The absolute bioavailability of clodronate from two different oral doses.

Clodronate (disodium clodronate tetrahydrate) is a bisphosphonate used in the treatment of hypercalcemia and osteolysis due to malignancy. Like all bisphosphonates, clodronate has low and variable oral bioavailability. The purpose of this study was to examine the absolute bioavailability of clodronate from two different oral doses. Thirty-one healthy young volunteers participated in this open, randomized, three-period, single-dose, cross-over study. The absolute bioavailability was calculated from the area under the serum clodronate-time curve in 48 h (AUC(0-48 h)) after administration of 800 or 1600 mg (Bonefos 400 mg capsules) of oral clodronate, or 30 mg (Bonefos 60 mg/mL infusion concentrate) of intravenous clodronate. The maximum concentration of clodronate in serum (C(max)), the time to maximum concentration (t(max)), the elimination half-life (t(1/2)), and the cumulative amount of clodronate excreted into urine in 48 h (Ae(0-48 h)) were also determined. The geometric mean of the absolute bioavailability of 800 mg of clodronate was 1.9% and that of 1600 mg 2.1%. The difference in the absolute bioavailability of these two doses was statistically nonsignificant. All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study.

Comparison of alfentanil, fentanyl and sufentanil for total intravenous anaesthesia with propofol in patients undergoing coronary artery bypass surgery.

We have studied the pharmacokinetics and pharmacodynamics of alfentanil, fentanyl and sufentanil together with propofol in patients undergoing coronary artery bypass graft surgery (CABG). Sixty patients (age 40-73 yr, 56 male) were assigned randomly to receive alfentanil, fentanyl or sufentanil and propofol. Plasma concentrations of these drugs and times for the plasma concentration to decrease by 50% (t50) and 80% (t80) after cessation of the infusion were determined. Times were recorded to awakening and tracheal extubation. Total dose and plasma concentrations of propofol were similar in all groups. Mean total doses of alfentanil, fentanyl and sufentanil were 443, 45 and 4.4 micrograms kg-1, respectively. Time to awakening did not differ significantly. In patients receiving fentanyl, the trachea was extubated on average 2 h later than in those receiving sufentanil and 3 h later than in those receiving alfentanil (P < 0.05). The t80 of fentanyl was longer (P < 0.05) than that of alfentanil or sufentanil, and there was a linear correlation between the t80 of the opioid and the time to tracheal extubation (r = 0.51; P < 0.01). However, the t50 values for these opioids were similar and did not correlate with recovery time. In conclusion, patients undergoing CABG and who were anaesthetized with fentanyl and propofol needed mechanical ventilatory support for a significantly longer time than those receiving alfentanil or sufentanil and propofol. On the basis of the interindividual variation observed, the time to tracheal extubation was most predictable in patients receiving alfentanil and most variable in patients receiving fentanyl, a finding which may be important if the patients are transferred to a step-down unit on the evening of the operation.

The effects of clodronate on increased bone turnover and bone loss due to ovariectomy in rats.

The present study was carried out to investigate the ability of clodronate to inhibit ovariectomy-induced bone loss and increased bone turnover in rats. Estradiol was administered as a reference compound. Seventy Sprague-Dawley rats were ovariectomized (OVX) or sham-operated (Sham) at the age of 90 days and divided into seven groups. Two Sham and two OVX groups received subcutaneously either the vehicle of clodronate or the vehicle of estradiol. Other OVX groups were given s.c. either disodium clodronate at two dose levels (5 mg/kg or 12.5 mg/kg twice a week) or 17 beta-estradiol (10 micrograms/kg five times a week) for 8 weeks. Femur length, volume, dry weight, and ash weight were determined, and proximal ends of tibiae were used for bone histomorphometry. Markers of bone metabolism were measured from urine and serum. A significant loss of 54% of trabecular bone area of proximal tibial metaphysis was found at 8 weeks after ovariectomy. Clodronate and estradiol inhibited (p < 0.001) this osteopenia. Both drugs prevented the decrease in ash weight/volume of the femur. The inhibitory effect of clodronate and estradiol on bone resorption in OVX rats could be detected also in decreased urinary excretion of hydroxyproline and lysylpyridinoline (p < 0.001). Clodronate and estradiol decreased (p < 0.001) the ovariectomy-induced enhanced tibial endocortical mineral apposition rate (Ec.MAR) on the lateral cortex to the level of the Sham group. In contrast, periosteal MAR analyzed on the medial side of tibial cortical bone did not change significantly in the OVX/Veh group. Estradiol decreased periosteal MAR to below the level in the Sham group (p < 0.01). These results suggest that ovariectomy of growing rats resulted in tibial and femoral osteopenia two months later. Clodronate as well as estradiol can suppress bone resorption and turnover in ovariectomized rats, inhibiting the development of osteopenia. Both clodronate doses (5 and 12.5 mg/kg) had beneficial effects in ovariectomized animals.