Hilli Sevelius

Nonlinear plasma level response to high doses of naproxen

The plasma level curves of oral doses of naproxen ranging from 125 to 900 mg were studied in normal sub;ects. Areas under plasma concentration vs time curves increased linearly with dose incmments up to 500 mg twice a day, but larger doses resulted in a plateau effect. Experiments with tritium‐labeled naproxen showed that there was no difference in the fraction of drug excreted in the stools whether the dose was 250 or 900 mg, eliminating incomplete absorption as a factor. Accelerated renal clearance at high doses because of disproportionate increases in the amount of unbound drug appeared to be the most likely explanation for the plateau effect.

Pharmacokinetics of naproxen overdoses

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subjects without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of J, 2, 3, or 4 gm (up to eight times the clinically e.ffective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

Naproxen‐probenecid interaction

Probenecid induced major alterations in the half‐life. renal clearance, and metabolism of naproxen. In 6 healthy subjects who received 500‐mg single oral doses of naproxen alone and (following two days of probenecid loading) with 500 mg of probenecid 4 times a day, there was an increase in naproxen plasma half‐life from the normal 14 to 37 hr. Twenty‐four hour naproxen plasma levels were doubled by probenecid. but the rate and extent of absorption were not affected. In an 8‐day chronic administration experiment (250 mg twice daily). naproxen steady‐state plasma levels measured before the morning dose were increased 50% by coadministration of 500 mg probenecid twice daily. The major probenecid effects on naproxen metabolism were a 66% reduction of the naproxen conjugates excreted in the urine and an increase in urinary 6‐0‐desmethyl naproxen. The renal clearance of unchanged naproxen was markedly depressed. We conclude that probenecid retards naproxen plasma clearance by inhibiting naproxen glucuronide formation and renal clearance of naproxen. The renal clearance effect is the result of the blocking of tubular secretion of organic anions by probenecid. Inhibition of conjugate formation by probenecid may be the result of successful competition for conjugative processes since a large percentage of both drugs are cleared from the plasma by conjugation. Because of this interaction, patients who receive naproxen and probenecid in combination will have higher steady‐state plasma levels of naproxen and form more of the 6‐0‐desmethyl metabolite than when probenecid is not used.

Naproxen‐aspirin interactions in man

Pharmacokinetic interactions between aspirin and other nonsteroidal anti‐inflammatory drugs, including naproxen, have been demonstrated in experimental animals. This study shows that simultaneous oral administration of aspirin and naproxen in man results in a small but statistically significant lowering of plasma levels of naproxen. This effect is not mediated by competition for drug absorption but is associated with enhanced renal clearance of naproxen or its metabolites. Salicylates displace naproxen from binding sites on plasma proteins, a phenomenon that may be responsible for the accelerated clearance. The clinical significance, if any, Of these findings is not yet established, but the relatively small magnitude of the effects noted suggests that the likelihood of a meaningful interaction is small.

Antitussive effect of ethyl dibunate in patients with chronic cough

Ethyl dibunate has been suggested for the suppression of eough on the basis of animal studies, eitrie aeid‐indueed eough studies on healthy humans, and by subjeetive evaluation in patients with ehronie eough. Continuous recordings on patients with chronie cough due to chronic bronchitis and obstruetive emphysema in this study failed to demonstrate that ethyl dibunate has any antitussive properties.

Objecfive evaluation of antitussive agents

Subjective evaluation of antitussives is unreliable. In the search for an ideal procedure for evaluation, several methods have been developed which use bronchial irritants for artificial cough production in selected subjects. The currently popular citric acid and the acetylcholine methods with healthy volunteers were re‐evaluated and in our hands were unsatisfactory. Abrief discussion of the use of electronic cough recorders in subjects with spontaneous coueb as the only other presently available objective procedure for evaluating the efficacy of antitussive agents is presented.

Gastroscopic Observations Following Aspirin and Naproxen Sodium Administration

A double-blind crossover study was conducted to compare the effects of aspirin (3.25 Gm/day) and a new nonsteroidal antiinflammatory drug, naproxen sodium (1.1 Gm/day), on the gastric mucosa of 12 healthy volunteers. Subjects were gastroscoped after one week on each drug, intragastric photographs were obtained, and gastric contents were examined for blood. Ten subjects exhibited some degree of gastric pathology following aspirin administration, compared with one subject with gastric pathology following naproxen sodium. Naproxen sodium also induced less gastrointestinal bleeding and caused fewer side effects than aspirin.