Pharmacokinetics of bepridil and two of its metabolites in patients with end-stage renal disease.

The pharmacokinetics of bepridil and 2 of its major metabolites (McN-A-2600 and McN-6303) were studied in 6 patients with end-stage renal disease (ESRD) before and after hemodialysis. Patients underwent dialysis 1 day after a single oral 200-mg dose of bepridil hydrochloride; blood was sampled for up to 7 days. The mean (+/- SD) peak plasma concentration, time of peak concentration, and area under the plasma concentration-time curve (0-168 hours) for each agent were as follows: bepridil, 806 +/- 321 ng/mL, 2.6 +/- 1.6 hours, 4.87 +/- 1.21 micrograms.h/mL; McN-A-2600, 57 +/- 16 ng/mL, 4.2 +/- 2.0 hours, 0.53 +/- 0.29 microgram.h/mL; McN-6303, 284 +/- 120 ng/mL, 4.7 +/- 1.5 hours, 4.06 +/- 1.11 micrograms.h/mL. The bepridil area under the curve corrected for dose was similar to that in healthy volunteers, suggesting that plasma clearance was unaffected by severe renal impairment. None of the compounds were removed by dialysis, and no rebound in plasma concentrations was observed after the end of dialysis. The disposition of bepridil appears to be unchanged in patients with ESRD; and is unaffected by hemodialysis. Thus, no dosage adjustment will be required for ESRD patients and those receiving hemodialysis with cuprophane filters.

Effects of meals and meal composition on the bioavailability of fenretinide.

The effects of meals and meal composition on the bioavailability of fenretinide, N-(4-hydroxyphenyl) retinamide, a synthetic retinoid undergoing clinical trials, were examined in two separate studies using an open, randomized, crossover design. In the first study, 13 healthy male volunteers received 300-mg doses of fenretinide (1) while fasting and (2) after a high-fat breakfast. In a subsequent study, 15 subjects received 300 mg fenretinide after each of three different test meals (high-fat, high-protein, and high-carbohydrate) separated by a 1-week washout period. Plasma specimens obtained over a 72-hour period after each treatment were assayed by high-pressure liquid chromatography to characterize the effects of a meal and meal composition on the bioavailability of fenretinide. Results from the initial study demonstrated a significant increase in the bioavailability of fenretinide after a high-fat meal. In the follow-up study, the bioavailability of fenretinide, as assessed by total area under the plasma concentration curve, was three times greater after the high-fat meal than after the high-carbohydrate meal. This supported the findings of the first study. Although to a lesser extent, the high-protein meal also produced a greater area under the curve than the high-carbohydrate meal. These combined findings demonstrate that the bioavailability of fenretinide is markedly influenced not only by administration with meals but also by the specific composition of such meals.

Analgesic oral efficacy of tramadol hydrochloride in postoperative pain.

Tramadol hydrochloride is a synthetic opiate agonist with a plasma elimination half-life of 5 to 6 hours and peak plasma levels at about 1 1/2 hours. It derives its activity from attachment to the mu-receptor and blockage of norepinephrine reuptake. The purpose of this single-dose, double-blind, placebo-controlled study was to determine the analgesic effectiveness of an oral administration of two dose levels of tramadol hydrochloride (75 or 150 mg) compared with the combination of 650 mg acetaminophen plus 100 mg propoxyphene napsylate in 161 patients with severe postoperative pain after cesarean section. Analgesia was assessed over a 6-hour period. Treatments were compared on the basis of standard scales for pain intensity and relief and a number of derived variables based on these data. A global rating of the study medication was also used to compare treatments. The three active treatments were effective analgesics, statistically superior to placebo for many hourly and summary measures. A dose response was seen between the two tramadol doses, with the 150 mg dose providing significantly greater analgesia over the lower dose. The 75 mg dose of tramadol was generally more effective than the acetaminophen-propoxyphene combination after hour 2, and significantly so for some hourly time points, as well as for the global rating of the medication. The 150 mg dose of tramadol was significantly more effective than the acetaminophen-propoxyphene combination from hour 2 through hour 6 for the sum of pain intensity differences and total pain relief scores, as well as for the global rating of the medication. Tramadol hydrochloride at both dose levels is an effective analgesic agent and at 150 mg is statistically superior to the acetaminophen-propoxyphene combination. No serious adverse effects were observed; however, dizziness was more frequently reported with 150 mg tramadol.

Alteration of retinol-binding-protein concentrations by the synthetic retinoid fenretinide in healthy human subjects.

Normal subjects received fenretinide (HPR), 200 mg/d, on three schedules. Schedule 1 was treatment for 28 d. Schedule 2 consisted of 14 d of treatment, 3 d hiatus, and a second drug course of 14 d, 10,000 IU vitamin A was administered during the 3-d hiatus. Schedule 3 was 14 d of treatment followed by a rest period of 7 d and then 14 d of treatment. Increase in plasma HPR was accompanied by an even higher increase in the metabolite N-(4-methoxyphenyl)-all-trans-retinamide (MPR). The administration of HPR was associated with a significant reduction in retinol-binding protein (RBP), which returned to pretreatment values after the drug treatment was discontinued. Reduction of plasma retinol was also observed. Use of interrupted schedules with resting periods of 3 and 7 d changed HPR, MPR, and RBP concentrations in plasma. Addition of vitamin A did not affect the pattern of the measured variables in the plasma.

A double-blind study comparing single dose of intramuscularly injected zomepirac to meperidine in the treatment of postoperative pain.

Eighty-eight patients with moderate or severe postoperative pain were entered into a double-blind, single-injection trial designed to assess the analgesic efficacy of intramuscular zomepirac 100 mg. Patients were randomly selected to receive zomepirac injection, meperidine 100 mg or meperidine 50 mg. By most criteria of analgesic efficacy, zomepirac was superior to meperidine 50 mg and as effective as meperidine 100 mg. In terms of peak analgesia (and of patients' global evaluations), both meperidine 100 mg and zomepirac were superior to meperidine 50 mg. Total analgesia provided by zomepirac was greater than that with meperidine 100 mg, which was greater than that with meperidine 50 mg. Significantly fewer patients needed remedication during the observation period, and mean time to remedication was significantly longer for the zomepirac group than for either meperidine group. No serious adverse effects were reported.

Effects of zomepirac on hemostasis in healthy adults and on platelet function in vitro.

Zomepirac, a new nonnarcotic analgesic, was studied in 25 healthy adults for possible effects on hemostasis. Given in a single 200-mg dose or for 15 days at 300 mg/day, zomepirac prolonged template bleeding time and caused transient decreases in platelet adhesiveness, in stimulated platelet aggregation, and in the release of platelet serotonin. The short duration of these effects contrasts with the known week-long duration of the effects of aspirin. Data from in vitro platelet function studies, correlated with plasma level determinations, indicate that these effects on platelet function in man are probably dependent only on the presence of intact zomepirac and not on any metabolites. The qualitative effects of zomepirac on platelets are assumed to be the consequence of reversible inhibition of prostaglandin synthetase in these cells. Platelet concentration and the humoral clotting mechanism were not affected by zomepirac. Although no unusual bleeding has been noted in patients given zomepirc postoperatively, it should be used with the same caution as aspirin in patients with known defects in platelet function or coagulation.

Cephradine excretion in humans with pH-altered urine.

In a random crossover study, ten healthy men were pretreated with ammonium chloride or sodium bicarbonate to alter urinary pH, and then were given a single 1-Gm dose of cephradine, either orally or intravenously. No significant changes were found in the terminal phase rate constant nor in the time or magnitude of peak concentration. Total recovery was greater than 90 per cent whenever degradation of cephradine did not occur. An unexplained but significant reduction in area under curve was present in data for prealkalinized subjects and for all subjects who took cephradine orally. Trapping of cephradine was not significant in the excretory pathway.