases of aplastic anemia (chlorpromazine, chloramphenicol and probably autoantibodytypes) are discussed. The known aplastic anemia inducing agents are the chloro-hydrocarbon rings (chloramphenicol, hexachlorcyclohexane, chlorpromazine, chlorpropamide and aliphatic potassium perchlorate) as well as phenylbutazone, sulfonamides, benzol, gold, certain antiepileptic drugs and compounds which contain arsenic or bismuth. Isolated erythroblastophthisis is an autoimmune disease and is mainly observed in young people. It is stressed that cases with aplastic anemia generally exhibit considerable immunosuppression. Therefore, gamma-globulins should be given when infection is observed in these cases. In cases refractory to 2-3 years of conventional treatment (steroids, especially androgens), splenectomy is a useful alternative. Five cases of acute leukemia (4 AML and one ALL) point up the considerable advances in the treatment of this group of diseases. Caution should be exercised in interpreting a remission as a cure, since in one of our cases a remission of 12 1/2 years was followed by a lethal relapse.-A case of Waldenström's disease with severe polyneuropathy is described which was associated with severe "neuritic defects" related to inclusions of paramyloid material in the nervous tissue.-In a case of acute porphyria complicated by paraplegia an impressive remission was achieved by forced diuresis with furosemide and sorbitol combined with intensive i.v. glucose therapy (reduction of delta-aminolevulic acid production.

Adolescent↗
PubMed1984

Oral hypoglycaemics in the first trimester and fetal outcome.

During a 5 1/2-year period we saw 171 pregnant women with established non-insulin-dependent diabetes; 78 patients received oral hypoglycaemic drugs during the 1st trimester and 93 did not. The outcome of pregnancy in these two groups is compared. Only two major congenital anomalies were seen in the tablet-taking group and the number of abortions (4) was not excessive. The perinatal mortality (PNM) rate was initially high after large doses of chlorpropamide or metformin had been given during the 1st trimester, but this was clearly related to inadequate diabetic control in later pregnancy. Among the last 50 of the total of 75 viable infants whose mothers received oral drugs early in pregnancy, the PNM rate was 40/1 000. We conclude that modern oral hypoglycaemic drugs are safe and useful, not only during later pregnancy but also during the 1st trimester, provided excellent control of blood glucose levels is achieved.

Abnormalities, Drug-Induced↗
PubMed1983

The pathogenesis of type II diabetes mellitus. A brief survey.

Type II, non-insulin-dependent, diabetes mellitus occurs worldwide, though with great variations in prevalence rates: the highest rates--about 30-35%--are reported for the Pima Indians and for the population of the island Nauru in the Pacific. The disease is to some extent inherited, but the mode of inheritance is unknown. Recent studies of the length polymorphism of the insulin gene, however, suggest that it may be possible to find a genetic marker for the disease. Obesity is common among type II diabetics, and the occurrence of the type II diabetes increases with age. One possible explanation is that both obesity and advanced age are associated with a decrease in insulin sensitivity. Insulin resistance is a common finding in type II diabetes; it has been demonstrated with several methods, including the euglycaemic insulin clamp technique. The role of insulin receptor and post-receptor defects in the pathogenesis of this insulin resistance is currently being studied with great interest. In addition to impairment of insulin sensitivity, there is a reduction in glucose-stimulated insulin secretion in individuals with type II diabetes. The primary defect of the disease, however, has yet to be established. Type II diabetes may well be a heterogeneous disorder with several different aetiologies; one argument for heterogeneity within the disease is the chlorpropamide alcohol flush reaction that can be demonstrated among about one third of type II diabetics. Further investigations of the pathogenesis of the disease are needed, and it is hoped that these will pave the way for the development of more specific therapy, and even prevention of the disease.

Age Factors↗
PubMed1984

The genetics of diabetes mellitus, including the South African perspective.

By and large, essential diabetes mellitus is thought to be 50% inherited and 50% environmental. In insulin-dependent diabetes mellitus (IDDM) there is a strong link with the HLA system with regard to the inheritance of 'susceptible' diabetic genes, especially the DR3 and DR4 alleles. In IDDM environmental factors act in a predisposed individual to initiate an immune response with resultant beta-cell damage and destruction. Non-insulin-dependent diabetes mellitus (NIDDM) has no clear HLA link, but has been shown in studies of twins to have a stronger genetic basis than IDDM. In NIDDM environmental factors (race, ethnicity, diet, obesity) have an important influence on the clinical expression of the disease and the severity of complications in a genetically predisposed individual. The non-insulin-dependent diabetes of the young (NIDDY) variant and the phenomenon of chlorpropamide-primed alcohol-induced flushing both underline the heterogeneity of NIDDM. Because of the heterogeneous nature and multifactorial inheritance pattern of diabetes mellitus, accurate genetic counselling is not possible as yet. However, data to date suggest that it is unwise to advise prospective parents not to procreate, since the overall risk of the development of clinical diabetes mellitus is extremely low.

Black People↗
PubMed1983

Clinical pharmacokinetics of sulfonylureas: a brief review.

All sulfonylureas seem to have similar mechanisms of action. Nevertheless, they may differ in their clinical effects because of differences in their pharmacokinetics and intrinsic activities. Second generation sulfonylureas, such as glibenclamide and glipizide, are much more potent than first generation sulfonylureas, such as tolbutamide and chlorpropamide. The former are, in fact, active at concentrations of the order of nmol/l, while the latter are active in the range of mumol/l. Accordingly, glibenclamide and glipizide are more efficient, and probably also less prone to cause pharmacokinetic interactions with other drugs, and with ethanol. In addition, glipizide and glibenclamide (new formulations) are completely bioavailable, which is a further advantage. Glipizide has a more rapid absorption and onset of action as well as a shorter half-life and duration of effect than glibenclamide. Accordingly, glibenclamide has a better effect on nocturnal and fasting blood glucose levels, but its use may also involve a greater risk of long-lasting hypoglycemia. At daily dosages of 5 mg or more, divided dosage seems unnecessary with glipizide, since effective concentrations will prevail throughout most of a 24 hour period. Efficacy may be improved if either drug is administered before, rather than together with, breakfast. High doses of glipizide may impair, rather than improve, glucose balance.

Biological Availability↗
PubMed1984

Modulation of lymphocyte adrenergic receptors and transformation responses by therapeutic drugs.

Lymphocyte transformation responses and adrenergic receptor (adrenoceptor) binding have been studied in the presence of therapeutic drugs. Chloroquine, propranolol and trifluoperazine were the most potent drugs investigated, inhibiting lymphocyte responses and the binding of adrenergic antagonists at 10(-5)M. Drugs such as salicylate and chlorpropamide, with little affinity for adrenoceptors but with a high capacity for binding to albumin, inhibited lymphocyte transformation at 10(-3)M; probably by displacing protein-bound ligands with an affinity for adrenoceptors. Metronidazole and allopurinol had no significant effect on lymphocyte transformation, or on adrenoceptor antagonist binding at 10(-3)M. Adrenoceptor affinity or receptor numbers and lymphocyte responses were increased by non-inhibitory concentrations of most drugs. We conclude that most drugs modify lymphocyte responses by interacting directly or indirectly with adrenoceptors. This modulation of adrenoceptors may have important implications, relating to the induction and control of asthma by drugs.

Binding, Competitive↗
PubMed1982

Defleecing effect of betamethasone and other long-acting corticosteroids, their influence on wool growth and some physiological processes in sheep.

The defleecing effects of the long-acting derivatives of prednisolone, triamcinolone and dexamethasone were compared with those of betamethasone alcohol when these steroids were administered at the rate of 3.3 mg/kg liveweight in three equal intramuscular injections of 1.1 mg to Merino wethers. Prednisolone showed no defleecing activity whereas the other steroids produced positive but variable responses. Prolonged depression of wool growth was evident following treatment with dexamethasone esters. Betamethasone alcohol injected intramuscularly at 1.1 mg/kg daily for 3 days produced a similar defleecing response to intravenous infusion of 3.3 mg/kg betamethasone phosphate over 8 days. A range of dose rates (0.3-3.3 mg/kg) of betamethasone as multiple and single intramuscular injections indicated that the minimum effective defleecing dose was approximately 2.1 mg/kg. The response to simultaneous administration of betamethasone and insulin or chlorpropamide (to increase glucose utilization) and glucose or xylazine (to increase hyperglycaemia) suggested that the gluconeogenic role of this steroid had little effect on fibre shedding. Thyroxine (300 micrograms per sheep) administered on the first day with an injection of betamethasone (0.9 mg/kg), and alone daily for 20 days thereafter, did not influence the changes in wool production resulting from betamethasone treatment. These results are discussed in relation to the molecular structure and physiological characteristics of a potentially specific defleecing steroid.

Adrenal Cortex Hormones↗
PubMed1981

Update on the Lannett and Pharmadyne decisions.

The implications of litigation concerning the authority of FDA in premarket approval of drugs are discussed. Since a recent paper on the Lannett and Pharmadyne decisions, several related court cases have been tried. The principal case discussed in Premo Pharmaceutical Laboratories, Inc. v. U.S., where the FDA's authority to require premarket approval of "me-too" drugs was temporarily thrown into jeopardy by a district court's decision involving Premo's Insulase brand of chlorpropamide tablets. However, an appeal, the decision was reversed and the case dismissed. The courts' opinions for these decisions are discussed, as well as related developments.

Drug Industry↗
PubMedDate not supplied

[Clinical trial with glypentide. Comparison with the hypoglycemic activity of other sulfonylurea compounds].

In 53 sulphonylurea-treated diabetic patients, the activity of glypentide and the patients' general tolerance of the drug were studied. The results show that the new oral hypoglycemic drug has a similar, and superior in many instances, activity to other similar drugs such as glybenclamide and glypizide, and to the activity of the classical sulphonylureas (chlorpropamide and carbutamide). The patients' tolerance of the drug was excellent. No digestive disorders, undesirable side effects or hypoglycemias were seen in the patients. Analysis of lipid levels showed that glypentide induces a significant decrease in total lipid and cholesterol values, being this action more marked in patients with normal body weight non-treated with a hypocaloric diet.

Administration, Oral↗
PubMed1994

Inappropriate medication use in community-residing older persons.

BACKGROUND: Elderly patients taking inappropriate drugs are at increased risk for adverse outcomes. We investigated the prevalence of inappropriate drug use and its predisposing factors in community-residing older persons. METHODS: We conducted in-home interviews with 414 subjects aged 75 years and older living in the community of Santa Monica, Calif. Inappropriate medication use was evaluated using explicit criteria developed through a modified Delphi consensus process. These criteria identified drugs that should generally be avoided in elderly community-residing subjects regardless of dosage, duration of therapy, or clinical circumstances. RESULTS: Based on these conservative criteria, 14.0% of the subjects were using at least one inappropriate drug. The most common examples were long-acting benzodiazepines, persantine, amitriptyline, and chlorpropamide. Subjects using three or more prescription drugs, compared with one or two, were more likely to be taking an inappropriate medication (odds ratio, 3.9; 95% confidence interval, 1.9 to 7.9). Furthermore, subjects with depressive symptoms had a higher risk of receiving inappropriate medications than nondepressive subjects (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1). CONCLUSIONS: Inappropriate drug use is a common problem in community-residing older persons. The risk of inappropriate drug use is increased in patients taking multiple medications and in patients with depressive symptoms.

Age Factors↗
PubMedDate not supplied

[A comparative evaluation of the effect of glurenorm and sulfonylurea preparations on the intravascular microcirculatory indices in type-II diabetes mellitus].

Analysis of the effects of glurenorm and some sulfonylurea drugs, such as maninil, minidiab, chlorpropamide, on some parameters of intravascular microcirculation has demonstrated the specific features of this drug. Though all these hypoglycemic agents favorably influence the microcirculation when carbohydrate metabolism compensation is attained, glurenorm improved the status of formed elements of the blood (red cell and platelet aggregation) more noticeably than the rest drugs, which fact recommends it as a drug of choice for patients with type II medium-severe diabetes with the predominant involvement of the cellular component of the microcirculation.

Adult↗
PubMed1994

Inappropriate drug prescribing for the community-dwelling elderly.

OBJECTIVE: To examine the amount of inappropriate drug prescribing for Americans aged 65 years or older living in the community. DESIGN: Cross-sectional survey of a national probability sample of older adults. SETTING: The 1987 National Medical Expenditure Survey, a national probability sample of the US civilian noninstitutionalized population, with oversampling of some population groups, including the elderly. SUBJECTS: The 6171 people aged 65 years or older in the National Medical Expenditure Survey sample, using appropriate weighting procedures to produce national estimates. MAIN OUTCOME MEASURES: Incidence of prescribing 20 potentially inappropriate drugs, using explicit criteria previously developed by 13 United States and Canadian geriatrics experts through a modified Delphi consensus technique. Three cardiovascular drugs identified as potentially inappropriate were analyzed separately since they may be considered appropriate for some noninstitutionalized elderly patients. RESULTS: A total of 23.5% (95% confidence interval [CI], 22.4% to 24.6%) of people aged 65 years or older living in the community, or 6.64 million Americans (95% CI, 6.28 million to 7.00 million), received at least one of the 20 contraindicated drugs. While 79.6% (95% CI, 77.2% to 82.0%) of people receiving potentially inappropriate medications received only one such drug, 20.4% received two or more. The most commonly prescribed of these drugs were dipyridamole, propoxyphene, amitriptyline, chlorpropamide, diazepam, indomethacin, and chlordiazepoxide, each used by at least half a million people aged 65 years or older. Including the three controversial cardiovascular agents (propranolol, methyldopa, and reserpine) in the list of contraindicated drugs increased the incidence of probably inappropriate medication use to 32% (95% CI, 30.7% to 33.3%), or 9.04 million people (95% CI, 8.64 million to 9.44 million). CONCLUSION: Physicians prescribe potentially inappropriate medications for nearly a quarter of all older people living in the community, placing them at risk of drug adverse effects such as cognitive impairment and sedation. Although most previous strategies for improving drug prescribing for the elderly have focused on nursing homes, broader educational and regulatory initiatives are needed.

Aged↗
PubMed1994

Polysubstrates: substances that interact with renal contraluminal PAH, sulfate, and NMeN transport: sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds.

Some N-containing xenobiotics were recently shown to behave as bisubstrates; that is, they interact with and are transported by both the contraluminal transport system for organic anions (PAH) and the contraluminal transport system for organic cations (NMeN). Thus we determined whether other classes of N-containing substrates, such as sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds, amongst them diuretics and other drugs, also interact with both transporters. To test this, we applied the stop-flow peritubular capillary perfusion method with initial flux measurements and determined app. Ki values for these substrates on PAH, sulfate and NMeN transport. We found that the following compounds interact with 1) the PAH transporter: benzene carboxylates, benzenesulfonylureas and benzenesulfonamides (as long as their acid pKa value is below 9.5). 2) the sulfate transporter: 2-anilinobenzoates, benzenesulfonylureas, polysubstituted sulfamoylbenzoates and some sulfamoylthiazides with electronegative charge accumulation around an anionic site. 3) the NMeN transporter: anilinobenzoates, sulfamoylbenzoates and benzenesulfonamides, if they bear an N-containing pyridine, pyrrolidine, furylmethylamino or thiazide group. There are, however, exceptions when H-bond formation might be responsible for interaction with that transporter. The data confirm the specificity rule for each transporter and the concept that one and the same substrate can match the requirements for several transporters. Thus the loop diuretics furosemide and piretanide, the thiazide diuretics hydrochlorothiazide, cyclopenthiazide and bendroflumethiazide and the sulfonylureas tolbutamide, chlorpropamide and torasemide interact with all three tested transport systems for PAH, sulfate and NMeN. Therefore, they are able to accomplish complex transport interactions with different transporters.

Animals↗
PubMed1976

[Non-saturable cooperative binding of tolbutamide to rat endocrine pancreas. Criteria of specificity].

The binding of 3H-tolbutamide to isolated islets, which shows a cooperative non-saturable pattern up to about 5 X 10(-5) M, was confirmed. Binding to exocrine pancreatic tissue shows much less cooperativity. Among congeners of tolbutamide, unlabelled carbutamide and chlorpropamide in isodynamic concentrations, as well as diazoxide in an exactly antagonistic amount, behave like tolbutamide 5 X 10(-5) M itselt by cancelling cooperativity when added to the labelled drug. Glipizide and glibenclamide do not.

Animals↗
PubMedDate not supplied

[Drug-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Review of literature].

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is caused by an incapacity of plasmatic hypotonia to inhibit antidiuretic hormone (ADH) secretion. This phenomenon leads to a water retention and an expanded extracellular fluid volume, and secondary to a dilution of plasmatic sodium and also to a renal loss of sodium. The SIADH is a relatively rare syndrome, which may occur in various circumstances: central nervous system diseases, cancers, infections... Sometimes, it may be observed as a drug-related side effect: carbamazepine, chlorpropamide, antidepressors, anticancer drugs are particularly involved.

Humans↗
PubMed1995

Traditional pharmacological management of non-insulin-dependent diabetes.

Most traditional hypoglycemic treatments for non-insulin-dependent diabetes mellitus (NIDDM) are of considerable antiquity. What we would now call a low-carbohydrate diet was first used in 1796; insulin was introduced in 1922; the (toxic) biguanide synthalin was used sparingly from 1926 until the Second World War; and tolbutamide and chlorpropamide were marketed in the late 1950s. Amphetamine was available as an anorectic agent in the 1950s. Hence, representatives of all our present treatments for NIDDM have been available for over 30 y, but there is still great uncertainty about how to use them best. This uncertainty is reflected in major variations in prescription rates from country to country. In spite of this formidable pharmacological armamentarium, we have to face the fact that glycemic control is unsatisfactory in the majority of patients with NIDDM; irrespective of the mode of treatment, less than a quarter have a normal glycated hemoglobin. We clearly need new approaches to control glycemia in NIDDM. Furthermore, in addition to high blood glucose, many patients with NIDDM also have hypertension, hyperlipidemia, and other atherogenic abnormalities that need to be tackled if mortality (predominantly from atherosclerotic vascular disease) is to be reduced. It seems improbable that a single drug will be found to cure the many metabolic abnormalities. Polypharmacy thus seems inevitable for many patients.

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Phototoxicity to sulphonamide derived oral antidiabetics and diuretics. Comparative in vitro and in vivo investigations.

The oral antidiabetics chlorpropamide, glibenclamide, glipizide, gliquiudone, glymidine, tolazamide and tolbutamide, and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide, and xipamide were investigated for potential phototoxicity in vitro using a cell culture model, and in vivo in hairless mice. After exposure to broad band UVA, the majority of the substances tested in vitro yielded a phototoxic action leading to loss of culture forming ability. In vivo, all tested substances induced edema or ulceration, and lead to a significantly increase in skin fold thickness of the mouse skin. In all, a number of substances not described to induce clinical photosensitivity nor phototoxicity in vitro or in vivo were detected in our testing. When determining potential photosensitizers, it seems important to utilize different test methods, as not all substances will exhibit action in a given assay.

Administration, Oral↗