The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.

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1 Because the 5-HTlA agonist anxiolytic azapirones have a common a2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (IPP), we measured central and peripheral a2-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day-1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day-'for 4 days and 5 mg on day 5) or placebo. 2 Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3 The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4 Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma lPP concentration which was higher on buspirone than on ipsapirone (2.76 ,ug 1-1, 95% CI:1.3-4.22 vs 0.65 ,ug I1-, 95% CI: 0.32-0.98, P = 0.006). 5 Mean AUC of the IPP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC IPP ratio was 6.45 and the AUC buspirone/AUC lPP ratio was 0.076. 6 The formation of the common metabolite IPP is greater with buspirone than with ipsapirone. Buspirone but not ipsapirone (both given in therapeutically equivalent doses) exerted a psychostimulatory effect and this could be attributed to the higher plasma lPP concentrations found with buspirone. 7 A clearcut antagonism of clonidine actions by IPP could not be demonstrated probably because the ratio of the exogeneous a2-adrenoceptor agonist (clonidine) to the endogenously formed a2-adrenoceptor antagonist (1 PP) could not be controlled.

assessed by QS2i provided the best parameter for evaluation of Pi-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4 In heart failure patients such a dobutamine test should allow separation of altered contractility and 3-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.

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