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Biomedical subjects

M M O'Brien

Publications and source records attributed to M M O'Brien.

29 records · Page 2Linked to original sources
PubMed1984

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Administration, Oral↗
PubMed1983

Polyol-pathway enzymes of human brain. Partial purification and properties of sorbitol dehydrogenase.

Sorbitol dehydrogenase was isolated from human brain and purified 690-fold, giving a final specific activity of 11.1 units/mg of protein. The enzyme preparation was nearly homogeneous, but was unstable at most temperatures. It exhibited a broad pH optimum of 7.5-9.0 in the forward reaction (i.e. sorbitol leads to fructose), and of 7.0 in the reverse reaction (i.e. fructose leads to sorbitol). Substrate-specificity studies demonstrated that the enzyme had the capability to oxidize a wide range of polyols and that the enzyme had a higher affinity for substrates in the forward reaction than in the reverse reaction, e.g. Km for sorbitol was 0.45 mM, and that for fructose was 480 mM. However, the Vmax. was 10 times greater in the reverse reaction. At high concentrations of fructose (500 mM) the enzyme exhibited substrate inhibition in the reverse reaction. The enzyme mechanism was sequential, as determined by the kinetic patterns arising from varying the substrate concentrations. In addition, both fructose and NADH protected the enzyme against thermal inactivation. These findings, together with product-inhibition data, suggested that the mechanism is random rapid equilibrium with two dead-end complexes.

Brain↗
PubMed1983

Pharmacokinetics of sulbactam in humans.

Sulbactam, a new beta-lactamase inhibitor, has pharmacokinetic characteristics in humans similar to those of ampicillin and amoxicillin. Its half-life in humans is approximately 1 h. In a two-compartment pharmacokinetic model, the apparent volume of distribution for the central compartment is approximately 12 liters, and half of the dose is found in the central compartment in the postdistributive phase. Approximately 75% of a parenteral dose is excreted unchanged in urine. The coadministration of sulbactam with ampicillin, penicillin G, or cefoperazone has essentially no effect upon the kinetics of either the beta-lactam antibiotic or sulbactam.

Adult↗
PubMed1982

Inhibition of human brain aldose reductase and hexonate dehydrogenase by alrestatin and sorbinil.

Human brain aldose reductase and hexonate dehydrogenase are inhibited by alrestatin (AY 22,284) and sorbinil (CP 45,634). Inhibition by alrestatin is noncompetitive for both enzymes, and slightly stronger for hexonate dehydrogenase (KI values 52-250 microM) than for aldose reductase (KI values 170-320 microM). Sorbinil inhibits hexonate dehydrogenase far more potently than aldose reductase, KI values being 5 5 microM for hexonate dehydrogenase and 150 microM for aldose reductase. The inhibition of hexonate dehydrogenase by sorbinil is noncompetitive with respect to both aldehyde and NADPH substrates, and is thus kinetically similar to the inhibition by alrestatin. However, sorbinil inhibition of aldose reductase is uncompetitive with respect to glyceraldehyde and noncompetitive with NADPH as the varied substrate. Inhibition of human brain aldose reductase by these two inhibitors is much less potent than that reported for the enzyme from other sources.

Aldehyde Reductase↗
PubMed1981

Kinetics of an orally absorbed aldose reductase inhibitor, sorbinil.

Kinetics of sorbinil, an orally absorbed reductase inhibitor, were examined in man. Peak plasma concentrations were 0.95 micrograms/ml after a single 50-mg oral dose and 3.6 micrograms/ml after a 250-mg dose. The apparent volume of distribution was 840 ml/kg. Elimination from plasma was slow with a terminal half-life between 6 and 24 hr after dose of 34 to 52 hr and a renal clearance of 6.0 ml/min/1.73 m2. Administration of 50 mg/day for 5 days induced a mean peak serum concentration of 1.9 micrograms/ml. A dose of 250 mg/day for 10 days induced a peak serum concentration of 10.6 micrograms/ml. A mean of one-third of the dose was ultimately recovered unchanged in urine. Sorbinil kinetics make it suitable for once-a-day dosing.

Administration, Oral↗
PubMed1980

Polyol-pathway enzymes of human brain. Partial purification and properties of aldose reductase and hexonate dehydrogenase.

Aldose reductase and hexonate dehydrogenase were isolated from human brain and partially purified. The two enzymes exhibited distinctive substrate-specificity profiles with a variety of aldoses,and aliphatic and aromatic aldehydes. Aldose reductase exhibited a high affinity for DL-glyceraldehyde (Km of 62 microM) and a low affinity (Km of 90 mM) for glucose, the physiological substrate of the polyol pathway. Hexonate dehydrogenase exhibited a relatively low affinity for D-glucuronate (Km of 4.6 mM) and a very low affinity for glucose (Km of 390 mM). Both enzymes exhibited a high specificity for NADPH, and both were inhibited competitively by NADP+. Hexonate dehydrogenase was inhibited by iodoacetate, iodoacetamide, N-ethylmaleimide and p-chloromercuribenzoate. Preincubation with 2-mercaptoethanol resulted in activation. Both enzymes were inhibited by a number of barbiturates (barbital, phenobarbital and pentobarbital) and by the central-nervous-system drugs diphenylhydantoin and ethosuccinimide. The substrate specificity and pattern of inhibition suggest that the two enzymes isolated correspond to two of four previously reported aldehyde reductases isolated from human brain.

Aldehyde Reductase↗
PubMed1967

Urinary pyrophosphate in normal subjects and in stone formers.

The urinary excretion of inorganic pyrophosphate was determined in nine normal subjects and also in eight patients with recurrent calcium-containing renal stones during varied levels of phosphate intake. The excretion of pyrophosphate and orthophosphate is virtually the same in the two groups at all levels of phosphate intake. It appears unlikely that a consistently reduced urinary excretion of pyrophosphate is a factor in the formation of urinary calculi. Pyrophosphate excretion rose and calcium excretion fell with increasing phosphate intake; this might be expected to have a beneficial effect in patients with recurrent calcium stones.

Adult↗