Sydney H. Dromgoole

Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis

Tolmetin kinetics were determined in the plasma and synovial fluid of five rheumatoid arthritis patients after they had ingested tolmetin (400 mg every 6 hr) for 7 days. Tolmetin was rapidly absorbed, with average peak levels in plasma and synovial fluid occurring at 45 min and 2 hr. The drug concentration in synovial fluid was higher than that in plasma for prolonged periods, while the rates of elimination from both plasma and synovial fluid were similar. The average half‐lifes of tolmetin in plasma and synovial fluid were 6.77 ± 1.47 hr and 6.90 ±2.3 hr. Total prostaglandin E levels in synovial fluid of these patients were suppressed for at least 24 hr after the last dose of tolmetin, suggesting that PGE synthesis continues to be suppressed even by the very low concentrations of tolmetin remaining after 24 hr.

Availability of salicylate from salsalate and aspirin

Salicylate availability from salsalate (SSA) and aspirin (ASA) was examined in six rheumatoid arthritis patients in a multiple‐dose double‐blind crossover study. Doses contained equimolar amounts of salicylic acid. After initial ASA treatment to achieve therapeutic salicylate levels (150 to 300 μg/ml) the patients received equimolar doses of SSA or ASA. When steady state was achieved patients were hospitalized, and blood and urine specimens were obtained during three dosing intervals and during the washout period that followed. Thereafter, patients were placed on the alternate medication for at least a week and the in‐hospital pattern was repeated. Despite insignificant differences in absorption of the formulations, as measured by urinary salicylate recovery, the plasma salicylic acid AUC was lower after SSA. Evidence indicates that this apparent lower availability of salicylate from SSA is due to incomplete hydrolysis to salicylic acid, the unhydrolyzed SSA being excreted mainly as glucuronide conjugates.

The effect of a high cholesterol diet on 20,25-diazacholesterol-induced myotonia

Abstract Myotonia induced by 20,25-diazacholesterol may be related to the accumulation of desmosterol which results when 20,25-diazacholesterol inhibits Δ 24 reductase; the increased (Na + + K + )-ATPase observed in this type of myotonia may also be involved. Rats were fed a high cholesterol diet (which inhibited cholesterol and hence desmosterol biosynthesis) and were dosed daily with 20,25-diazacholesterol or water. Corresponding groups were fed a normal diet and dosed with 20,25-diazacholesterol or water. Electromyography, plasma and muscle sterols, and erythrocyte membrane ATPase were measured serially for each group. Drug-treated rats on the normal diet became myotonic within 3 weeks; their plasma and muscle desmosterol were 84 and 69% of the total sterols, respectively. Their (Na + + K + )-ATPase was not significantly increased until 8 weeks of treatment. In contrast, drug-treated rats on the high cholesterol diet never became myotonic; the plasma and muscle desmosterol never exceeded 15%, and the (Na + + K + )-ATPase never exceeded the control level. Changing the high cholesterol diet to normal after 100 days resulted in myotonia within 10 days in the drug-treated rats; while their plasma and muscle desmosterol increased rapidly, no increased ATPase was seen. Reinstituting the high cholesterol diet reversed these sterol changes and abolished myotonia in 2 weeks. We conclude that 20,25-diazacholesterol-induced myotonia can be prevented or reversed by a high cholesterol diet, that the time course of desmosterol accumulation is similar and may be related to the appearance and degree of myotonia, and that the increased (Na + + K + )-ATPase is probably a secondary effect.

Clinical Pharmacology of Tolmetin: Comparisons in Rheumatoid Arthritis Patients and Normal Volunteers

Abstract: The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24‐hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24‐hour drug‐free period, after which they received a single 400‐mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple‐dose and single‐dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400‐mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.

Alteration of muscle and red cell sodium and potassium in 20,25-diazacholesterol-induced myotonia.

Myotonia was induced in rats by a single oral dose of 20,25-diazacholesterol. Myotonia as determined by electromyography developed in 12 days, and was maintained for 20 days. Accompanying the myotonia there was a significant decrease in intracellular sodium that, when compared with controls, was most marked in white glycolytic muscles such as white vastus lateralis [24.6 (se ± 4.3) percentage of decrease (P < 0.005)], and the paraspinal muscles [18.0 (se ± 4.4) percentage of decrease (P < 0.01)], and least in red oxidative muscles such as soleus (3.8 (se ± 4.4) percentage of decrease, not significant). No change in intracellular potassium was observed. The changes in muscles are probably the result of a decreased membrane permeability for sodium. No alteration in serum, or red cell sodium, potassium, or chloride was observed, and (Na+ + K+)ATPase of the red cells remained constant.

Comparison of Tolmetin Kinetics in Rheumatoid Arthritis and Matched Healthy Controls

We could find no significant differences in the kinetics of tolmetin when comparing five rheumatoid arthritis patients with moderate disease activity with a carefully matched group of normal healthy volunteers. Further, there were no discernible clinically significant differences in the kinetics of tolmetin when comparing a single dose to one week of therapy. These results, although limited by the small number of subjects involved and the large interpatient variability, suggest that it may be possible to extrapolate pharmacokinetic data from normals to patients with moderately active disease.