Oral oseltamivir 75 mg once daily for 6 weeks effectively prevented clinical influenza in vaccinated frail older subjects using significant concomitant medications in a residential care setting. The treatment was well tolerated and provided additional protection to that afforded by vaccination.

The oral absorption of a 10-mg oral dose of the novel 5-hydroxytryptamine (5HT1D) agonist, 311C90, was compared during a moderate or severe migraine headache and in a migraine-free period in an open, two-period study. The safety and efficacy of 311C90 in acute migraine were also assessed. Twenty patients attended the clinics during a moderate or severe migraine attack and 18 patients returned for a second dose in a migraine-free period. 311C90 was less rapidly absorbed during a migraine attack compared to the migraine-free period, consistent with gastric stasis during a migraine attach. The median area under the curve (AUC) was 15.7 ng/mlh lower during a migraine (median AUC: 18.4 ng/ml.h, range: 0-60.8 ng/ml.h) compared to the migraine-free period (median AUC: 33.4 ng/ml.h, range 9.4-79.5 ng/ml.h) (95% confidence interval: 6.9, 25.3) and the time to reach maximum plasma concentration was delayed (n = 18). Eleven out of 20 patients experienced a significant improvement in migraine headache intensity at 2 h post-dose. Plasma 311C90 concentrations were generally higher in those patients who responded to treatment with 311C90 in the plasma, but there was one patient with no quantifiable 311C90 in the plasma whose headache improved. Minor adverse experiences were reported in 11 out of 20 patients during a migraine attack and in 11 out of 18 patients outside an attack. They occurred shortly following drug administration and were of short duration, but their occurrence did not appear to be related to plasma 311C90 concentration. There were no clinically significant changes in blood pressure or 12-lead ECG during the assessment period.

Aims Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT 1D agonist for the acute treatment of migraine. Methods After an initial test i.v. infusion, bioavailabilty was assessed by comparison of AUC after an i.v. infusion (3.5 mg ) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 mCi [ 14 C]-zolmitriptan, to five men and one woman on a single occasion. Results Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and iv dosing. Mean±s.d. oral bioavailability was 0.49±0.24 (0.38±0.16 in men and 0.60±0.28 in women). After oral dosing, C max and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-life was significantly longer after oral dosing (mean 22%, 95% CI 6-35%). Mean±s.d. values for CL, V z and t 1/2,z after i.v. dosing (all subjects) were 8.7±1.7 ml min −1 kg −1 , 122±32 l and 2.30±0.59 h respectively. Following administration of 25 mg [ 14 C]-zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4±6.5% in urine and 27.1±6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1±6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [ 14 C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N-desmethyl metabolite (183C91), the inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabilites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose. Conclusions The data suggest that zolmitriptan undergoes first-pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailabilty for an acute oral migraine treatment and there are no significant unidentified metabolites in man.

Aims Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT 1D -receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. Methods Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. Results Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CL R . After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml −1 h compared with 86.5 ng ml −1 h after the single 10 mg dose (95% CI for ratio 0.76-1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CL R . There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg ) was significantly lower than that after placebo (147 mmHg, 95% CI for difference −18, −2) and that after the last 5 mg dose (148 mmHg, 95% CI −19, −3). Conclusions Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.