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At least 19 recordsLinked to original sources

PubMed1979

[Biguanide-induced and - associated lactic acidosis: serum and tissue biguanide levels in hyperlactaemia and lactic acidosis (author's transl)].

An investigation was carried out on 30 diabetic patients in an attempt to clarify the relationship between serum biguanide levels and raised lactate. No consistent relationship was demonstrable between the serum biguanide level, administered dosage and time of administration. There was also no correlation between biguanide and lactate increase. It is not justifiable to quote a specific serum level of biguanides in defining lactic acidosis. A causal association between biguanide medication and lactic acidosis seems to be possible only by determination of serum and tissue levels. Determination of biguanide levels was carried out in the serum and tissue of a patient who had died as a result of lactic acidosis after phenformin administration. While the serum levels were only slightly higher than the therapeutic range, both liver and kidney tissue showed highly toxic levels. Furthermore, the amount of biguanides in the body was calculated in another patient successfully treated for lactic acidosis after buformin therapy. A differentiation should be made between biguanide-induced and biguanide-associated lactic acidosis. In both forms serum levels can be within relatively low ranges. In the former condition, the biguanides alone are responsible for the development of lactic acidosis by blocking the respiratory chain. In the latter condition they aggravate an already existing pathological condition, and can, therefore, represent a lethal factor.

Acidosis↗

PubMed1975

The effects of biguanides on thrombokinase, thrombin and trypsin.

A purified preparation of bovine thrombokinase (activated Factor X) loses the ability to hydrolyze TAME (p-toluenesulfonyl-L-arginine methyl ester) when it is incubated at 37 degrees in 0.25 M Tris. HCl buffer, pH 7.4 with lauroxypropyl biguanide, N1, N5-dimethyl, N1-lauroxypropyl biguanide, N1-p-chlorophenethyl, N5-phenethyl biguanide, or N1-methyl, N1-p-chlorobenzyl, N5-o,p-dichlorobenzyl biguanide. Activity is lost much more slowly when 0.15 M NaCl is also present. Lauroxypropyl biguanide is the most potent of the compounds tested, 0.22 mM causing thrombokinase to lose almost all of its activity in about 30 minutes at 37 degrees in pH 7.4 buffered saline. Topical bovine thrombin also loses activity when incubated with either of the lauroxypropyl biguanides but not with the diphenethyl or the dibenzyl compound. Instead, the latter biguanides accelerate thrombin's hydrolysis of TAME. The percent acceleration is not affected or only slightly decreased by the presence of 0.15 M NaCl or KCl, and it is also unaffected by incubating the enzyme with the compounds in buffered saline for 4 to 120 minutes. Purified bovine trypsin is stabilized by both lauroxypropyl and the diphenethyl biguanide when incubated at 37 degrees in pH 7.4 buffered saline for the 60 minute test period but neither compounds has any effect on its rate of hydrolysis of TAME. It is postulated that the enzymes first react rapidly and reversibly with all of the test biguanides and, depending upon the enzyme and the substrate, the rate of hydrolysis of the substrate is unaffected, accelerated or inhibited. The lauroxypropyl biguanides also undergo a second, slower reaction with both thrombokinase and thrombin that produces loss of enzymatic activity. The dibenzyl and diphenethyl biguanides also undergo this second slow reaction with thrombokinase but not with thrombin, and none of the biguanides undergo this second reaction with trypsin.

Animals↗

PubMed1976

[The importance of lactate acidosis as a side effect of biguanide therapy].

A survey of the literature leads to the conclusion that lactic acidosis should be considered as a side effect of therapy with biguanides. Essential for the development of lactic acidosis seems to be the preexistence or the acute development of renal insufficiency. However, the over-dosage (for instance in the case of attempted suicide) causes acidosis (lactic acidosis) in healthy persons also. Using the experimental animal lactic acidosis is demonstrated following biguanide application. Diagnosis of lactic acidosis is substantiated by acidosis with lactic acid concentrations higher than 8-10 meq/l (= 72-90mg/100 ml) and with considerably increased lactate/pyruvate ratios (50-150). Generally a non ketotic acidosis of diabetic patients (especially under biguanide-therapy) should be considered to be a lactic acidosis. On the other hand the existence of lactic acid concentrations higher than 8-10 meq/l ist characteristic for a lactic acidosis. The prognosis of lactic acidosis induced by biguanides is not too good. Therapy of the acidosis using bicarbonate is not sufficient in most cases. The intravenous application of glucose (or glucose substitutes), perhaps with additional insulin, might be indicated by hypoglycemia. However, this therapy might cause an additional increase in lactic acid concentration. Treatment of choice might be dialysis, effecting the elimination of the biguanides. If peritoneal dialysis is performed acetate containing solutions should be used. Biguanide induced lactic acidosis is prevented by a very cautious selection of patients suited for biguanide therapy. The performance of renal function tests is absolutely necessary if therapy with biguanides is intended. Additionally, periodical control of renal function is required in patients treated with biguanides (at least twice a year). Biguanide therapy should be performed only with extreme caution, because decrease in renal function is very common in older patients.

Acidosis↗

PubMed1977

Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides.

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. Biguanides did not alter faecal weight or faecal fat excretion, but they decreased faecal bile acid excretion. All biguanides tested increased deconjugation of glycocholic acid, as determined by a simple breath test technique. Vitamin B12 malabsorption was most prominent in patients on metformin. Discontinuation of biguanide treatment, or administration of antibiotics, normalized or improved the increased deconjugation of bile acids and the Schilling test. Decreased faecal bile acid excretion, positive 14C-glycocholate breath tests, pathological Schilling tests and the reversal of pathological tests by antibiotic treatment suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic-factor-vitamin B12-complex to bacteria, is responsible for the previously observed pathological Schilling tests in diabetics on biguanides. Bile acid malabsorption, possibly responsible for the cholesterol-lowering effect of biguanides, does not occur in diabetics on biguanides. Whether qualitative changes in small intestinal bile acid composition might affect cholesterol metabolism remains to be determined.

Biguanides↗

PubMed1978

[The risk of lacticate acidosis: a comparison of the 3 biguanides in treatment of diabetics (authors' transl)].

Hyperlactaemia was induced by means of a standard exercise test in 10 diabetics receiving normal treatment with biguanides (either buformin, metformin, or phenformin) in combination with either a sulfonylurea or insulin. The treatment regimen was then continued without biguanides for 3 weeks and the exercise test was repeated at the end of this period. All 3 biguanide preparations induce hyperlactaemia in diabetics. Physical stress leads to an additional increase in lactate, which reaches pathological proportions. Discontinuation of biguanide treatment leads to a significant decrease in resting and stress values. In a comparison of the 3 biguanide products, phenformin induced significantly higher lactate values in response to exercise than buformin. Of the biguanides, phenformin appears to carry the greatest risk of causing hyperlactaemia in susceptible patients, induced by concurrent circumstances, with progression to severe lacticate acidosis. The special pharmacokinetic properties of phenformin and the 8-fold higher incidence of lacticate acidosis than under buformin or metformin therapy support this observation.

Acidosis↗

PubMed1992

Biguanide-associated lactic acidosis. Case report and review of the literature.

PURPOSE: The biguanides are a class of oral hypoglycemic agents that are commonly used in the treatment of diabetes mellitus. Such agents include metformin, phenformin, and buformin. The use of phenformin was discontinued in the United States in 1976 because of probable association with lactic acidosis. However, metformin is currently in common use in many parts of the world. In this report, we describe a patient with severe lactic acidosis secondary to metformin administration, and review the literature relevant to biguanide-associated lactic acidosis. PATIENT: We describe a diabetic man with end-stage renal failure and diabetes mellitus who was hospitalized with life-threatening lactic acidosis (lactate, 10.9 mmol/L). Unbeknownst to the hospital staff, he was being treated with metformin, which had been prescribed in Indonesia. RESULTS: Arterial blood gas analysis revealed a pH of 6.76 and a bicarbonate level of 1.6 mmol/L prior to treatment. Following therapy, which included oxygen, volume expansion, other supportive therapy, and hemodialysis, the patient completely recovered and was discharged from the hospital. CONCLUSIONS: Lactic acidosis can complicate biguanide therapy in diabetic patients with renal insufficiency. We review the literature relevant to the pathogenesis and therapy of biguanide-associated lactic acidosis. Physicians who have completed their training after 1976 may not be familiar with metformin and other biguanides, but with the increasing numbers of immigrants to the United States, physicians should be aware of the potential complications of these medications.

Acidosis, Lactic↗

PubMed1976

[Treatment of primary hyperlipoproteinemias type IV with different biguanides (author's transl)].

In 12 patients with primary type IV hyperlipoproteinemia the lipid lowering effect of constant doses of the biguanides metformin, phenformin and buformin was compared. After a 2 months dietary period bodyweight and initial triglyceride and cholesterol plasma concentrations were stabilized. The three biguanides were given for two months each, and this 6 months drug period was followed by another dietary period. While, 0.15 g phenformin and 2.55 g metformin reduced triglycerides by about 50% the reduction by 0.30 g buformin was only half. This was due to 4 nonresponders with initial triglycerides of more than 700 mg/100 ml. In contrast the triglyceride lowering effect of the other two biguanides was positively correlated to the pretreatment triglycerides. The cholesterol lowering effect of biguanide treatment was far less pronounced. There were no significant alterations of body weight and no influence on basal insulin and glucose concentrations. In conclusion, all three biguanides tested in a dosis of 3 tablets each are effective in lowering triglycerides although differing in efficiency and depending from the degree of typ IV hyperlipoproteinemia.

Biguanides↗

PubMed1978

[Haemodialysis in the treatment of biguanide-induced lactate acidosis (author's transl)].

Severe lactate acidosis developed in nine diabetics on biguanide. When lactate acidosis was diagnosed all patients had reduced renal function, six being oligoanuric. Pre-existing chronic renal failure as a factor in the development of lactic acidosis was excluded in five patients, normal renal function being restored later. All patients were dialysed, seven surviving. This mortality rate is lower than that reported by others for biguanide-induced lactate acidosis. Rapid biguanide elimination by dialysis was demonstrated both in vitro and in vivo. The in vivo clearance of buformin was 83 +/- 43 ml/min (mean +/- SD, n = 4), that of phenformin 68 +/- 33 ml/min (n = 7). The main advantages of haemodialysis in the treatment of biguanide-induced lactic acidosis are rapid removal of toxic biguanides and excess lactate and the ability to administer sodium bicarbonate adequately without risking hypernatraemia and fluid overload.

Acidosis↗

PubMed1992

Biguanide related lactic acidosis: incidence and risk factors.

The objective of this study was to evaluate in an open population the incidence and risk factors of biguanide related lactic acidosis. All patients currently treated in the Department of Diabetes and Lipid Metabolism of the Instituto Nacional de la Nutrición and their records were reviewed for the present use or history of administration of biguanides. The study was complemented with a revision of all admissions of diabetic patients to the emergency room during 1987-1990. In the outpatient study, 235 cases were included. No case of lactic acidosis was found. A high percentage of the biguanide treated patients had one or more lactic acidosis related risk factors. In the emergency study, 609 admissions of 273 patients were included. In 17 patients a metabolic non-ketotic acidosis was diagnosed. The frequency of non-ketotic acidosis for the different treatments was: 29.4 cases x 1000 emergency admissions for sulphonylurea treated group, 32 for sulphonylurea plus phenformin treated and 47.94 for type II insulin treated patients. All cases had severe precipitant diseases that can cause lactic acidosis with or without associated biguanide administration. No metformin related cases were found. The conclusions of this study are that biguanides in general and metformin in particular are not associated with a high risk of lactic acidosis. Severe systemic dysfunction associated with intercurrent diseases, frequently observed in diabetic patients, is the main determinant for the appearance of lactic acidosis.

Acidosis, Lactic↗

PubMed1978

[Four cases of fatal lactic acidosis during biguanide therapy (author's transl)].

Four case reports of lactic acidosis occurring during biguanide treatment (2 with phenormin, 2 with buformin) are analysed. Three of the patients died in a toxic state of lactic acidosis, whilst the fourth patient survived lactic acidosis, but died 11 days later due to myocardial infarction. In spite of serum biguanide levels within the therapeutic range, one patient had highly toxic hepatic levels of phenformin (13,500 ng/g tissue). Two factors are essential for the treatment of lactic acidosis: 1. rapid diagnosis: history of biguanide intake; clinical symptoms; acid-base imbalance; rapid lactate determination to establish the diagnosis. 2. therapy: correction of acidosis, insulin and glucose; shock treatment; forced diuresis and/or haemodialysis. From the high numbers of biguanide-treated diabetics and the incidence of lactic acidosis in other countries it can be assumed that this toxic side effect of biguanide treatment occurs relatively frequently in Austria too, but remains largely undetected.

Acidosis↗

PubMed1978

[The effect of oral butyl-biguanide on oral glucose tolerance and renal glucose reabsorption in normal human subjects in vivo (author's transl)].

1. Oral glucose tolerance in 11 normal subjects was significantly improved after peroral administration of 150 mg of butyl-biguanide. 2. On the other hand maxiumum capacity of renal glucose reabsorption (TmG) and lowest glomerular glucose filtration rate at which glucosuria was recorded (F min) remained uninfluenced after 150 mg of butyl-biguanide in 7 normal subjects. 3. These results are compatible with the hypothesis that the oral administration of therapeutic doses of biguanides yields concentrations at the luminal face of the intestine which inhibit glucose resorption. Plasma concentrations following oral intake of the same dose of biguanide are too low to exert any inhibiting action on renal glucose reabsorption as demonstrated by the present in vivo studies. 4. Urinary flow rate and inulin clearance remained unaltered after butyl-biguanide in these normal subjects.

Administration, Oral↗

PubMedDate not supplied

[Treatment of diabetes mellitus with long-acting biguanides].

The paper discusses of the results of treatment with preparations of phenylethylbiguanide (dibotin, meltrol, dipar, dibophen-retard), of butylbiguanide (silubin-retard, buforming-retard) and of dimethyl-biguanide (glucophage-retard). All these preparations were of prolonged action. The treatment was carried out in 242 patients. The saccharolytic action of the active agent contained in one tablet of each type of biguanide was approximately the same. Biguanides of prolonged action were highly effective in obese patients with diabetes mellitus of moderate severity. The best results were obtained in complex treatment with biguanides of prolonged action together with sulfonylurea preparations of the second generation. There were noted almost no toxic reactions from the use of biguanides up to 2 tablets a day.

Adult↗

PubMed1975

Inhibition of bile salt absorption by blood-sugar lowering biguanides.

The effect of blood sugar lowering biguanides (phenethyl-, butyl- and dimethylbiguanide) upon jejunal and ileal transport of bile salts (tauro- and glycocholate) was tested in rat small intestine by an in vitro technique. Giguanides inhibited active transport of bile salts in the ileum, but did not affect diffusional absorption of bile salts in the jejunum. The inhibitory effect was time-dependent and not reversible under in vitro incubation conditions, suggesting that biguanides must enter intestinal mucosal cells in order to exert their inhibitory action on active transport of glucose analogues, amino acids, calcium and bile salts. Since biguanides achieve high tissue concentrations in the small intestine even after parenteral administration, inhibition of ileal bile salt reabsorption by biguanides could possibly explain the lipid- and cholesterol-lowering effect of these oral antidiabetic drugs.

Animals↗

PubMed1979

Biguanide-induced lactic acidosis in Finland.

Twenty-four patients with biguanide-induced lactic acidosis were reported to the Adverse Drug Reaction Register of the Finnish National Board of Health from 1974-1977. Of them, 23 had been treated with phenformin and one with metformin. The mean age of the patients was 71 years, and all but one were more than 65 years of age. The mortality rate was 63%. One patient had cirrhosis of the liver and one was already known tohave had impaired renal function. Fourteen of the patients had a normal serum creatinine concentration either before or after the development of lactic acidosis. Thus, in most patients it had not been possible to prevent development of lactic acidosis by observing the contraindications to biguanide therapy. Most patients had some form of co-existing cardiovascular disease. Tetracycline therapy was a probable precipitating factor in three cases. Based on the statistics of biguanide consumption in Finland, the annual incidence of biguanide-induced lactic acidosis in 1976 and 1977 was between 1/2000 and 1/3000 and that of fatal lactic acidosis was 1/4000.

Acidosis↗

PubMed1975

Studies on juvenile--type diabetes in children. Assessment of control under treatment with constant and variable doses of insulin with or without addition of biguanides.

Studies were carried out in juvenile-type diabetics in a home for diabetic children which offered the advantages of both "normal" living conditions and strict medical and dietetic control. In 43 insulin-dependent, juvenile diabetics, blood glucose was determined at least 3 times, and some times on 6 occasions, per 24 hours on 3 days a week over 3 months. Blood glucose was estimated in every case of suspected insulin reaction. Determination of cholesterol, triglyceride, growth hormone and antibodies against bovine and porcine insulin were also carried out. Randomized groups of patients were treated alternately with 1) constant, 2) variable insulin doses, 3) addition of biguanides (metformin). Calculated parameters included mean daily blood glucose, mean of absolute differences between daily blood glucose values, daily insulin requirements, frequency of verified insulin reactions and mean blood glucose profiles pre- and postprandially. Addition of biguanides did not decrease blood glucose differences nor the frequency of hypoglycemic episodes. Daily insulin doses were lowered by the drug. Variable insulin doses appeared to be superior to constant ones. Daily insulin requirements were positively correlated with age and weight of patients. Elevated levels of cholesterol were lowered by biguanides. In suspected cases of insulin reaction, blood glucose levels above 100 mg/100 ml were found in more than 40%. No differences existed in insulin requirements, age and duration of diabetes between childhood diabetics with or without significant titers of insulin antibodies. Three postprandial blood glucose determinations gave no essential information over and above the 3 preprandial estimations as far as blood glucose fluctuations were concerned. No smoothing effect of biguanides was apparent from the study whereas an insulin-sparing effect is exerted by these drugs as well as a lowering of elevated levels of cholesterol.

Adolescent↗

PubMed1979

Quantitative structure-activity relationships for biguanides, carbamimidates, and bisbiguanides as inhibitors of Streptococcus mutans No. 6715.

Thirty-seven compounds, including 17 biguanides, 6 carbamimidates, and 14 bisbiguanides, were evaluated for potential antiplaque activity by measuring their minimum inhibitory concentrations [MIC (M)] against Streptococcus mutans no. 6715. Linear regression analysis was conducted with the log 1/MIC (M) values and log P, pi, sigma, and MR. The best correlation for the biguanides (r2 = 0.92) was obtained with log P and (log P)2. When the biguanides were included with the carbamimidates, essentially the same correlation (r2 = 0.91) was obtained with log P and (log P)2. The best correlation for the bisbiguanides (r2 = 0.70) was also obtained with log P and (log P)2. Use of an indicator variable (I) for the bisgiguanides allowed all three groups to be included in one equation, which accounted for over 87% of the variance in the data for inhibition of bacterial growth. These results from the classical parabolic model were also compared with those from the recently developed bilinear model.

Biguanides↗

PubMed1977

[Lactic acidosis in diabetics on biguanides (author's transl)].

A systematic search for cases of lactic acidosis among diabetics on biguanides revealed ten during an eight-month period, while in the preceding ten years not a single case had been definitely diagnosed. This represents a prevelance of 1 in 2000 patients admitted to hospital. All ten were over 60 years old and had previously been treated for heart failure. Most of them had suffered from renal insufficiency for some time. There was no case of biguanide overdosage. Criteria for the diagnosis of lactic acidosis are lactic concentration in blood averaging 18.4 mmol/l and a low pH, averaging 6.9. Serum-biguanide concentration (measured by radioimmuno-assay) was markedly increased. Most of the patients were in circulatory shock on admission or soon after and all of them had a history of gastro-intestinal complaints. Despite intensive treatment with insulin and glucose and careful correction of the acidosis with bicarbonate four of the ten patients died.

Biguanides↗

PubMed1979

[Serum concentration of lactate in diabetic patients treated with biguanides in relationship to renal function (author's transl)].

Lactate, pyruvate, creatinine, urea, blood sugar and the serum concentration of phenformin or buformin were analyzed in the venous blood of a total of 90 diabetics who received biguanides regularly for at least one month. The creatinine clearance as well as the lactate-pyruvate quotient were computed. Age, body weight and size as well as duration of medication were recorded. Twenty-three diabetics who did not receive biguanides were used for control. Almost all patients revealed a mostly minor hyperlactatemia which was also observed in the control group. There was no significant difference between the two groups. There was no relationship between renal function, the serum lactate level and the biguanide concentration.

Aged↗