Disease relevance of PHENFORMIN

• Phenformin in the treatment of livedo vasculitis [1].
• Phenformin and lactic acidosis [2].
• Phenformin-associated lactic acidosis accounted for 7% of the episodes of metabolic acidosis and 27% of deaths due to metabolic acidosis in diabetics [2].
• Prerenal azotemia was present at the time of admission in all but one of these patients, but renal function was normal at the time of discharge in those patients with phenformin-associated lactic acidosis who survived [2].
• Phenformin-associated pancreatitis [3].

High impact information on PHENFORMIN

• Phenformin-induced lacticacidosis associated with impaired debrisoquine hydroxylation [4].
• In contrast, in 18 patients with phenformin-induced lactic acidosis, the increase in anion gap at admission was much greater than the decrease in bicarbonate [5].
• Hyperamylasemia was not significantly more frequent in patients with phenformin-associated lactic acidosis than in patients with lactic acidosis who had not received phenformin [6].
• Letter: Phenformin in diabetes mellitus [7].
• When AMP-activated protein kinase activity is increased by 5-aminoimidazole-4-carboxamide-riboside, phenformin, or by the expression of a constitutively active form, isoproterenol-induced lipolysis is strongly reduced [8].

Chemical compound and disease context of PHENFORMIN

• Lactic acidosis associated with phenformin therapy. Evidence that inhibited lactate oxidation is the causative factor [9].
• As with other cases of lactic acidosis associated with phenformin therapy, this subject had impaired renal function as evidenced by serum creatinine levels of 2 mg./100 ml. and BUNs of 40 mg./100 ml [9].
• Using uniformly labeled 14C L-lactate, we have studied the turnover and oxidation of lactic acid in a patient who presented with a mild lactic acidosis while on phenformin medication [9].
• This is largely due to the historical experience of lactic acidosis with phenformin, despite the fact that metformin does not predispose to this when compared with other therapies [10].
• In all cases phenformin lowered the blood glucose values, and all patients showed a reduction of glycosuria [11].

Biological context of PHENFORMIN

• Effect of phenformin on gluconeogenesis from lactate and intracellular pH in the isolated perfused guinea pig liver [12].
• The kinetics of phenformin and its metabolite, p-hydroxyphenethylbiguanide, was studied in eight diabetic patients with varying degrees of renal impairment [13].
• Phenformin has shown the characteristic properties of an antifibrinopathic agent in that it prolongs thrombin time and enhances fibrinolysis [14].
• Since no evident influence of phenformin on the intestinal absorption of amino acids could be demonstrated, this effect may be explained by a local action on the intestinal wall exposed to high concentrations of the drug, resulting in the inhibition of the insulin secretion stimulating activity of the gut [15].
• Effects of phenformin on blood sugar, serum triglyceride, thrombin time, euglobulin clot lysis time and cardiovascular complications were studied in maturity onset diabetes and in atherosclerotic patients with or without diabetes, for a period of 14-18 months [14].

Anatomical context of PHENFORMIN

• Gluconeogenesis from lactate and hepatic cell pH (pHi) were measured in the isolated perfused livers of starved guinea pigs in the presence and absence of phenformin (phenethylbiguanide) [12].
• When compared with phenformin, metformin was less active in increasing insulin binding to cultured cells, the ratio between the two drug responses being similar to that of their therapeutic dosage in patients [16].
• Since vitamin B12malabsorption has been described in diabetics on biguanides and inhibition of bile acid absorption found in rat ileum the effect of treatment with different biguanides (phenformin, buformin, metformin) on bile acid metabolism and vitamin B12 absorption was assessed in maturity onset diabetics [17].
• The hypothesis is advanced that the phenformin-induced increase in gut GLI secretion may bring about competition of the latter with pancreatic glucagon for receptors in liver cell membranes, reducing the effect of glucagon on the liver, and thus contributing to a decrease in glycaemia [18].
• After a 24-h preincubation with maximal stimulatory concentrations of phenformin, specific [125I] insulin binding to its receptors in the four different cell lines were increased over control by 67.2 +/ 17.0%, 101.3 +/- 11.5%, 65.1 +/- 8.0%, and 44.0 +/- 12.1%, respectively (mean +/- SE) [19].

Associations of PHENFORMIN with other chemical compounds

• Phenformin accumulation (cf impaired renal function) further reduces pyruvate removal by decreasing its conversion to glucose, but in addition alters the redox state [20].
• The observed decrease in lactate consumption and glucose output in the presence of phenformin was associated with a fall in pHi [12].
• Intraduodenal infusion of the amino acid mixture provoked a greater increase in plasma insulin than intravenous infusion of L-arginine, this increase being significantly inhibited by phenformin only in the first case [15].
• All three compounds for which there is good in vivo evidence for an association between their metabolism and the debrisoquine oxidation polymorphism (viz., sparteine, guanoxan and phenformin) were potent competitive inhibitors of the reaction [21].
• 2-deoxyglucose stimulated Thr49 phosphorylation of endogenous TPS5 in Arabidopsis cells, whereas phenformin did not [22].

Gene context of PHENFORMIN

• Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos [23].
• Plasma glucagon suppression by phenformin in man [24].
• Triglyceride levels, gastrin secretion, growth hormone levels, and increments of alpha-amino nitrogen were not affected by phenformin [24].
• The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1 [25].
• After treatment with phenformin, the fasting plasma gut GLI was higher than the control value in eleven of thirteen patients [18].

Analytical, diagnostic and therapeutic context of PHENFORMIN

• The specificity of the assay was investigated, and phenformin metabolites were characterized by thin-layer chromatography [26].
• The half-life (t 1/2) for the elimination of drug from plasma after intravenous injection in 5 normal subjects (1.52 +/- 0.3 hr) (mean +/- SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr) [27].
• Following inhibition of 35% of degradation by 1.5 h of perfusion with insulin (5 nM), subsequent exposure to phenformin (2 microM) produced only a slight additional inhibition which did not exceed 38% of basal proteolysis [28].
• The effects of administration of phenformin and clofibrate to 32 breast cancer patients who underwent radical mastectomy and suffered from hormonal metabolic disturbances involving a decline in immunologic response were investigated [29].
• A simple post-column derivatization method for the fluorometric determination of biguanides (buformin and phenformin) in serum by high-performance liquid chromatography is described [30].

References