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Biomedical subjects

M M Reidenberg

Publications and source records attributed to M M Reidenberg.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of 11 beta-hydroxysteroid dehydrogenase by gossypol and bioflavonoids.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes hydrocortisone to inactive cortisone in the kidney and is an important regulator of renal K+ clearance. Gossypol, in clinical trials as an antifertility drug for men in China, was associated with episodes of hypokalemia. To learn whether gossypol and other structurally similar compounds in plants can inhibit 11 beta-OHSD activity, purified enzyme from rat liver and in human renal cortical microsomes was studied. Rat liver enzyme was inhibited by glycyrrhetinic acid > gossypol >> morin > quercetin >> rutin. Glycyrrhetinic acid, gossypol, and morin inhibited activity of the human kidney enzyme. Enzyme in microsomes from five human kidneys had an IC50 (S.D.) of 1.5 (1.2) mumol/L for glycyrrhetinic acid; enzyme in microsomes from six human kidneys had a 50% inhibitory doses of 147 (25) mumol/L for gossypol. Our observations indicate that gossypol and other compounds in plants can inhibit 11 beta-OHSD activity and may thereby increase K+ excretion.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Inhibitory effects of gossypol on corticosteroid 11-beta-hydroxysteroid dehydrogenase from guinea pig kidney: a possible mechanism for causing hypokalemia.

Inhibition of 11-beta-hydroxysteroid dehydrogenase (11-beta-OHSD) in the kidney can cause excess mineralocorticoid effect and hypokalemia. To find out if gossypol, a potential oral contraceptive for men that has been associated with cases of hypokalemia, inhibits this enzyme, its effect on guinea pig kidney was studied. Working with microsomes from the kidney cortex, and using corticosterone as the substrate, racemic gossypol was found to be a competitive inhibitor of 11-beta-OHSD with a Ki of 67 +/- 5 microM. The (+) enantiomer was a little more potent than the (-) enantiomer. Microsomes from the kidneys of animals given gossypol for 2 weeks had lower enzyme activities than saline-treated animals. Microsomes from a strain of hairless guinea pigs had lower intrinsic enzyme activity than the normal animals. We conclude that there is genetic variation in the activity of this enzyme and that it can be inhibited by gossypol.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Stereoselective interaction between gossypol and rat plasma.

Gossypol, a potential male oral contraceptive, is chiral and chemically reactive. The present study was done to learn more about the stereoselective activity of this drug. The isomers were equipotent in hemolyzing erythrocytes in protein-free buffer while (+) gossypol was a more potent hemolysin than (-) in plasma. Both isomers disappeared from buffer at the same rate while (-) disappeared from plasma much faster than (+). Treating plasma with aspirin or DNFB to react with the free amino groups on the protein, slowed the disappearance of (-) gossypol. We conclude that (-) gossypol binds to free amino groups on protein and this stereoselective protein binding may account for some of the pharmacokinetic or pharmacodynamic difference between the two isomers of gossypol.

Animals↗
PubMed1990

Dopamine clearance in critically ill infants and children: effect of age and organ system dysfunction.

To learn if there are age-related differences in the pharmacokinetic behavior of dopamine, plasma dopamine clearance was determined in 27 acutely ill infants and children who were receiving a continuous intravenous infusion of the drug. Steady-state clearance was calculated from dopamine concentration in arterial blood. Dopamine clearance was 60.7 +/- 28.1 ml/kg/min. The age of the patient exerted an effect on clearance of dopamine (r = -0.63; p less than 0.05), and dopamine clearance was nearly twice as rapid in children younger than 2 years as it was in older children (82.3 +/- 27.7 ml/kg/min versus 45.9 +/- 17.0 mg/kg/min). Conjugated bilirubin exerted an age-independent effect on clearance of dopamine; clearance was 44.8 +/- 28.6 ml/kg/min in children with abnormal conjugated bilirubin (greater than or equal to 0.9 mg/dl) and 70.1 +/- 2.56 ml/kg/min in children with normal conjugated bilirubin (less than 0.9 mg/dl). Clearance was lowest (29.8 +/- 5.7 ml/kg/min) in the four children who had both hepatic and renal dysfunction. Age is an important determinant of dopamine clearance, explaining in part the clinical observation that infants and young children require higher infusion rates.

Adolescent↗
PubMed1990

Lack of effect of glutathione depletion by L-buthionine-S,R-sulfoximine on gentamicin nephrotoxicity in rats.

The mechanism of gentamicin-induced renal proximal tubular cell injury is not known, but generation of reactive oxygen species with subsequent lipid peroxidation has been proposed. In this study, male adult rats were given gentamicin and L-buthionine-S,R-sulfoximine (BSO), a selective glutathione (GSH)-depleting agent, to determine the effects of GSH depletion on acute gentamicin-induced nephrotoxicity. Urinary N-acetyl-beta-glucosaminidase (NAG) excretion increased equally in the groups given gentamicin alone compared to the groups given gentamicin and BSO. BSO treatment alone did not increase NAG excretion. GSH depletion by BSO did not enhance either gentamicin-induced azotemia or the degree of cell necrosis seen by light microscopy. In conclusion, BSO-induced GSH deficiency does not enhance acute gentamicin nephrotoxicity, suggesting that reactive oxygen species are not the major initiating cause of gentamicin-induced acute kidney injury.

Acetylglucosaminidase↗
PubMed1989

The teaching of clinical pharmacology in Europe and North America.

A recent survey conducted under the auspices of the WHO shows that on average in European medical schools only 28 hours of teaching are devoted to clinical pharmacology, whereas over 100 hours are devoted to pharmacology. In many schools no clinical pharmacology is taught, and there is a lack of trained individuals and posts in clinical pharmacology. In North America there is a similar lack of clinical pharmacology teaching.

Europe↗
PubMed1989

Increased renal tubular cell excretion by patients receiving chronic therapy with gold and with nonsteroidal anti-inflammatory drugs.

Using rheumatoid arthritis patients who were receiving gold as models, we evaluated the renal effects of the chronic administration of very low doses of a nephrotoxic drug. The heavy metal gold has been shown to increase urinary enzyme excretion when it is given in usual doses for the treatment of rheumatoid arthritis. It is not clear whether the increased urine enzyme excretion caused by long-term drug therapy represents injury to the kidney or whether it is merely an effect of the drug. Urinary N-acetyl-beta-glucosaminidase and renal tubular cell excretion rates were measured in 19 patients who were receiving chronic treatment with gold and with nonsteroidal anti-inflammatory drugs for rheumatoid arthritis, in 10 patients who were receiving nonsteroidal anti-inflammatory drugs, and in 8 healthy control subjects. No subjects showed evidence of kidney disease. Both renal tubular cell and enzyme excretion rates were elevated in the gold-treated group. This showed that there was increased renal tubular cell turnover in this group, which suggests low level renal tubular injury and not merely an effect of the usual dose of gold.

Acetylglucosaminidase↗
PubMed1988

Determination of gossypol enantiomers in plasma after administration of racemate using high-performance liquid chromatography with precolumn chemical derivatisation.

A high-performance liquid chromatographic assay with precolumn chemical derivatisation was developed for the determination of gossypol enantiomers in plasma, after administration of the racemate. Racemic gossypol acetic acid in plasma was extracted into acetonitrile and analysed using a reversed-phase column and a coulometric detector in the redox mode. To separate the enantiomers, 30 microliters of the chiral derivatising reagent, (R)-(-)-2-amino-1-propanol (50 mg/ml) and 15 microliters of 20% (v/v) acetic acid were added to the acetonitrile layer which was then heated at 60 degrees C for 100 min. The mobile phase used to resolve the derivatised enantiomers was 0.2 M phosphate buffer (pH 3.5)-acetonitrile (38:62, v/v). At a flow-rate of 1.5 ml/min, the retention times for derivatised (+)-gossypol and (-)-gossypol were 4.0 and 7.8 min, respectively. Two cancer patients received 10 mg racemic gossypol acetic acid three times a day. In one patient, the racemic, (+)- and (-)-gossypol acetic acid plasma concentrations after 65 days of therapy were 317, 213 and 104 ng/ml, respectively. In the other patient, these values were 362, 210 and 152 ng/ml, respectively, after a week of therapy. This represents, to our knowledge, the first determination of the individual enantiomer levels of gossypol after administration of the racemate.

Aged↗