Tolerability and pharmacokinetics of the collagenase-selective inhibitor Trocade in patients with rheumatoid arthritis.

OBJECTIVES: The purpose of this study was to assess the tolerability and multiple-dose pharmacokinetics of Trocade in rheumatoid arthritis patients. METHODS: Forty-eight patients entered this double-blind, placebo-controlled, multiple ascending dose study. Patients received Trocade (25, 50, 100 or 150 mg) or placebo once daily for 28 days. Tolerability was assessed daily. Plasma pharmacokinetics was assessed on days 1 and 28. Trough blood samples were collected weekly. RESULTS: Trocade was well tolerated, with no differences in the adverse event profile compared with placebo. There were no relevant changes in laboratory parameters, vital signs or 12-lead ECG recordings. Plasma concentration profiles showed that Trocade was rapidly absorbed and most was eliminated within 24 h. The area under the plasma concentration-time curve and the maximum plasma concentration reached increased with dose, but this increase was not proportional to dose. No relevant accumulation was seen. CONCLUSIONS: Trocade was well tolerated for the 28-day study period. From exposure data, doses of 100 and 150 mg were expected to yield plasma levels associated with efficacy, and from trough concentrations the doses of 25 and 50 mg were also expected to be efficacious.

Magnesium and lithium antagonism of carbachol- and electrically-induced smooth muscle contractions in the rat gastrointestinal tract.

The pharmacological actions of lithium and magnesium have been investigated using isolated smooth muscle preparations from the rat gastrointestinal tract. Tissue contraction was evoked by means of carbachol or electrical field stimulation and the degree of inhibition of contraction caused by lithium was measured. Lithium effects were compared with those of the chemically similar ions, magnesium and calcium, by manipulation of the physiological buffer solutions. Lithium antagonism was enhanced when tissue contractile mechanisms were dependent on extracellular calcium concentration in the bathing fluid. This suggests that lithium is acting at the cell membrane by preventing calcium entry via ion channels. These results are consistent with evidence from clinical studies which indicate low cellular accumulation of lithium at therapeutic concentrations.

Magnesium inhibition of carbachol-induced contractions of the rat uterus and gastrointestinal tract: ex vivo effect of long term streptozotocin-induced diabetes.

Rats were rendered diabetic by a single administration of streptozotocin (STZ). They were maintained in the diabetic state for six weeks before being killed, and diabetic state was confirmed by routine urine and blood glucose estimations. The contractile sensitivity of jejunum, colon, stomach fundus and uterus to carbachol was reduced in control animals by increasing buffer magnesium concentration from 1.9 mmol/litre to 23.8 mmol/litre. This magnesium effect was reversed in the colon, stomach fundus and uterus of streptozotocin-diabetic animals, with contractile sensitivity being enhanced in the presence of increased magnesium concentration. In the jejunum, however, the magnesium effect was not reversed by STZ-induced diabetes. In diabetic animals, magnesium generally had the opposite effect on gastrointestinal and uterine tissues when compared with control animals. This suggests that, in the diabetic condition, any altered gastrointestinal function may be due to an underlying difference in the sensitivity to changes in magnesium.