Pharmacokinetics of two novel rectal controlled-release morphine formulations.

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC0-24 72.7 +/- 13.2 for the oral preparation versus 98.6 +/- 35.7 and 105.8 +/- 37.3 ng.hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (tmax 2.3 +/- 0.8 versus 3.1 +/- 2.3 and 5.0 +/- 1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3 +/- 1.6 versus 10.4 +/- 5.5 and 9.5 +/- 4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (Cmax 7.75 +/- 2.66 ng/mL) was significantly lower than the low-viscosity suppository (Cmax 9.23 +/- 2.85 ng/mL) and the oral tablet (Cmax 10.4 +/- 2.78 ng/mL) formulations (P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.

A liquid chromatographic method for the determination of danazol in human serum.

A liquid chromatographic method for the determination of danazol in human serum has been developed. Reversed-phase C8 and C18 columns were used with a column-switching valve, isocratic elution and UV detection. Sample pretreatment involved extraction of the drug with pentane-methylene chloride. The method enabled the measurement of the drug at a concentration as low as 1 ng ml-1, with precision of 15.0% and accuracy of 8.3%. The method was used to run a two way replicated pharmacokinetic study of danazol. The main pharmacokinetic parameters were (mean of two periods): AUCinf = 480.94 ng x h ml-1, Cmax = 53.2 ng ml-1, tmax = 2.5 h, t0.5 = 18.00 h.

The effect of age on ranitidine pharmacokinetics.

Oral ranitidine was given to 68 healthy subjects between 18 and 75 years old at a dosage of 150 mg twice a day for seven doses. Fifteen subjects were 18 to 35 years old (group I), 19 subjects were 36 to 50 years old (group II), 19 subjects were 51 to 65 years old (group III), and 15 subjects were 66 to 75 years old (group IV). Venous blood samples were drawn and the AUC from 0 to 12 hours, the maximum plasma concentration, the time of the maximum plasma concentration, the minimum plasma concentration, and the elimination t1/2 were determined. When groups III and IV were compared with groups I or II, significant (P less than 0.05) increases were seen in the AUC(0-12) (42% and 50%), the maximum plasma concentration (36% and 41%), the minimum plasma concentration (91% and 85%), and the elimination t1/2 (29% and 33%). Positive linear correlations were found when the AUC(0-12) (r = 0.68; P less than 0.01), the maximum plasma concentration (r = 0.34; P less than 0.01), the minimum plasma concentration (r = 0.55; P less than 0.01), and the elimination t1/2 (r = 0.46; P less than 0.01) were regressed with age. Our results suggest that it may be appropriate to consider dosage adjustments for patients over 50 years of age who take ranitidine.

Fecal blood loss during isoxicam and piroxicam administration for 28 days.

After an 11-day baseline period, groups of eight healthy men received isoxicam, 200 mg once a day, or piroxicam, 20 mg once a day, for 28 days. Fecal blood loss (FBL) was quantitated by the 51Cr-labeled erythrocyte method. FBLs for both isoxicam and piroxicam were only slightly higher than baseline for the first 3 drug dosing days, confirming the results of a previously published 4-day study of piroxicam, but FBL subsequently steadily increased, with maxima occurring for most subjects receiving isoxicam in 2 or 3 weeks and for most subjects receiving piroxicam in 3 or 4 weeks. This implies that dosing for 7 days or less, as is frequent in FBL studies of nonsteroidal anti-inflammatory drugs, may be insufficient to detect the peak drug-induced FBL. In week 4, FBL for both drugs was elevated approximately 0.6 ml/day over baseline. FBLs in week 4 were comparable to those reported for naproxen and less than those reported for indomethacin and acetylsalicylic acid. Statistical analyses of weekly plasma drug minimum concentrations suggest steady state was reached at week 2 for isoxicam and week 3 for piroxicam. There were large between-subject variations in steady-state plasma drug concentrations for both drugs. One subject in each drug group indulged in excessive alcohol consumption during the medication period, with a concomitant significant increase in FBL, which suggests exacerbation of the drug effect.

Minimization of gastric damage with enteric-coated aspirin granules compared to buffered aspirin.

This study involved a randomized parallel groups comparison of the effects of aspirin formulated as enteric-coated granules (25 subjects) or as buffered tablets (26 subjects) with that of a lactose placebo (5 subjects), on the gastric and duodenal mucosa, as determined by endoscopic examination 2 h after a fasting single 975-mg dose. A grading scale of 0 (no damage) to 4 (severe damage) was used. The granule formulation produced a statistically significant (p less than 0.05) lower severity (mean 0.40 +/- 0.58 vs. 3.00 +/- 0.94) and incidence (36% of subjects vs. 100%) of gastric lesions than the buffered aspirin formulation. None of the lesions produced by the granule formulation or the placebo was considered clinically significant by the blinded endoscopist, whereas 17 subjects on the buffered formulation (65%) had clinically meaningful stomach damage. The incidence of duodenal lesions was minimal and comparable for the two formulations.