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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↗
PubMed2004

Resistance, biguanide sorption and biguanide-induced pentose leakage during encystment of Acanthamoeba castellanii.

AIMS: This study investigates the effects of biguanides during encystment of Acanthamoeba castellanii. METHODS AND RESULTS: A non-nutrient encystment system was used to investigate the changes in the levels of sorption (uptake) of three non-cysticidal concentrations (10, 20 and 50 microg ml(-1)) of chlorhexidine diacetate (CHA) and polyhexamethylene biguanide (PHMB) as well as their effects on viability and leakage of pentose sugars during the first 36 h of encystment. Trophozoites treated with CHA or PHMB were more sensitive and generally sorbed more of each biocide than cysts. During encystment, the largest increases in resistance developed between 18 and 36 h for both biguanides with the resistance emerging to biguanide concentrations of 10 or 20 microg ml(-1) between 18 and 24 h. At 50 microg ml(-1) resistance emerged between 24 and 36 h. There was a general decrease in biocide sorption during encystment between 0-24 and 0-21 h for CHA and PHMB, respectively, at a concentration of 50 microg ml(-1). The greatest decline in biguanide-induced pentose leakage was between 0 and 12 h. CONCLUSIONS: The results suggest that during encystment some of the changes in the susceptibility to CHA or PHMB may be related to decreases in the levels of biocide sorption, which is limited by the developing cyst wall. SIGNIFICANCE AND IMPACT OF THE STUDY: During encystation, changes occur in biguanide sensitivity. The physical barrier of the cyst wall may be an important factor in limiting biocide sorption.

Acanthamoeba↗
PubMed2003

Determination of biguanide groups in polyhexamethylene biguanide hydrochloride by titrimetric methods.

The biguanide concentration of polyhexamethylene biguanide hydrochloride (PHMB-HCl) was measured by non-aqueous titration with HClO4, argentometric titration, the Kjeldhal method, and colloidal titration. The summation value of non-aqueous titration and argentometric titration corresponded to two titrable nitrogens in five nitrogens per one unit of PHMB-HCl, and consisted with the result of the Kjeldhal method to the five nitrogens. The colloidal titration of PHMB-HCl at pH 2.05 was equal to that with the two nitrogens. The relative standard deviations of non-aqueous titration, argentometric titration, the Kjeldhal method, and colloidal titration were 0.50% for 8 runs, 0.13% for 7 runs, 3.61% for 6 runs, and 0.69% for 6 runs, respectively.

Biguanides↗
PubMed1999

Electron-microscopic study of the bactericidal effect of OPB-2045, a new mono-biguanide disinfectant produced from biguanide group compounds, against Pseudomonas aeruginosa.

The bactericidal activity of OPB-2045 (1-(3,4-dichlorobenzyl)-5-octylbiguanide monohydrochloride hemihydrate) at several concentrations against Pseudomonas aeruginosa IFO 13275 was investigated morphologically by transmission and scanning electron microscopy. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of OPB-2045 against P. aeruginosa were the same, at 12.5 microg mL(-1), suggesting that it may be a suitable disinfectant for use in the medical field. Test bacteria were treated at concentrations of one half the MIC value (6.25 microg mL(-1)), the MIC value (12.5 microg mL(-1)), twice the MIC value (25 microg mL(-1)) or ten times the MIC value (125 microg mL(-1)) at 37 degrees C for 30 min or 6 h and the cells were then examined by transmission and scanning electron microscopy. The cell damage evident after 6h incubation was greater than observed after 30 min incubation. Especially, at one half the MIC, no cell damage was evident after 30 min incubation, but damaged cells were observed after 6 h incubation. The proportion of empty cells of P. aeruginosa increased as the concentration of added disinfectant was increased, and the release of intracellular components was also recognized. These results suggest that OPB-2045 acts on the cell membrane and cell wall of P. aeruginosa, and destroys their integrity at the level of the MIC (MBC). With the increase in OPB-2045 concentration and the increase in reaction time, the bactericidal effect increased markedly. Agglutination of the cells was observed at high concentrations of OPB-2045. This indicates that the bactericidal effect at high concentrations of OPB-2045 differs from that at low concentrations. A clear cell-damaging effect against the test strain was recognized which was dependent on the OPB-2045 concentration and the incubation time. From experiments concerning the relationship between the number of surviving bacteria and MIC values in soybean casein digest broth, the decrease in bacterial numbers was found to be dependent on the OPB-2045 concentration. We conclude that it would be a useful contribution to the medical field to supply a new disinfectant to be employed in preventive countermeasures against infection caused by pathogenic bacteria.

Anti-Infective Agents, Local↗
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↗
PubMed1980

[The effect of biguanides on insulin sensitivity of maturity onset diabetics (author's transl)].

The effect of short-term treatment with biguanides on the insulin sensitivity (KITT) of maturity onset diabetics was tested by means of an insulin tolerance test. On the basis of their long-term blood glucose response to biguanide therapy, the patients were classified retrospectively as biguanide-responsive subjects (n = 10) and as biguanide-non-responsive subjects (n = 10). Both group showed the typical marked reduction in insulin sensitivity of maturity onset diabetics. After three days of biguanide treatment, a highly significant (p less than 0.001) increase in insulin sensitivity was noted in the group of biguanide responders, which was significantly (p less than 0.02) correlated with their previous blood glucose response to long-term biguanide therapy. In the biguanide non responders, insulin sensitivity was not significantly altered by biguanides. It is suggested that the blood glucose lowering action of biguanides is due, at least in a definite group of patients with maturity onset diabetes, to a reduction of insulin resistance.

Aged↗
PubMed2003

Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents.

Various biguanide derivatives are used as antihyperglycemic and antimalarial drugs (e.g., 1,1-dimethyl biguanide (metformin), phenylethyl biguanide (phenformin), N-(4-chlorophenyl)-N'-(isopropyl)-imidodicarbonimidic diamide (proguanil)); however, no common mechanism has been suggested in these controversial therapeutic actions. Biguanides bind endogenous metals that inhibit cysteine proteases independently, e.g., Zn(2+), Cu(2+), Fe(3+). Here, various biguanide derivatives are reported to be metal-interactive inhibitors of cathepsin B from mammals and falcipain-2 from Plasmodium falciparum. Structural homologies were identified among the Phe-Arg protease substrate motif and the metal complexes of phenformin and proguanil. Molecular modeling revealed that the position of the scissile amide substrate bond corresponds to the biguanide-complexed inhibitory metal when the phenyl groups are homologously aligned. Binding of the phenformin-metal complex within the active site of human cathepsin B was modeled with computational docking. A major binding mode involved binding of the drug phenyl group at the protease S2 subsite, and the complexed inhibitory metal shared between the drug and the protease Cys29-His199 catalytic pair. Cysteine protease inhibition was assayed with carbobenzyloxy-PHE-ARG-7-aminomethylcoumarin substrate. In the absence of metal ions, phenformin was a weakly competitive protease inhibitor (apparent K(i) several microM); however, metformin was noninhibitory. In contrast, the metal complexes of both metformin and phenformin were protease inhibitors with potency at therapeutic concentrations. Biguanide-metal complexes were more potent cysteine protease inhibitors than either the biguanide or metal ions alone, i.e., synergistic. Similar to chloroquine, therapeutic extracellular concentrations of metformin, phenformin, and proguanil caused metal-interactive inhibition of lysosomal protein degradation as bioassayed in primary tissue using perfused myocardium. The biguanide moiety is identified as a past and future structural scaffold for synthesis of many protease inhibitors. Results are discussed in relation to Zn(2+)-interactive inhibition of insulin degradation in hormone target tissues, and Fe(3+)-interactive inhibition of hemoglobin degradation in parasite food vacuoles. Previous studies on insulin hypercatabolism and insulin resistance are speculatively reviewed in light of present findings.

Animals↗
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↗
PubMed1996

Effects of polyhexamethylene biguanide and chlorhexidine on four species of Acanthamoeba in vitro.

We determined the relative minimal inhibitory and minimal amoebicidal concentrations of chlorhexidine digluconate and polyhexamethylene biguanide for four species of Acanthamoeba. The amoebae were grown in peptone-glucose-yeast extract broth for 72 h in tissue culture flasks. Either washed trophozoites (approximately 10(5)) or cysts (approximately 10(5)) were incubated in the enrichment broth in 96 well microtiter trays. Antimicrobial concentrations of the biguanides were determined from microscopic examinations of methylene blue uptake and from subcultures. In general, killing was time dependent. Minimal amoebicidal concentrations at 24 h ranged from 50 to 100 mg/ml and to as low as 25 mg/ml by 72 h. Trophozoites were killed more rapidly than cysts. Both biguanides had similar levels of activity. A synergistic combination of chlorhexidine and polyhexamethylene biguanide (total concentration 25 mg/ml) was most evident for A. castellanii and A. polyphaga. Cysts of A. culbertsoni and A. hatchetti stained more rapidly after exposure to the combination of biguanides than to the single biguanides, but there were no statistically significant differences in the final numbers of dead or stained cysts after exposure to the combination or to the single biguanides.

Acanthamoeba↗
PubMedDate not supplied

[Use of biguanide preparations in the treatment of diabetes mellitus].

The blood content of lactic acid was measured in 186 patients with overt diabetes mellitus. The patients had normal or excess body weight and were placed on different treatment methods during decompensation, subcompensation and compensation stages. During diabetes mellitus compensation attained with different treatment methods as well as during treatment including biguanides in the presence of normoglycemia, the mean blood level of lactic acid did not differ significantly from its mean content in normal subjects. Patients with decompensated diabetes mellitus manifested a significant elevation of the mean blood content of lactic acid. There was a definite relationship between the glycemia and high lactic acid level in the blood. Based on an analysis of the reported data and own materials the conclusion is drawn that biguanides should not be used in the treatment of decompensated diabetes mellitus, since this may lead to an increase in blood lactic acid and to the growth of lactic acidosis risk. It is proposed that contraindications to the use of biguanides in diabetes mellitus patients should also include hyperglycemia. Indications to the use of biguanides in diabetes mellitus patients are provided as well as the table of diseases in which biguanides are contraindicated. A list of drugs incompatible with biguanides is also presented. It is recommended that biguanides should not be applied for over 4 to 6 months. It is also recommended that detection of blood lactic acid should be introduced into medical practice on a wider basis, since lactic acidosis cannot be diagnosed without using such a test.

Adolescent↗
PubMed2002

Phagocytosis affects biguanide sensitivity of Acanthamoeba spp.

The incidence of Acanthamoeba keratitis, a disease associated with contact lens wear, has been in apparent decline with the advent of multipurpose contact lens solutions. The concentrations of the biguanides chlorhexidine digluconate (CHX) and particularly polyhexamethylene biguanide (PHMB) included in multipurpose solutions (MPSs) are sublethal for amoebae. We evaluated by flow cytometry the effects of these two biguanides on phagocytosis of particles and the survival of trophozoites of Acanthamoeba castellanii and A. polyphaga. Trophozoites of A. castellanii and A. polyphaga (10(6)/ml) were exposed to solutions of 5 and 50 microg of PHMB and CHX per ml in the presence and absence of particles (i.e., heat-killed yeasts and bacteria and latex beads). In addition, trophozoites were exposed to particles treated with these concentrations of the two biguanides. In the absence of particles, trophozoites of A. polyphaga appeared to be more resistant to the biguanides than those of A. castellanii. In the presence of particles, the rates of survival of both species were decreased. In most instances, particles treated with sublethal concentrations of both biguanides that were adsorbed onto the particles reduced the incidence of phagocytosis. Particles present in MPSs in contact lens cases may be involved in the decreased incidence of Acanthamoeba keratitis.

Acanthamoeba↗
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↗