Blood concentrations of ICI 35 868 have been determined in rat, pig, rabbit and cat after single i.v. injections. In all species the initial distribution volume was greater than blood volume and the overall distribution volume was large. Half-lives of the distribution phase were extremely short (1-6 min) and the terminal half-lives were also short (16-55 min). In all species examined a correlation existed between the systemic blood concentration of ICI 35 868 and duration of sleep, with concentrations in the range 1-4 micrograms ml-1 being effective in producing unconsciousness. No changes in pharmacokinetics or in the effective concentration occurred on repeated administration or after infusion.

No abstract

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5 -- 1 microgram/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1 -- 2h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5-1 microgram/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.

Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half‐life in the elderly was significantly longer (8.8 +/‐ 0.9 h) compared with that in the young (5.8 +/‐ 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post‐dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.