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Biomedical subjects

D E Drayer

Publications and source records attributed to D E Drayer.

At least 37 records · Page 2Linked to original sources
PubMed1984

Increased urinary enzyme excretion in workers exposed to nephrotoxic chemicals.

Nephrotoxic chemicals are commonly present in the environment, particularly in the workplace. The level of occupational exposure to these chemicals has been so reduced that exposure to these agents now rarely causes clinically evident acute renal disease. A sensitive indicator of renal injury, urinary excretion of N-acetyl-beta-glucosaminidase, was utilized to evaluate persons exposed in the workplace to lead, mercury, or organic solvents, for evidence of renal effects from this exposure. None of the persons had clinically evident renal disease by history, none had hypertension, and all had normal findings on urinalysis. When compared with appropriate control populations, workers exposed to lead, workers exposed to mercury, and two of three groups of workers exposed to organic solvents had significant increases in urinary acetyl glucosaminidase activity. The third group of laboratory workers with low exposure to organic solvents had no increase in urinary acetyl glucosaminidase activity. It is concluded that exposure to environmental nephrotoxins at levels currently considered safe can produce renal effects as manifested by elevations of urinary acetyl glucosaminidase excretion. It is speculated that these renal effects are not always innocuous.

Acetylglucosaminidase↗
PubMed1984

Pubertal changes in net renal tubular secretion of digoxin.

To evaluate the effect of puberty on the net renal tubular secretion of digoxin, we measured the ratio of digoxin clearance to creatinine clearance in 23 patients aged 4 to 21 yr and correlated this ratio with both sexual maturity (Tanner stage) and chronologic age. All subjects were at steady-state levels for digoxin treatment; all had normal serum creatinine values for age as well as normal serum potassium levels. Mean ratio for immature children (n = 14, Tanner 1 through 3.5) was 1.45 +/- 0.66. Mean ratio for mature adolescents (n = 9, Tanner 4 through 5) was 0.95 +/- 0.28. The difference between the two groups was significant (P less than 0.05). When patients were regrouped by age using either 13 or 15 yr as a cutoff, the difference in ratios was no longer statistically significant. Based on 45 subjects (new and from our previous study) aged 2 mo to 80 yr, there was a significant decrease in the clearance ratio with increasing age, but when the 23 subjects aged 4 to 21 yr were analyzed separately, the correlation between ratio and age was not significant. It appears that the decrease in net renal tubular secretion of digoxin from childhood to adulthood correlates better with full sexual maturation at puberty (Tanner 4 through 5) than with chronologic age. This observation may represent a developmental change in pharmacokinetics with broader significance than for digoxin disposition alone.

Adolescent↗
PubMed1984

Clinical consequences of the lipophilicity and plasma protein binding of antiarrhythmic drugs and active metabolites in man.

In two series of antiarrhythmic drugs tested, as the octanol/water partition coefficient increases so do the following: elimination from the body by biotransformation, first-pass biotransformation in the liver and gastrointestinal tract after oral administration, protein binding to some extent, and penetration into brain tissue. Patients receiving lipophilic beta-adrenoreceptor blocking drugs may experience more central nervous system side effects than those receiving hydrophilic beta blockers. Structural modification of a drug, guided by the concept of bioisosterism, may allow the disassociation of therapeutic from toxic activities. Alpha-1 acid glycoprotein is the major plasma protein that binds the basic antiarrhythmic drugs. Antiarrhythmic drug metabolites are generally more polar (less lipophilic) and less plasma protein-bound than the parent drugs.

Adrenergic beta-Antagonists↗
PubMed1984

Alteration of drug-protein binding in renal disease.

The protein binding of acidic drugs but not basic drugs is decreased in serum from patients with poor renal function. This decreased binding is due to the retention of compounds that displace drugs from their binding sites on albumin. Phenytoin and valproic acid are the 2 drugs that require a change in the values for therapeutic levels to allow for this decreased binding.

Humans↗
PubMed1984

Optimizing metoclopramide control of cisplatin-induced emesis.

Using an original high-pressure liquid chromatographic assay, we measured serum levels of metoclopramide and defined a concentration-response relationship for metoclopramide control of cisplatin-induced emesis. Using a metoclopramide regimen of 2 mg/kg body weight intravenously every 2 hours for four doses, we found that serum levels greater than 850 ng/mL immediately before the third dose were associated with complete control of emesis (less than three episodes) in 78% of patients and partial control (three to five episodes) in 18%. No patient with levels less than 850 ng/mL had complete control of emesis; only 42% had partial control (p less than 0.001). Increases in dosage for patients with low levels and poor responses improved control in four of five patients. Elderly patients had drug levels similar to those of young patients but had fewer episodes of emesis (p = 0.044), suggesting that elderly patients have increased sensitivity to this drug. The metoclopramide dose can be raised up to 2.75 mg/kg with an improvement in emetic control in patients who have an inadequate response to doses of 2 mg/kg and no toxicity.

Adult↗
PubMed1983

Increased excretion of urinary N-acetyl-beta-glucosaminidase in essential hypertension and its decline with antihypertensive therapy.

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is increased in patients whose renal function is impaired by a variety of kidney diseases, and may provide an index of renal injury. To assess its role in essential hypertension, we measured urinary levels of NAG in 80 subjects with essential hypertension (and no evidence of renal disease) and 30 normal controls. NAG values were measured before therapy and after 3 and 12 months of treatment with diuretics. The mean urinary NAG value (+/- S.D.) for the normotensive subjects was 29 +/- 16 nmol per hour per milligram of urinary creatinine. The median value for the untreated hypertensive subjects was 53, and the mean was 65 +/- 61 (P less than 0.01). Systolic blood pressure was directly correlated with NAG levels, whereas diastolic pressure, age, sex, and race were not. Eighty patients followed for one year attained their ultimate blood-pressure reduction within three months (from a mean of 158/103 mm Hg to one of 138/91 mm Hg; P less than 0.001), whereas the urinary NAG level had not declined significantly at three months (from 60 +/- 43 to 54 +/- 54) but had changed significantly at one year (to 45 +/- 28; P less than 0.01 as compared with the initial value). These data suggest that NAG is frequently elevated in patients with high blood pressure even though there is no other evidence of renal damage, and that it can be reduced by successful antihypertensive therapy.

Acetylglucosaminidase↗
PubMed1983

N-acetyl-beta-glucosaminidase and beta 2-microglobulin. Their urinary excretion in patients with renal parenchymal disease.

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin (beta 2M) was studied in 43 patients with various forms of renal parenchymal disease. Patients with membranous nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, obstructive pyelonephritis, nephrosclerosis, and minimal change nephropathy generally had urinary NAG and beta 2M levels more than 3 SDs above those seen in normal subjects. Patients with progressive renal disease averaged higher NAG and beta 2M urinary levels than those with the same renal lesion and stable function. Since elevated urinary levels of NAG and beta 2M suggest renal tubular injury or dysfunction, our observations suggest tubulointerstitial involvement in a wide variety of renal diseases.

Acetylglucosaminidase↗
PubMed1983

Plasma levels, protein binding, and elimination data of lidocaine and active metabolites in cardiac patients of various ages.

The serum and urine levels of lidocaine and two active dealkylated metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were determined by HPLC in 33 cardiac patients receiving lidocaine for more than 1 day. Clinical assessment of nervous system toxicity was carried out at the time of blood drawing. The ratios in serum of MEGX to lidocaine and of GX to lidocaine were 0.36 +/- 0.26 (mean +/- SD) and 0.11 +/- 0.11. Lidocaine and MEGX binding to serum proteins from seven patients 2 days after their myocardial infarctions were 55.4 +/- 5.9% and 14.3 +/- 3.0%. After correction for this difference in protein binding, the MEGX/lidocaine ratio in serum water was 0.68 +/- 0.49. MEGX levels in serum water were 80% or more of the lidocaine levels in 11 of the 33 patients. GX binding was 5 +/- 4%. Even after correction for protein-binding differences, GX levels in serum water were low compared to lidocaine levels. The steady-state serum GX concentration normalized for lidocaine infusion rate declined with age. Of 27 patients without toxicity, six had serum lidocaine levels above 8 micrograms/ml. Five of six patients with toxicity had levels less than 8 micrograms/ml. The renal clearance of lidocaine, MEGX, and GX was less than creatinine clearance in most patients. We conclude that MEGX, but not GX, contributes to the pharmacologic activity of lidocaine therapy in a substantial fraction of patients. We also suggest that the concept of a single value for the upper limit of the therapeutic level of lidocaine in serum is an oversimplification because it does not take into account individual differences in drug-protein binding or accumulation of active metabolites.

Aged↗
PubMed1983

Cross reactivity of the EMIT digoxin assay with digoxin metabolites, and validation of the method for measurement of urinary digoxin.

In evaluating the EMIT (Syva Co.) digoxin assay, we found no cross reactivity between dihydrodigoxin, the major digoxin metabolite, and the EMIT digoxin antibody from two different lots. However, the antibody does cross react, essentially completely, with the digoxin hydrolysis metabolites digoxigenin, digoxigenin mono-digitoxide, and digoxigenin bis-digitoxide. The EMIT method can be used to measure digoxin in urine diluted at least 50- to 100-fold with digoxin-free human plasma; the inter-assay coefficient of variation of this assay is 6%. In addition, we validated the manual EMIT serum digoxin assay, using external ("TRI-rac") quality controls.

Cross Reactions↗
PubMed1982

Microsomal hydroxylation as measured by pentobarbital elimination in patients with idiopathic systemic lupus erythematosus.

A mechanism postulated for drug- or chemical-induced systemic lupus erythematosus (SLE) is that the chemical is covalently bound to nuclear macromolecules increasing the immunogenicity of the macromolecule. This may require metabolic activation by oxidation. There are many similarities between drug-induced and idiopathic SLE. Twelve patients with idiopathic SLE and 12 normal subjects were given 100 mg pentobarbital orally to evaluate their microsomal hydroxylating activity. Plasma pentobarbital concentration was measured by gas-liquid chromatography. Mean plasma pentobarbital half-life was 24 +/- 10 (mean +/- SD) hr in the SLE patients, which is only slightly shorter than the 26 +/- 12 hr in the control subjects. The mean apparent volume of distribution in the patients was 1.28 +/- 0.30 l/kg, which is slightly above the 1.00 +/- 0.37 l/kg in the normal subject (P less than 0.05). Mean metabolic clearance rate in the SLE patients was 0.045 +/- 0.022 l/hr/kg, which is more than the 0.028 +/- 0.008 l/hr/kg in the normal control subjects (P less than 0.02). Since the metabolic clearance rate of a drug is the proper value for evaluating metabolism rate, we conclude that patients with SLE hve an increased elimination rate for drugs or other foreign compounds that are biotransformed by microsomal oxidation and may more rapidly bioactivate chemicals to reactive compounds.

Adolescent↗
PubMed1982

Age and renal clearance of cimetidine.

In 35 patients (ages 20 to 86 yr) receiving cimetidine therapeutically two serum samples and all urine formed in the interim were collected for analysis of cimetidine by high-pressure liquid chromatography and for creatinine. Cimetidine clearance decreased with age. The extrapolated 6-hr serum concentration of cimetidine per unit dose, after intravenous cimetidine, increased with age of the patients. The ratio of cimetidine clearance to creatinine clearance (Rc) averaged 4.8 +/- 2.0, indicating net tubular secretion for cimetidine. Rc seemed to be independent of age and decreased with increasing serum concentration of cimetidine, suggesting that secretion of cimetidine is a saturable process. There was only one case of dementia possibly due to cimetidine (with a drug level of 1.9 microgram/ml 6 hr after a dose) in a group of 13 patients without liver or kidney disease who had cimetidine levels above 1.25 microgram/ml. Thus, high cimetidine levels alone do not always induce dementia.

Adult↗
PubMed1981

Long-term antiarrhythmic therapy with acetylprocainamide.

Nineteen patients whose arrhythmias were initially suppressed with acetylprocainamide underwent long-term treatment with this drug. Eleven patients were still taking the drug at the end of 12 months. Drug withdrawal with substitution of a placebo caused an increase in ventricular premature beats. Thus, suppression of ventricular premature beats persisted for 1 year. The eight withdrawals from the study were due to death during the year (n = 6) or recurrence of arrhythmias. The deaths occurred in patients who were in New York Heart Association functional class II (one patient), III (three patients) and IV (two patients). Ventricular performance, assessed from systolic time intervals, improved with drug therapy and declined during drug withdrawal. Symptomatic effects were common, with seven patients requiring a reduction in dosage or discontinuation of therapy. Three patients treated for 3 years continued to show drug suppression of ventricular premature beats compared with the level during placebo substitution. Small amounts of procainamide were present in all patients because of in vivo deacetylation of acetylprocainamide. Many patients with good initial responses to this drug had recurrent arrhythmias during long-term therapy. For this reason, the usefulness of acetylprocainamide as an antiarrhythmic drug appears to be limited.

Acecainide↗
PubMed1981

Acetylprocainamide therapy in patients with previous procainamide-induced lupus syndrome.

Acetylprocainamide was used to treat 11 patients with previous procainamide-induced lupus syndrome for their cardiac arrhythmias. Three patients from whom procainamide had been withdrawn and whose lupus was in remission did not have a recurrence during a course of acetylprocainamide therapy of a longer average duration than their prior procainamide therapy. Lupus symptoms subsided during treatment in two patients who had symptoms when acetylprocainamide was started. Drug fever developed in one patient, and another had a mild recurrence of lupus symptoms during high-dose acetylprocainamide therapy that regressed with dosage reduction. All patients had small amounts of circulating procainamide from in-vivo deacetylation of acetylprocainamide. These observations strongly support the hypothesis that the aromatic amino group on procainamide is important for induction of the lupus syndrome and that acetylating this amino group blocks the lupus-inducing effect.

Acecainide↗
PubMed1981

Liquid chromatography and fluorescence spectroscopy compared with a homogeneous enzyme immunoassay technique for determining quinidine in serum.

Sera from 67 cardiac patients being treated with quinidine were analyzed for this drug by both a homogeneous enzyme immunoassay (EMIT) and a fluorescence procedure (double-extraction method). Of these samples, 47 were also analyzed for quinidine and its major metabolite in serum, (3s)-3-hydroxyquinidine, by liquid chromatography. Results by the EMIT procedure correlated well with those by both the chromatographic and fluorescence procedures, but EMIT gave, on the average, 25% higher values for quinidine than did the chromatographic procedure. The EMIT procedure is therefore not totally specific. (3s)-3-Hydroxyquinidine and dihydroquinidine (a contaminant present in standard quinidine formulations) each show cross reactivity in the EMIT assay for quinidine. Nevertheless, the EMIT assay for quinidine is acceptable for clinical use because these two compounds are also pharmacologically active.

Chromatography, High Pressure Liquid↗
PubMed1981

Improved method for the measurement of cimetidine in human serum by reverse-phase high-pressure liquid chromatography.

An improved method for the measurement of cimetidine in human serum by reverse-phase HPLC has been developed. The assay involves the addition of the following to 1.0 ml serum: 5 ml of ethyl acetate/isopropanol (96:4 by volume); 0.1 ml of 5N NaOH; and 0.1 ml of the internal standard, N-cyano-N'-methyl-N"-[3-(4-imidazolyl)propyl]-guanidine, which is a close structural analog of cimetidine. The extracted cimetidine is quantitated with high-pressure liquid chromatograph containing a reverse-phase column and a variable-wavelength UV detector (228 nm). The mobile phase consists of methanol in 5 mM K2HPO4 (adjusted to pH 2.8) as a 10:90 mixture by volume. At a flow rate of 2 ml/min, the retention times for the internal standard and cimetidine are 2.8 and 6.2 min, respectively. The standard curve for cimetidine is linear from 0.1 at least 4.0 micrograms/ml in serum. The CV of this assay for cimetidine, obtained from analysis of six replicate samples of a 1.0 microgram/ml serum pool, is 2%. The CV of this method obtained from the daily analysis (N = 12) of the 1.0 microgram/ml cimetidine standard, is 3%, and that from the 0.5 microgram/ml standard is 5%. Cimetidine was found to be stable in refrigerated or frozen serum for 1 month and in whole blood for 24 hr either at room temperature or refrigerated. In the serum from 13 patients receiving cimetidine therapy, the trough cimetidine levels varied from less than 0.1 to 2.7 mg/ml.

Blood Specimen Collection↗