The comparative steady-state bioavailability of the active ingredients of Madecassol.

The comparative steady-state bioavailability of asiatic acid was studied in 12 healthy male and female volunteers following oral administration of approximately equimolar doses of either asiatic acid (12 mg) or the glycoside derivative of asiatic acid, asiaticoside (24 mg). Both asiatic acid and asiaticoside are constituents of the marketed dermatological product Madecassol. Asiaticoside is converted in vivo to asiatic acid by hydrolytic cleavage of the sugar moiety. Steady-state AUC0-12h values for asiatic acid on either regimen were similar (614 +/- 250 ng.h/ml following asiatic acid compared to 606 +/- 316 ng.h/ml following asiaticoside) indicating comparable bioavailability for asiatic acid with the two ingredients at approximately equimolar doses. Since asiatic acid is considered to be the most therapeutically active ingredient of Madecassol, the current data suggest that the therapeutic effects of asiaticoside may be mediated through conversion to asiatic acid.

Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine.

1. The principal aim of this study was to investigate the effect of renal impairment on the pharmacokinetics of nicardipine following intravenous and oral dosing. 2. The plasma clearance of nicardipine was significantly lower at 6.5 ml min-1 kg-1 in patients with impaired renal function, compared with a mean value of 10.4 in patients with normal renal function and with 12.5 ml min-1 kg-1 in patients on regular haemodialysis treatment. 3. In comparison to the patients with normal renal function, there were significant increases in AUC and Cmax in the patients with renal impairment. These increases were particularly marked during chronic dosing - AUC was increased by 163%, Cmax by 127% and apparent oral bioavailability by 90%. There were no such increases in the dialysis group whose values were similar to those for normal renal function. 4. There were no significant differences in volume of distribution or protein binding, nor in the measured indices of hepatic function to account for the reduction in drug clearance in the patients with renal impairment. 5. The results of this study indicate that renal impairment may have a significant and potentially important impact on the disposition of a drug which, under normal circumstances, is highly extracted by the liver. Accumulation of a metabolic 'inhibitor' substance is a possible explanation.

Quantitative aspects of the urinary excretion of meptazinol and its metabolites in human volunteers.

1. The urinary excretion of meptazinol and its metabolites has been studied in five healthy human volunteers following oral administration of 200 mg of the 3H-labelled drug. 2. Meptazinol was well absorbed, with 90% of the radioactivity excreted in the urine; elimination of drug-related material took place rapidly. 3. Metabolism was extensive, no unchanged material being detected in the urine. Following selective enzymic hydrolysis the major metabolites were identified as glucuronide and sulphate conjugates of the parent drug present in an approximate ratio of 4:1. 4. A number of minor metabolites, also present in conjugated form, were tentatively identified.

The systemic availability of meptazinol in man after oral and rectal doses.

We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design. Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined. The tmax values for the 100 mg and 150 mg suppositories (median = 0.5 h) were statistically significantly shorter than for the tablet (median = 1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route. Despite substantial intersubject variation in Cmax the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p less than 0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).

The disposition of meptazinol after single and multiple intravenous administration to pregnant and non-pregnant women.

We have studied the disposition of the centrally-acting analgesic meptazinol in a group of age-matched non-pregnant and pregnant (36-38 weeks gestation) women. Ten non-pregnant and nine multiparous pregnant volunteers each received a single i.v. dose of meptazinol hydrochloride (equivalent to 25 mg base). A further group of 9 non-pregnant (including four of the original participants) and 10 multiparous pregnant subjects were given repeated i.v. doses of meptazinol hydrochloride (each equivalent to 10 mg base) at 30-min intervals for 2.5 h. Meptazinol plasma concentrations were determined by HPLC using fluorescence detection and the pharmacokinetic variables investigated. After single dosing there were no statistical differences in half-life, clearance, or apparent volume of distribution between the two groups, suggesting that the disposition of meptazinol was not altered by pregnancy. This was confirmed in the repeated dose study, in which no significant differences occurred in either the plasma concentrations achieved or in areas under the curves between the non-pregnant and pregnant subjects. Furthermore, the steady-state concentrations were comparable with those predicted from the single dose results. This indicates that there should be no requirement for dosage alteration of meptazinol during pregnancy.

Pharmacokinetics of meptazinol after parenteral administration in the elderly.

We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (greater than 70 years), and have compared with the results from 14 healthy, young volunteers (ages 20-40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p less than 0.01) prolongation in t1/2Z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.

Pharmacokinetics of temazepam in geriatric patients.

A single dose of temazepam 10 mg, as a solution in soft gelatin capsules, was given to 10 fasting geriatric in-patients (mean age 83 years) in a stable clinical condition. The mean peak plasma concentration was 306 ng/ml, with a median time of 0.75 h to peak concentration. Temazepam was eliminated from plasma in a biexponential manner, with a distribution phase (mean t1/2 alpha = 0.7 h) predominating for 3 h. The drug had a mean elimination half-life of 8.7 h. In a chronic study, in which temazepam 10 mg p.o. was given nightly to 13 patients, the plasma concentrations on Days 3, 5, 8, 12 and 15 were not significantly different from each other, showing rapid attainment of steady state levels and the lack of drug accumulation.

Postoperative analgesia with Duromorph.

The analgesic effects and bioavailability of a slow-release preparation of morphine (Duromorph) were studied in 12 patients with acute postoperative pain. Duromorph produced significant analgesia within 1-2 h of administration i.m., and there was a progressive decrease in the mean pain score for at least 8 h. None of the patients requested or received additional analgesia within 12 h, and the incidence of side-effects was similar to that associated with i.m. morphine. During the 8-h study, plasma concentrations of morphine slowly increased for 3 h, and then gradually declined. After 3 h, concentrations were invariably greater than those produced by conventional doses of morphine sulphate i.m. The study confirmed that Duromorph was an effective analgesic with a prolonged duration of action, which was suitable for the management of postoperative pain.

Buccal morphine--a new route for analgesia?

The analgesic effects of buccal and intramuscular morphine were compared in a prospective, double-blind, double-dummy study in forty patients who experienced pain after elective orthopaedic operations. Each patient simultaneously received a buccal tablet and an intramuscular injection, only one of which contained morphine sulphate (13.3 mg); the patients were randomly allocated to two equal groups so twenty patients received each active preparation. The two preparations produced a similar degree of postoperative analgesia, assessed by the mean reduction in pain score and the pain relief score. Peak plasma morphine concentrations were slightly lower after buccal than after intramuscular administration but they declined more slowly; consequently, the drug's bioavailability was 40-50% greater after buccal than after intramuscular administration. The adverse effects of buccal morphine were generally less than those of intramuscular morphine.

Prolonged release extradural morphine.

The effects of extradural administration of a microcrystalline preparation of morphine (Duromorph) were studied in 5 patients with postoperative or malignant pain. As assessed by pain scores on a visual analogue scale, the effects of the analgesic were extremely variable; the best results were obtained in patients with postoperative pain. Two patients with chronic pain due to malignant disease developed slow respiratory rates. The plasma concentration of morphine usually followed a biphasic pattern; an initial peak between 0.5 and 1.5 hours was succeeded by a second, large peak between 6 and 12 hours. There was little or no apparent relation between the plasma concentration of morphine and the relief of pain, suggesting that Duromorph may have a local effect on the spinal cord.

Elimination of phenoperidine in liver disease.

The disposition and elimination of phenoperidine was studied in five normal subjects, and in six patients with hepatic disease. Plasma concentrations of phenoperidine were generally higher in patients with hepatic dysfunction. Secondary peaks were observed between 15 and 105 min (particularly in patients with liver disease). In the patients the terminal half-life of phenoperidine was prolonged by approximately 50%, mainly because of a decrease in the clearance of the drug. There was little or no change in the total apparent volume of distribution. However, the differences between normal subjects and patients with hepatic disease were not statistically significant. The results suggest that slight or moderate impairment of hepatic function does not significantly affect the kinetics of the drug, and that modification of its dosage may not be required.

Quantitative capillary column gas chromatographic method for the determination of glycopyrronium in human plasma.

A new sensitive and selective capillary column gas chromatographic method for the anti-cholinergic agent glycopyrronium bromide in human plasma is described. The procedure involves preliminary ion-pair extraction of the drug into dichloromethane, followed by concentration and analysis of the ion-pair complex by capillary column gas chromatography using a nitrogen-sensitive detector. The method depends on the thermal dequaternisation of the quaternary ammonium compound and can be used to detect 5 ng/ml in a 3-ml plasma sample. The assay procedure has been applied to the determination of the plasma concentration of glycopyrronium after intravenous administration to an anaesthetised patient.

Intraoperative bradycardia and hypotension associated with timolol and pilocarpine eye drops.

A 69-yr-old man, who was concurrently being treated with pilocarpine nitrate and timolol maleate eye drops, developed a bradycardia and became hypotensive during halothane anaesthesia. Both timolol and pilocarpine were subsequently identified in a 24-h collection of urine. Timolol (but not pilocarpine) was detected in a sample of plasma removed during surgery; the plasma concentration of timolol (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant bradycardia and hypotension. Pilocarpine may have had a contributory effect.

Effect of urine pH on the elimination of phenoperidine.

The effect of urine pH on the plasma concentration and elimination of phenoperidine and its main metabolites was studied in six volunteers. The clearance of unchanged phenoperidine in acid urine was significantly greater than in neutral or alkaline urine. By contrast, the elimination of its basic metabolites was enhanced in uncontrolled or alkaline urine. Other pharmacokinetic parameters were not significantly affected.

Effect of antacids on the plasma concentration of phenoperidine.

The effect of antacids on the plasma concentration of phenoperidine was studied in six volunteers. All subjects received the same dose of phenoperidine (15 micrograms kg-1) on different occasions in the presence, and absence of, an antacid preparation. In control studies, secondary peaks in the plasma concentration of phenoperidine were invariably observed; these were entirely eliminated, or modified substantially, by the concurrent administration of antacids. In the latter conditions, plasma concentrations of phenoperidine were greater during the first 20 min, and the area under the plasma concentration--time curve between 0 and 20 min was significantly greater than in control studies. In contrast, the plasma clearance of the drug was almost identical in control conditions and during treatment with antacids. After the oral administration of phenoperidine to two subjects, the systemic bioavailability of the drug was 9.9% and 13.9% respectively.

Plasma concentration and metabolism of phenoperidine in man.

The plasma concentrations of phenoperidine were measured in five patients during general anaesthesia. The concentration of the drug decreased rapidly between 2 and 40 min and then declined more slowly. Detectable concentrations of phenoperidine were present in plasma for at least 3 h. In the five patients, the distribution half-life of the drug ranged from 3.19 to 14.23 min and the elimination half-life from 47.31 to 162.30 min. Unchanged phenoperidine and two identified metabolites (pethidine and norpethidine) were present in urine.