Studies on the metabolism of D-penicillamine and its interaction with probenecid in cystinuria and rheumatoid arthritis.

Four patients with recurrent cystine stones and 5 with rheumatoid arthritis (RA) were studied. After a single dose of D-penicillamine to cystinuric patients, cystine excretion decreased considerably. Cysteine-penicillamine mixed disulfide (CSSP) and penicillamine disulfide (PSSP) metabolites appeared within 1-2 h (CSSP/PSSP approximately equal to 4.8-8.6). In RA, cystine excretion remained negligible (CSSP/PSSP approximately equal to 1.4-2.9). With daily D-penicillamine in RA (CSSP/PSSP ratios were usually greater than 7 in those with favorable clinical response. CSSP/PSSP ratios may help to predict prognosis and adjust penicillamine dosage. Coadministration of probenecid is contraindicated in hyperuricemic cystinuric patients because of increased cystine and decreased CSSP and PSSP excretion.

Effects of diuretics on urate and calcium excretion.

Forty-nine patients with gout, many with hypertension and/or renal calculi, were given hydrochlorothiazide, furosemide, or ticrynafen. Diuresis and increased clearances of sodium (Na), potassium (K), chloride (Cl), and calcium (Ca) occurred after a single dose of hydrochlorothiazide, 100 mg, or furosemide, 40 mg, orally. There was very slight change in urate and phosphorus clearances. With prolonged use of hydrochloride or furosemide, diuresis and increased electrolyte excretion disappeared. Urate and Ca excretion fell with hydrochlorothiazide. With long-term use of furosemide, urate excretion was suppressed, but Ca excretion was sustained. Ticrynafen produced diuresis and increased clearances of Na, K, and Cl. Calcium excretion was increased after a single dose and minimally decreased after long-term use. Most striking was the severe and rather sustained uricosuria. Though ticrynafen is an effective uricosuric, natriuretic, and antihypertensive agent, its hepatotoxicity and nephrotoxicity mitigate against its clinical use.

The natural history of hyperuricemia among asymptomatic relatives of patients with gout.

1. Hyperuricemia is common among the gouty relatives as reported by others (8-11). It is of interest to note that serum urate fluctuates periodically. Hyperuricemia is not necessarily maintained in a steady state throughout the years. Thus a single determination of serum uric acid can be misleading. 2. Development of gout from asymptomatic hyperuricemia is often correlated with the degree of hyperuricemia as observed from population or family studies (12-14). The data presented indicate that unequivocal hyperuricemia is more often accompanied by excessive excretion of uric acid, diminished excretion of ammonia and abnormally high plasma glutamic acid. All are undoubtedly important risk factors for gout. 3. The elevated glutamate could be due to a deficiency of glutamic dehydrogenase, as postulated by Pagliara and Goodman (15). In presence of intracellular accumulation of glutamate in glutamic dehydrogenase deficiency, renal production of ammonium may be reduced due to its inhibitory action on glutaminase 1. As a result of a renal block of ammonia formation, the glutamine in surplus may be diverted for uric acid synthesis. 4. Long-term studies indicate serum urate in most hyperuricemia relatives of gout can be modified by environmental factors, such as diet, weight and changes of life style. When hyperuricemia is under better control, the potential hazard of developing symptomatic gout may be circumvented.