Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

Abstract. Positron emission tomography (PET) and 11C. raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85 % dopamine D 2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D 2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.

Essex RM10 7XS1 The effects of P-adrenoceptor antagonists given in single doses by oral or intravenous routes were examined in two double-blind controlled studies performed in healthy volunteers. Heart rate and peak expiratory flow rate (PEFR) were measured at rest and during standardized exercise. 2 Propranolol 80 mg and metoprolol 100 mg orally tended to reduce, and propranolol and metoprolol 0.2 mg/kg intravenously did reduce the physiological increase in PEFR during exercise; oxprenolol 80 mg orally and 0.2 mg/kg intravenously did not. Practolol 200 mg orally reduced this increase, but practolol 1 mg/kg intravenously did not. 3 In a third study of similar design, pindolol 0.05 mg/kg intravenously did not affect exerciseinduced increase in PEFR. 4 Heart rate during exercise was reduced to a comparable extent at different times by all the active treatments. SOxprenolol and pindolol share with practolol the property of partial agonist activity, which might contribute to their apparent lack of effect on airways resistance. A further possibility is that aadrenoceptor blockade helps to maintain exercise-induced increase in PEFR.

Summary:The pharmacokinetics of flupirtine after a single oral dose of 100mg have been studied in patients with moderate renal impairment and in healthy elderly subjects aged 66-83 years. Mean elimination half-life of flupirtine was higher in elderly patients than in younger normal subjects, and this was associated with an increased maximum serum concentration and reduced clearance. The mean half-life in patients with renal impairment was higher than in normal subjects.There was no correlation between observed elimination half-life and degree of renal impairment, but the creatinine clearance of most patients fell in a narrow range between 43 and 60 ml/min. In the light of these results and until further information is available, it would be prudent to start treatment of patients who are elderly or have evidence of renal impairment with half the dose of flupirtine recommended for younger patients with normal renal function.

1 The acute cardiovascular response to nicardipine was investigated using non invasive techniques in normal subjects. 2 In six subjects, i.v. nicardipine in an increasing dose (0.5-20 mg) was compared with saline, under double-blind conditions. A dose related increase in heart rate and fall in blood pressure were found. Pre-ejection period (PEP) and PEP/left ventricular ejection time (LVET) ratio of the systolic time intervals were shortened in a clearly dose related manner. Total electromechanical systole index (QS2 I) was decreased and LVET index prolonged. 3 In four subjects increasing oral doses (10-40 mg) of nicardipine, administered in a randomized double-blind placebo control design, demonstrated the same pattern, marked changes being found with the 40 mg dose.4 Comparison with nifedipine in a double-blind-placebo controlled balanced trial in six subjects confirmed that 40 mg nicardipine and 20 mg nifedipine exhibited similar effects. Maximum response was reached between 0.5 and 1.5 h, and changes in some cardiovascular variables were still evident at 3 h.