Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of causes of death in a population of 3,113 diabetics was carried out for a period of eight years and those patients dying of some form of diabetic coma identified. Of 1,274 deaths, only 22 (1.73%) were primarily due to coma; 7 hypoglycaemia, 8 ketoacidosis, 3 hyperosmolar coma and 4 lactic acidosis. Three of the ketoacidosis patients may have died from other causes. Most deaths occurred in patients with long-standing diabetes. In the hypoglycaemic group all were on insulin and several had been difficult to control for many years. Infection was an important precipitating factor for ketoacidosis and hyperosmolar coma. Phenformin was the cause of all cases of fatal lactic acidosis. It is reassuring that death from coma is a comparatively rare event in known treated diabetic patients.
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PMID:Fatal coma in diabetes. 677 28

The kinetics of phenformin and its metabolite, p-hydroxyphenethylbiguanide, was studied in eight diabetic patients with varying degrees of renal impairment. Plasma and urinary phenformin and p-hydroxyphenethylbiguanide levels were determined by the multiple selected ion monitoring technique. Phenformin half-lives were unrelated to the degree of renal impairment, whereas reduced renal clearances of insulin and creatinine were significantly correlated with a prolonged half-life of the metabolite. The excretion of p-hydroxyphenethylbiguanide was quite variable (between 4.9% and 27% of total urinary drug loss), probably due to a genetic polymorphism of hepatic mechanisms for hydroxylation. A reduced formation of the metabolite was concomitant with marked increases in the amount of circulating phenformin. A positive reciprocal correlation was detected between areas under the plasma curve of phenformin and both the renal clearance of the unchanged drug and the percentage of metabolite formation. A reduced hydroxylation of phenformin seems, therefore, to be responsible for the high plasma levels of the drug previously described in toxic patients.
Diabetes 1981 Aug
PMID:Defective hydroxylation of phenformin as a determinant of drug toxicity. 725 May 34

Intraperitoneal injection of hydrocinnamic (beta-phenylpropionic) acid inhibited gluconeogenesis from 14C-1-alanine, 14C-1-oleate oxidation, and intensified 14C-1-glucose oxidation in normal and diabetic rats. Hydrocinnamic acid induced significant hypoglycemia in intact animals and normalized hyperglycemia in rats with alloxan diabetes in the course of 24 hours after the administration. Phenformin proved to decrease glucose oxidation in the intact and diabetic rats, producing no marked effect on fatty acid oxidation, whereas in intact animals it caused moderate hypoglycemia and failed to influence hyperglycemia in the rats with alloxan diabetes. Fatty acid oxidation inhibitors are suggested as means of pathogentic therapy in diabetes mellitus.
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PMID:[Fatty acid oxidation inhibitors - a new group of antidiabetic drugs. 2. Experimental study of the hypoglycemic effect of hydrocinnamic acid compared with phenformin]. 741 17

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.
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PMID:Comparative tolerability profiles of oral antidiabetic agents. 784 43

Phenformin, a drug used in the treatment of diabetes mellitus frequently associated with potentially fatal cases of lactic acidosis, has been removed from market in the USA and several European countries. However, cases of lactic acidosis are still reported in countries where phenformin is available, either because well-known contraindications for its use are not observed, or because the prodromic syndrome of the lactic acidosis is not diagnosed. This study describes two cases of lactic acidosis, the treatment used and the final outcome. The authors point out that plainly evident contraindications were ignored in both cases, while the prodromic syndrome remained unrecognized even by specialists. The management of lactic acidosis continues to be a challenge. There is no optimal treatment and early recognition is essential. The authors call for greater attention in the use of phenformin and its eventual removal from market, especially in the light of alternative therapies which prove to be equally valid and easier to administer.
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PMID:[Lactic acidosis induced by phenformin: a still forgotten iatrogenic complication]. 901 72

Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign sources. Another biguanide, metformin, was reintroduced to the United States market for the treatment of diabetes. Biguanide-induced lactic acidosis should be included in the differential diagnosis of elevated anion gap metabolic acidosis. We present a case of phenformin-induced lactic acidosis in which we were consulted at the local poison control center. We also review its pathophysiology, presentation, and treatment. A review of the actions of phenformin illustrates the mechanism of pathology that may also occur with metformin. Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine.
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PMID:Phenformin and lactic acidosis: a case report and review. 984 5

One hundred and two dentate patients with type II diabetes mellitus and 98 non-diabetic subjects were examined for oral conditions and metabolic state. Self-reported health behaviour was analysed. From factor analysis four factors emerged: general health behaviour (GHB), perceived fatigue (PF), diet control (DC) and regular diet (RD). In diabetics PF, DC and RD were significantly higher than that in non-diabetics. Patients with diabetes were more likely to control their disease through a programme of decreased kilojoule intake leading to weight management. However, they tended to tire. The mean gingivitis index was significantly higher (p < 0.01) among diabetics (2.39) than among non-diabetics (1.99). The number of missing teeth was significantly higher (p < 0.01) for diabetics (6.7) when compared with non-diabetics (4.3). On the other hand, aetiological factors (plaque, calculus) and the level of dental health behaviour as expressed in the HU-DBI scores were similar. Probing pocket depth did not differ statistically between groups. The increasing number of missing teeth in diabetics may primarily result from severe periodontitis with tooth mobility or deep pockets. Findings in this study suggest that the difference in the severity of periodontitis between diabetics and non-diabetics was significant although aetiological factors and the level of dental health behaviour were similar.
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PMID:Comparison of health behaviour and oral/medical conditions in non-insulin-dependent (type II) diabetics and non-diabetics. 984 81

Phenformin is a biguanide compound that can modulate glucose metabolism and promote weight loss and is therefore used to treat patients with type-2 diabetes. While phenformin may indirectly affect neurons by changing peripheral energy metabolism, the possibility that it directly affects neurons has not been examined. We now report that phenformin suppresses responses of hippocampal neurons to glutamate and decreases their vulnerability to excitotoxicity. Pretreatment of embryonic rat hippocampal cell cultures with phenformin protected neurons against glutamate-induced death, which was correlated with reduced calcium responses to glutamate. Immunoblot analyses showed that levels of the N-methyl-d-aspartate (NMDA) subunits NR1 and NR2A were significantly decreased in neurons exposed to phenformin, whereas levels of the AMPA receptor subunit GluR1 were unchanged. Whole-cell patch clamp analyses revealed that NMDA-induced currents were decreased, and AMPA-induced currents were unchanged in neurons pretreated with phenformin. Our data demonstrate that phenformin can protect neurons against excitotoxicity by differentially modulating levels of NMDA receptor subunits in a manner that decreases glutamate-induced calcium influx. These findings show that phenformin can modulate neuronal responses to glutamate, and suggest possible use of phenformin and related compounds in the prevention and/or treatment of neurodegenerative conditions.
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PMID:Phenformin suppresses calcium responses to glutamate and protects hippocampal neurons against excitotoxicity. 1200 68

Phenethylbiguanide (DBI) was given to 70 unselected but not obese diabetic patients who were receiving restricted diabetic diets. The only side effects attributed to the drug were anorexia, nausea, vomiting and diarrhea in 28 patients. These symptoms subsided with reduction of dosage. No evidence of serious toxicity has been demonstrated in clinical and metabolic studies. In 27 of the 70 patients diabetes was controlled adequately with DBI alone, and more stable control was obtained in 11 labile diabetics who received DBI in combination with insulin.The mechanism of action is not definitely known.
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PMID:Phenethylbiguanide in diabetic patients; clinical and metabolic effects. 1363 34

Biguanides can function as oral antihyperglycemic drugs. They were used for diabetes mellitus or prediabetes treatment over the last nine decades, but they lost their popularity in 1970s because of phenformin and regained with metformin. For metformin, the most common side effects are diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is lactic acidosis. Phenformin was removed from the markets before 1970, because it caused lactic acidosis in 40-65 patients in 100,000 patient-years. Metformin causes lactate accumulation only in patients who have hepatic failure, renal failure or in patients who attempt suicide with high dosage of drugs. In this report, we present five patients who used high doses of metformin for suicide attempt.
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PMID:Suicide commitment with metformin: our experience with five cases. 2374 66


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