Bismuth subsalicylate: history, chemistry, and safety.

Pepto-Bismol, which contains bismuth subsalicylate (BSS) as the active ingredient, has been marketed in the United States for more than 80 years. In the gastrointestinal tract, BSS is converted to salicylic acid and insoluble bismuth salts. The salicylate portion of BSS is extensively absorbed (greater than 90%) and excreted in urine. The maximal daily dose of Pepto-Bismol (4.2 g of BSS) results in peak concentrations of salicylate in plasma considerably below the level of salicylate toxicity. In contrast, little bismuth from BSS is absorbed from the gastrointestinal tract (less than .005%). Extended dosing of Pepto-Bismol (3.14 g of BSS/d) for up to 6 weeks produced a mean concentration of bismuth in blood of 16.1 +/- 7.9 ng/g, considerably below concentrations in blood that have been reported to cause neurotoxicity. Neurotoxicity studies in animals and human safety data indicate that Pepto-Bismol can be used safely for its acute indications and for up to 3-4 weeks of extended dosing.

Effect of L-dopa on renal handling of uric acid.

Several reports have indicated that L-dopa may cause hyperuricemia and gout. The reports of hyperuricemia have generally been explained on the basis that L-dopa is known to produce a false hyperuricemia by interfering in the colorimetric analysis of uric acid. Our studies of the interference of L-dopa in the analysis of uric acid revealed that the false elevation of uric acid produced by therapeutic plasma concentrations of L-dopa is minor. The present studies used the Sperber in vivo chicken technique to determine whether L-dopa interferes with the renal excretion of uric acid. We found that a 440 mg/kg dose of L-dopa given by stomach tube results in a 30% decrease in the renal tubular excretory transport of [14C]uric acid. L-Dopa infused along with [14C]uric acid into the renal portal circulation also decreases the excretory transport of [14C]uric acid. In addition, i.v. L-dopa at 8.5 or 11.6 mumol/min/leg causes an increase in plasma urate of 26 or 45%, respectively. During infusion of L-[14C]dopa into the peritubular circulation, the 14C-label was excreted into the urine at a rate equivalent to 35% that of simultaneously infused p-aminohippuric acid or [3H] tetraethylammonium. The excretory transport of 14C-label was inhibited by probenecid. Because the renal tubular excretory transport of uric acid in chickens has many similarities to that of man, the results suggest that inhibition of uric acid excretory transport may be one of the effects of L-dopa, or its metabolites, in man.

Interference of levodopa and its metabolites with colorimetry of uric acid.

Reportedly, levodopa (L-DOPA) administration produces spuriously high values for plasma uric acid as measured by the commonly used phosphotungstic acid-hydroxylamine colorimetric method. We confirm this interference, not only by L-DOPA but also by three of its major metabolites: dopamine, 3,4-dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylacetic acid. However, at therapeutic concentrations in plasma (less than 5 mg/L), the maximum spurious uric acid concentration due to L-DOPA is less than 2 mg/L. Also, at reported peak plasma concentrations of L-DOPA plus three of its major metabolites, the maximum spurious uric acid concentration due to all four compounds combined is less than 8.5 mg/L. Therefore, the hyperuricemia observed with this method in some patients who are chronically receiving L-DOPA cannot be attributed only to interference by L-DOPA and its metabolites in the colorimetric determination of uric acid. Evidently L-DOPA may increase laboratory values for plasma uric acid concentrations, both by pharmacological and chemical mechanisms.

Renal venous portal contribution to PAH and uric acid clearance in the chicken.

The contributions of the renal venous portal and the renal arterial circulations to the renal clearance of p-aminohippuric acid (PAH) and uric acid were determined in the unanesthetized chicken by the simultaneous use of the urinary clearance technique and the Sperber preparation. The [3H]PAH apparent tubular excretion fraction (ATEF) and the clearance of inulin (CIn) were used as indicators of the renal portal and renal arterial contributions, respectively, in a planar equation for total PAH clearance. This equation accurately reflects the renal clearance of PAH as well as the renal venous portal and renal arterial contributions to the total renal clearance of PAH. The equation suggests that under normal conditions approximately 50% of the renal clearance of PAH or uric acid comes from the renal venous portal circulation, with the remaining 50% coming from the arterial circulation. An inverse hyperbolic relationship between the filtration fraction (CIn/CPAH) and the [3H]PAH ATEF was found, demonstrating that the filtration fraction in the chicken decreases from a value of 18 to approximately 6% as the renal portal plasma flow increases from zero to a maximum value. Our equation for total clearance was also used with results of experiments on inhibition of uric acid excretory transport by L- and D-dopa and by probenecid to locate the probable sites of action of those inhibitors.

Tolerance and dependence after chronic administration of clonidine to the rat.

Acute administration of clonidine (10-70 microgram/kg, IP) disrupted operant behavior maintained by a fixed ratio schedule of reinforcement [1]. When chronically administered (100 microgram/kg, IP and 3 microgram/ml in drinking water) tolerance to the behavioral depressant effect developed within a few days and was complete by 14 days. Abrupt termination of drug treatment in tolerant rats resulted in an abstinence reaction which was characterized by suppression of operant performance for as long as one week. These results demonstrated the development of tolerance to and dependence on clonidine in rats. These behavioral observations in rats may be related to rebound hypertension and irritability of patients given this alpha-adrenergic agonist for treatment of hypertension.

Pressure-dependent PAH and creatinine transport from the brain ventricles.

The brain ventricular system of the adult dog was perfused with an artificial cerebrospinal fluid (CSF) containing inulin, creatinine and radioactively labeled p-aminohippuric acid (PAH) and mannitol. Inflow and outflow rates and concentrations of test molecules were measured at different intraventricular pressures, allowing calculation of their steady-state rates of removal from the ventricles. Clearance of inulin, a measure of CSF bulk absorption varied nearly with intraventricular pressure (- 15 to +12 cm H2O relative to the external auditory meatus). The efflux coefficient (Ko; representing clearance of a molecule by means other than bulk absorption) for mannitol was independent of intraventricular pressure. Ko's for PAH and creatinine were pressure dependent. PAH and creatinine efflux may be related to the amount of fourth ventricular choroid plexus surface exposed to the perfusion fluid. Ko's for creatinine and PAH (46 plus or minus 4 mul/min; 34 plus or minus 4mul/min, respectively) were significantly greater than mannitol (16 plus or minus 8 mul/min) at comparable intraventricular pressures, suggesting that both creatinine and PAH leave the CSF by an active process in addition to passive diffusion.