Biomedical subjects
Publications and source records attributed to L Balant.
Different doses of glibenclamide and of 4-transhydroxy-glibenclamide (main metabolite in man) were administered i.p. to rats and blood glucose was measured. The comparison of the doses capable of producing a 30% decrease of the glycemia shows that 4-trans-hydroxy-glibenclamide is about 6.5 times less potent than glibenclamide in our experimental conditions.
Three electrophoretic techniques are usually available in the clinical laboratories for the qualitative investigation of urinary protein patterns: 1) acetate cellulose, 2) immuno-electrophoresis; and 3) SDS-polyacrylamide gel electrophoresis. Proteinuria (the excretion of proteins in excess of 150 mg/day or 100 microgram/min) usually signifies either increased permeability of the glomerular-capillary membrane of diminished tubular reabsorption. Since glomerular disease is associated with an increased clearance of albumin and higher molecular weight proteins, whereas tubular damage is associated with the predominant excretion of proteins of lower molecular weight than albumin, it seems logical to establish a classification of proteinuria according to the molecular weight of its constituents. One can thus basically distinguish 5 types of proteinurias: 1) physiological; 2) tubular; 3) selective glomerular; 4) non selective glomerular; and 5) mixed proteinurias. Additionally one must distinguish "myeloma proteinurias" where monoclonal complete or incomplete gamma-globulins are found in the urine. Clinically it may be useful to determine the qualitatively normal or pathologic character of a quantitatively normal proteinuria, especially in the following conditions: 1) for early diagnosis of nephropathy in patients, such as diabetics, which are particularly prone to suffer from renal complications; 2) to confirm the clinical cure or to predict the recurrence of renal diseases; and 3) in such situations as orthostatic, or myeloma proteinuria, or any elevation of the urinary protein output of unknown etiology.
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In a group of 29 patients treated with digoxin for cardiac failure, only 16 showed increased calcium and potassium concentrations in saliva. There was no correlation in the 29 patients between serum digoxin levels and concentrations of salivary electrolytes. On the other hand, in 4 normal subjects treated with digoxin no change in salivary electrolytes was noted. It is concluded that modifications in salivary electrolytes seen in patients with cardiac failure treated with digitalis are not due to this drug. However, a retrospective clinical study showed a good correlation between clinical signs of cardiac failure and increased levels of salivary calcium, potassium and CaX Kproduct. It is suggested that this phenomenon is due to the well-known adrenergic stimulation in patients with cardiac failure.
Renal insufficiency is a factor which predisposes to hypoglycemic accidents in subjects treated with hypoglycemic sulfonylureas. Glibenclamide (glyburide) is eliminated from the body mainly by metabolism, with the result that renal insufficiency has little effect on its biotransformation. In order to determine to what extent the retention of the metabolities intervenes in such hypoglycemic accidents, rats with ligatured ureters received intraperitoneal injections of 1 mg/kg glibenclamide or hydroxy-glibenclamide (the main metabolite), or of saline. For each animal there was a control animal which had undergone a simulated operation. For six rats with renal insufficiency, glibenclamide caused hypoglycemia of the same intensity as in the control group but more prolonged. With hydroxy-glibenclamide the glycemia was signficantly lower than in the control group. Hydroxy-glibenclamide has an obvious hypoglycemic activity which represents 1/6 of that of the parent drug, but 50--100 times that of tolbutamide. Its retention contributed to the intensification and prolongation of the hypoglycemic effect of glibenclamide in rats with renal insufficiency.
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A study has been conducted to determine the accuracy of breath-H2 measurements for quantitating the malabsorption of small amounts of carbohydrate. H2 pulmonary excretion was measured after an overnight fast at 30-min intervals for 4 h in 7 healthy subjects after ingestion of 4 doses of lactulose (2.5,5,10 and 50 g). In 3 subjects the test was repeated without lactulose. The volume of H2 excreted was directly proportional to the amount of ingested lactulose: mean cumulative H2 excretion over a 2-h period after 5, 10 and 50 g was 2.9, 6.6 and 37.6 ml H2 respectively; H2 response after the 2.5-g dose was not perceptible. Individual H2 excretion before lactulose ingestion was highly variable: 0.096 +/- 0.075 mlH2 (mean +/- 1 SD); the individual base line rate over a fasting period showed marked fluctuations. It is concluded that the inter- and intraindividual variations of H2 excretion limit the accuracy of the H2 breath test for quantitating malabsorption of small amounts of carbohydrate.
Plasma concentrations of tolamolol and bufuralol (beta-blocking agents) were measured after oral and intravenous administration to healthy volunteers. The plasma levels of their main metabolite was also determined. Simultaneously, the effect of the drugs on the heart rate and blood pressure was monitored under various stimuli (isoproterenol, exercise or orthostatism) and Valsalva maneuver. When given orally, the two drugs are extensively metabolized by a hepatic first-pass effect. After reaching the systemic circulation, they are metabolized in the liver to hydroxylated derivatives with similar pharmacologic activity as the parent molecule. For tolamolol it is possible to demonstrate a good correlation between parent drug blood levels and the pharmacodynamic effect; this relation is less evident for bufuralol. The pharmacokinetic analysis of the behaviour of the two beta-blocking agents and their main metabolite makes it possible to explain this difference in part. The results of the present study emphasize the importance of measuring metabolites when dose-action relationships are investigated.
D-xylose pharmacokinetics has been studied in 6 healthy subjects by serial measurement of blood and urinary levels following oral and intravenous administration of two doses of D-xylose (5 and 25 g successively). Furthermore, patients with obesity, renal or hepatic insufficiency, or with a T-drain after cholecystectomy, are also investigated. Both the rate and completeness of D-xylose absorption and the apparent distribution volume of D-xylose present noteworthy interindividual variations, so that the time and value of the peak blood level are highly variable as between healthy subjects. Renal insufficiency increases the apparent elimination half-life of D-xylose and notably reduces D-xylose renal excretion. This study provides pharmacokinetic evidence of the very wide range of blood and urinary levels observed in the D-xylose tolerance test, and emphasizes the fact that D-xylose urinary excretion alone is not a reliable index of intestinal absorption.
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Glibenclamide, a hypoglycemic sulfonylurea, is extensively metabolized by the body and eliminated primarily in the form of its hydroxylated derivatives. The major metabolite, 4-trans-hydroxy-glibenclamide, is usually cleared rapidly from the bloodstream, but in certain pathological states (e.g. renal failure) blood levels of this product may increase. A protocol therefore was designed to test the hypoglycemic potency of this important metabolite in rats. Various quantities were injected intraperitoneally, and alterations in blood glucose concentrations were measured during a 5-hour period and compared to those in animals similarly treated with glibenclamide and in saline-injected controls. Using the dose capable of decreasing blood glucose levels by 30% (ED30) as a comparative index, it was observed that the metabolic has a marked hypoglycemic activity; though 6--7 times less potent than the parent drug, 4-trans-hydroxy-glibenclamide is nevertheless more potent than tolbutamide. Thus, while the glibenclamide metabolite probably has little influence on blood glucose when its clearance is normal, this product may exert marked effects if allowed to accumulate in the blood, as for example in renal failure. Finally, the role of such sulfonylurea metabolites should be taken into account when attempting to explain the occasional excessive and sustained hypoglycemia which occurs in some diabetic patients treated with these drugs.
Side effects due to ingestion of nalidixic acid in a 46 year old patient with phenacetine-induced interstitial nephritis and severe renal failure are reported. This observation underlines the point that, besides the direct neurotoxic effect of nalidixic acid, disturbance of the acid-basic equilibrium could be seen in patients with renal failure in particular. A hypothetical pharmacokinetic model suggests that two metabolites of nalidixic acid could provide enough hydrogen ion to induce acidosis in cases of renal failure.