Dennis E. Drayer

Effect of Acetylator Phenotype on the Rate at Which Procainamide Induces Antinuclear Antibodies and the Lupus Syndrome

To investigate the relation between acetvlator phenotype and the development of procainamide-induced lupus, we determined the rate of development of antinuclear antibodies in 20 patients of known acetylator phenotype receiving chronic procainamide therapy. The duration of therapy required to induce antibodies in 50 per cent of slow (11) and rapid (nine) acetylators was 2.9 and 7.3 months respectively. The median total dose that produced ant;bodies was 1.5 g per kilogram and 6.1 g per kilogram respectively. After one year antibodies had developed in 18 patients. Retrospective studies of patients in whom procainamide lupus had developed revealed that the duration of therapy required for induction in 14 slow and seven rapid acetylators was 12 +/- 5 and 48 +/- 22 months respectively (P less than 0.002). We conclude that acetylator phenotype influences the rate at which procainamide induces antinuclear antibodies and probably the lupus syndrome. Antibody production is probably related to the parent compound or a non-acetylated metabolite.

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.

Cumulation of N‐acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function

N‐Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 µg/ml 3 hr after a dose of procainamide which is well above the 3‐hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 µg/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 µg/ml) and 38 days (0.9 µg/ml) after procainamide was stopped, indicating a half‐life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.

Antibodies to Nuclear Antigens in Patients Treated with Procainamide or Acetylprocainamide

ANTIBODIES to nuclear antigens develop in patients who have been treated with procainamide. The prevalence of antinuclear antibodies ranges from 50 to 80 per cent1 2 3 4 5 6 7 and increases with th...

Increased Excretion of Urinary N-Acetyl-β-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.

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.

A nonradioactive iothalamate method for measuring glomerular filtration rate and its use to study the renal handling of cibenzoline

A high-pressure liquid chromatographic method was developed to measure nonradioactive iothalamate in serum and urine for use in estimating glomerular filtration rate (GFR). This method was used to study the renal handling of cibenzoline, an experimental antiarrhythmic drug. The mean cibenzoline clearance was 3.5 pm 2.5 (SD) times the glomerular filtration rate. The clearance of non-protein-bound cibenzoline was seven times GFR, indicating excretion by the renal tubular secretory pathway for organic bases. This drug, at the doses used, did not lower creatinine clearance, indicating that the effect of basic drugs competing with creatinine for the base secretory pathway appears to be dose and drug dependent.

Theoretical basis for interest in acetylprocainamide and clinical experiences with this new antiarrhythmic agent.

In conclusion, it was the differential responses of slow and rapid acetylators to procainamide therapy that gave the initial clues that acetylprocainamide might be a safer drug than procainamide. So far, the experience with acetylprocainamide has been encouraging.

N-acetyl-ß-glucosaminidase and ß2-Microglobulin in Renal Disease-Reply

In Reply. —We thank Dr Sogaard for his comments. His generalization that NAG excretion is correlated with GFR should not always be applied when one is comparing different types of disease. For example, our patients with obstructive nephropathy had higher serum creatinine values than our patients with membranous nephropathy (5.7±2.2 [mean±SD] v 2.1±1.9; P v 410±349; P