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At least 19 recordsLinked to original sources
PubMed1977

Serum phenformin concentrations in patients with phenformin-associated lactic acidosis.

Phenformin concentrations were measured in serum from seven patients with phenformin-associated lactic acidosis, and initial values ranging from 20 to 625 ng./ml. were obtained. Five of the seven patients had serum concentrations within the usual therapeutic range of up to 241 ng./ml. Serum phenformin concentrations were measured serially, and apparent half-lives of 5, 25, and 30 hours were obtained in three patients with serum creatinine concentrations of 1.7, 7.6, and 6.0 mg./dl., respectively. Although the half-life of phenformin was prolonged in azotemic patients, no correlation between serum creatinine concentration and serum phenformin could be demonstrated; furthermore, the severity of lactic acidosis as measured by arterial pH and lactate concentration did not correlate with the serum creatinine concentration.

Aged↗
PubMed1996

Phenformin-associated lactic acidosis due to imported phenformin.

OBJECTIVE: To emphasize the continued incidence of phenformin-associated lactic acidosis. CASE REPORT: We report a case of phenformin-associated lactic acidosis in a Chinese man who received phenformin while in China. Diagnosis was made; the patient was treated appropriately and survived. COMMENTS: Phenformin-associated lactic acidosis may still occur in the U.S.

Acidosis, Lactic↗
PubMed1984

The effects of phenformin on the transport and metabolism of sugars by the rat small intestine.

The effects of 0.25-10 mM phenformin on sugar transport and metabolism have been studied in a preparation for the combined perfusion of the vascular bed and the lumen. At all concentrations the effects of vascular phenformin were more pronounced than those of luminal phenformin. Phenformin inhibited galactose transport across the intestine, the pattern of inhibition depending on whether the phenformin was added to the luminal or vascular compartments. The active accumulation of galactose in the mucosal epithelial cells was also abolished. There was a linear relationship between the percentage reduction in mucosal ATP levels and vascular phenformin concentration. Phenformin reduced the rate of glucose uptake from the lumen, and the proportion of this glucose which reached the vascular effluent. Most of the glucose which did not reach the vascular side could be accounted for by the formation of lactic acid. Vascular phenformin increased glucose uptake from the vascular medium by ca 88%, 97% of which could be accounted for by lactate formation. Phenformin was sequestered by the mucosa when added to the vascular, but not the luminal, perfusates. There was very little translocation of intact phenformin across the gut in either the mucosal or serosal directions. It is suggested that the effects of phenformin on the gut mainly derive from an inhibition of mitochondrial oxidative phosphorylation, with a small contribution from a direct effect on the brush border, more pronounced at high phenformin concentrations. The results are consistent with the idea that phenformin delays sugar absorption in man, and that the intestine may be a significant source of lactate production in lactic acidosis.

Adenosine Triphosphate↗
PubMed2002

Phenformin suppresses calcium responses to glutamate and protects hippocampal neurons against excitotoxicity.

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.

Adenosine Triphosphate↗
PubMed1977

The absorption of phenformin and its effects on glucose and water absorption in isolated perfused rat small intestine.

The effects of phenformin on glucose and water absorption from isolated perfused rat small intestine were studied. Luminal phenformin inhibited glocose and water absorption progressively as its concentration was increased from 0-1-1-0 mg.ml-1. At 0-5 mg phenformin ml-1, inhibition increased with time of exposure to phenformin up to 15 min and thereafter remained constant. Arterial infusion of phenformin (1-0 mg-ml-1) produced less inhibition of glucose and water absorption. The site of phenformin's action appeared to be intracellular. Phenformin absorption from a luminal perfusate (0-5 mg-ml-1) was measured. Although it was rapidly absorbed (22 microgram.cm intestine-1.h-1) from the lumen, less than 2 microgram.cm-1.h-1 appeared at the serosal surface of the intestine. In subsequent phenformin-free perfusion, only 25% of the absorbed phenformin was recovered in the luminal and serosal effluents.

Animals↗
PubMed1978

Epidemiology of adverse drug reactions to phenformin and metformin.

Adverse drug reactions (ADRs) to phenformin and metformin reported to the Swedish Adverse Drug Reaction Committee during 1965--77 were analysed in relation to sales and prescription data. The biguanides accounted for 0.6% of all reported adverse drug reactions but for 6% of the fatal cases (all phenformin). Sixty-four ADRs to phenformin and eight to metformin were classified as causal relation "probable" or "not excluded." Fifty-one of these reactions (71%) were lactic acidosis, all but one being reactions to phenformin. After 1973 phenformin was prescribed less in Sweden and metformin became predominant. A nationwide prescription survey during 1975--6 disclosed no differences in age and sex between patients receiving phenformin and metformin. The mean daily doses prescribed in 1976 were 74 mg of phenformin and 1.5 g of metformin. The numbers of ADRs to the two drugs reported during 1975--7 were related to use. The relative incidences of ADRs reported for phenformin and metformin did not differ. Significantly more cases of lactic acidosis and deaths were reported for phenformin.

Acidosis↗
PubMedDate not supplied

Do metformin and phenformin potentiate differently B-cell response to high glucose? An in vitro study on isolated rat pancreas.

The study investigated the effects of metformin and phenformin, at "therapeutic" concentrations, on the pancreatic A-, B- and D- cell response to glucose using the isolated perfused rat pancreas model. Changes in the rate of pancreatic lactate output after these biguanides were also evaluated. Metformin--at 1.5 micrograms/ml--and phenformin--at 100 ng/ml--were separately infused both at 160 mg/dl and 300 mg/dl glucose levels. Neither metformin nor phenformin affected glucagon or somatostatin secretion during these two metabolic stimuli with glucose, nor did they significantly influence insulin response to the lower glucose stimulus. Both metformin and phenformin enhanced insulin response to 300 mg/dl glucose infusion and increased the second phase of the B-cell secretory profile but only phenformin significantly enhanced the pancreatic lactate output rate during the 300 mg/dl glucose infusion. Infusion with dichloroacetate (a stimulator of the mitochondrial pyruvate oxidation) or with verapamil (a calcium antagonist) alone did not modify the insulin response to high glucose concentrations. During metformin infusion dichloroacetate neither modified metformin's effects on B-cell response to high glucose nor did it affect the pancreatic lactate output rate. On the other hand dichloroacetate opposed phenformin's effects on the B-cell response to high glucose and reversed the rise in the pancreatic lactate output rate. Verapamil inhibited the effect of metformin on the B-cell response to high glucose but failed to affect phenformin's influence on high-glucose induced insulin release. These data suggest both metformin and phenformin potentiate--at least in rats--the late phase of insulin secretory response to high glucose. However metformin seems to influence pancreatic B-cell activity mainly by facilitating the trans-membrane calcium ion influx responsible for the second phase of insulin release. Phenformin's influence seems indirect since it increases pancreatic lactate production which mediates the enhanced B-cell response to glucose.

Animals↗
PubMed1989

The hyperlactatemic effect of biguanides: a comparison between phenformin and metformin during a 6-month treatment.

To compare the chronic hyperlactatemic effect of phenformin and metformin, we performed a double-blind study in 10 non insulin-dependent diabetics without any other known hyperlactatemic condition. After a pre-study period, each patient was allocated to a 6-month treatment with phenformin (50 mg bid) or metformin (850 mg bid) in random sequence. Body weight values were not significantly different between phenformin and metformin. Diabetic control was significantly (p less than 0.001) improved by both biguanides versus pre-study, but was the same during metformin and phenformin: HbAI = 13.8 +/- 0.3 SEM% during pre-study 9.7 +/- 0.2% during phenformin, 10.2 +/- 0.2% during metformin. Mean values of plasma lactate during metformin were significantly lower versus phenformin (1.30 +/- 0.05 vs 1.64 +/- 0.05 mmol/l, p less than 0.001). Mean values of plasma lactate/pyruvate ratio during metformin were significantly lower versus phenformin (16.92 +/- 0.59 vs 22.65 +/- 0.87, p less than 0.001), but not versus pre-study (16.19 +/- 0.51). These results indicate that: 1) during a 6-month treatment with a diabetic control of similar degree phenformin produces a significantly higher hyperlactatemic effect vs metformin; 2) metformin treatment is associated with less impairment of intracellular redox state versus phenformin, and therefore should be considered advantageous in the long-term treatment of non insulin-dependent diabetics.

Acidosis, Lactic↗
PubMed1975

The effect of phenformin-HCl on patients with diabetes mellitus, studied under strict balance conditions.

Under strict balance conditions we studied the effect of phenformin in 5 patients with diabetes mellitus. In all cases phenformin lowered the blood glucose values, and all patients showed a reduction of glycosuria. Contrary to other reports body weight increased during phenformin treatment. This was accompanied by positive nitrogen, phosphorus and calcium balances. The weight gain can be explained by the positive caloric balance, mainly caused by the diminished glycosuria. No change in B.M.R. or R.Q. was seen. During phenformin treatment there was a drop in cholesterol and total lipid levels in 4 patients. No conclusions could be drawn about the effect of phenformin on triglycerides, phospholipids and lipoprotein spectra. Phenformin treatment did not affect the disappearance of glucose, nor the insulin levels after intravenous glucose loading. During oral glucose loading phenformin caused a significant fall in blood glucose levels, accompanied by an increased insulin response in one patient. In the other 4 patients phenformin had no effect on either parameter.

Aged↗
PubMed1981

[Toxic effect of the combination of propranolol and phenformin combination in anesthetized dogs].

Phenformin (20 mg/kg subcutaneously) as well as propranolol (0.3 mg/kg. i.v.) induced an increase in blood lactate level in the normal anesthetized log; with phenformin a slight decrease in the arterial pH was noted. The combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg. i.v.) induced a more rapid increase in lactate level, a slight reduction of arterial pH and led to the death of the animals in all cases. After a chronic treatment by phenformin (20 mg/kg daily orally during 7 days, the administration of phenformin (20 mg/kg subcutaneously) induced lactic acidosis in 3 out of the 8 animals and death within 150 minutes. In the animals pretreated by phenformin, the combined administration of phenformin (20 mg/kg subcutaneously) and propranolol (0.3 mg/kg i.v.) caused the death of all the animals without the occurrence of lactic acidosis. These results point to the possible toxicity of the propranolol-phenformin combination.

Anesthesia↗
PubMed1984

The effect of phenformin and other adenosine triphosphate (ATP)-lowering agents on insulin binding to IM-9 human cultured lymphocytes.

In the present study, we investigated the mechanism by which the antidiabetic drug phenformin increases insulin binding to its receptors in IM-9 human cultured lymphocytes. After a 24-hr preincubation, phenformin induced a twofold increase in specific 125I-insulin binding, and removal of phenformin was followed 6 hr later by a return in binding to control levels. This effect of phenformin on insulin binding was not a consequence of either inhibition of cell growth, changes in cellular cyclic adenosine monophosphate (AMP) levels, or changes in guanosine triphosphate (GTP) content. Since phenformin is known to inhibit various aspects of cellular energy metabolism, the relationship between 125I-insulin binding and energy metabolism in IM-9 cells was investigated. The phenformin-induced increase in insulin binding to IM-9 cells was related to a time- and dose-dependent decrease in ATP levels. Other agents that lowered ATP levels, including antimycin, dinitrophenol, and 2-deoxyglucose, also raised insulin binding. These studies indicated, therefore, that phenformin enhances insulin binding to receptors on IM-9 cells and that this effect on insulin receptors may be related to alterations in metabolic functions that are reflected by a lowering of ATP levels.

Adenosine Triphosphate↗
PubMed1977

Plasma glucagon suppression by phenformin in man.

In an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p less than 0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p less than 0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments of alpha-amino nitrogen were not affected by phenformin. Thls, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.

Adult↗