Pharmacoclinical dosing strategy in neuroleptic resistant schizophrenic patients treated by clozapine: Clinical evolution, plasma and red blood cell clozapine and desmethylclozapine and whole blood serotonin

174S

BIOL. PSYCHIATRY

Poster session

1997:42'1S-2975

165-571

In vitro Investigations of drug-drug Interactions with zoteplne at CYP450

D.J. McCormick, T. Stewart. D.T. Vowles. Knoll Pharmaceuticals, Nottingham. England Zoteplnels a broad spectl\lm antipsychotic drug which Is prImarUy cleared, In man, by metabolism. A prlmary Phase 1 metabolic route of N-
165-581

Rlsperldone Induced Inhibition of neuronal activity In the dorsal raphe nucleus: mechanism of action

P. Hertel. G.G. Nomikos, N. Undblom, T.H. Svensson. Department of Physiology and Pharmacology. OMs/on of Pharmacology, Karolinska Inslitutet. Stockholm. Sweden ObJectfves: We have previously shown that rlsperidone (RISP) dose-
165-591

Atypical antlpsychotlcs affect prefferentlally dopamine but not dopac extracellular levels In rat dorsal striatum

K.S. Rayevsky, T.D. Sotnikova. R.A. Gainetdinov. Institute of Phannacology

RAMS. Moscow. Russia

The acute enects of some typlcaJ and atypical antlpsychollcs on the dopamine (DA) release and metaboIlsm In the dorsal striatum of freely moving rats were llUdied with transcerebraI micIOdialysls technique. Classical neuroleptlcs haloperidol (0.05, 0.1 and 0.2 mglkg). thiOproperazine (0.1, 0.2 and 0.4 mglkg) and apiperone (0.02. 0.04 and 0.07 mW\
m

level approximately at the same degree (200% and 160%, respectively). The ability of the drugs to affect preferentially OA release or DOPAC extrac:elUar level In rat striatum correlates to their relative affinities at 03 and D2 OA receptors. It Is concluded that typical and atypical antipsychotic drugs ~ be clearly distinguished on the besis of their ability to affect preferentiaJly OA synthesis/metabolism or release In rat dorsal striatum in vilIO.

165-60

I Effects Haloperidol concentration In human brain tissue: of dosage, duration of treatment and drug-free time

J. Komhuberl, A. Schultz 2, P. Riederer 2. , Departments ofPsychia~ University of Gc'Jttingen, Germany. 2 Departments of PsjlChia~ University 01 WQrzburg. Germany Methods: We have measured haloperidol concentrations In pD$tmottem human brain tissue (cortex temporalis, nd. caudatus, ncl. dentatus. corpus callosum, gyrus cinguli) of patients previously been treated with haloperidoL Haloperidol was measured using HPLC and fluorescence detection (7 male and 4 female patients, age 48-94 years, haloperidol dosage 0.5-15 (mean:t: SO 4.3 :4.1) mgldayoral, duration of treatment 3-581 (70.1 : 170.7) days. drug-free time 1-15 (3.2 ± 4.7) days, postmortem-time 3.5-40 his). The impact of Independent varlables on mean brain haloperidol COIIC81IlJ ationa was estimated using linear and non-linear regression analysis assuning • simple linear effect of dosage, a saturation effect with Incteasing duration of treatment and an exponential decay with Increasing drug-free time. Results: IntraindivlduaJly, concentrations were very SilTUlar In the diff8f8nl brain regions examined. Therefore, mean haloperidol concentrations ...,. calculated for each patient. Mean haloperidol concentrations Increased with dosage and decreased with drug-free time. Both variables together explained 82% of the variance of mean haloperidol concentretions. The duration of treatment had no turther explanatory effect, a result that might be related 10 the small number of cases and the low variance 01 duration of treatment.

165-61 I The efficacy of zoteplne In schizophrenia: A study analysis of BPRS rating scores

Clare P. Welch. Andrew T. Kilpatrick, Andrew Butler. John A. Tweed. Knoll Pharmaceuticals, Nottingham, UK

The efficacy of the broad spectrum antipsychotic, zotepine. has been c0n•

firmed in several studies in schizophrenic patients but a comparison of study results sometimes proves difficult. Zotepine has a high afflTlity for a runber of serotonergic (5 HT2a , 5 HT2c • 5 hie. 5 ht7) and dopaminergic (O,-ike (0,,05) and D2-lika (02' 03, D.}] receptors. (Needham et at. 1996, Roth et aI 1994, Leysen et aI 1993). In addition zotepine is a potent Inhibi10r d nor-adrenaline uptake. We wished to compare the results from studies of this drug using a comparator drug or placebo where the Brief Psychiatrlc Rating Scale (BPRS) was used as the prime measure of efficacy. A literature search was undertaken to Identify comparator studies that used the BPAS rating scele as a measure of efficacy. Ten studies were Identified. The stan• dardised difference and associated confidence Intervals were c:aJculated lor each study besed on the equation: (". - /le¥sd Ill. - /le) where fl. ancs /le are the mean responses for zoteplne and the comparator I'8Sp8ClIyely. This method 01 analysis gives a visually acceptable and easily ~ ehec.. sible method of comparing study results. The data confirm the efficacy of zotepine In schizophrenia and demonstrates a consistent advantage O\IW the comparator drugs In all but one study as measured by the BPRS scaJe.

165-621

Pharmacocllnlcal dosing strategy In neuroleptic resistant schizophrenic patients treated by clozaplne: Clinical evolution, plasma and red blOOd cell clozaplne and desmethylclozaplne and whole blood serotonin

N. Aymard 1.3, A. VIaIa 2, C. Boyer' • F. CaroIl2. ' Unitd PharmacoIog;. Clinique. France. 2Dept M9d'teo-Psycho1ogiqve 1~me ant CHS SaM1te Anne, France, 3 Univ. ReM Descartes, Paris, France The aim of this open study was to propose a more rational therapeutic approach for psychotic patients treated with cIozaplne (Cloza), using rr-. surement of plasma (P) and red blood cell (RBC) levels of cIoza ancs N desmethytcloza (0 Cloza), the major metabolite less active but more ~ (agranUlocytosis). The RBC Is representative of the free active drug fraction. Clozaplne's efficacy Is mediated through serotonlnergic (5 HT) mec:hanisrns

BIOL. PSYCHIATRY

poster session ill

8tld the acute 5 HT blocage may result In Increase In 5 HT tumover, so we

cloSed whole blood 5 HT. The study concemed 12 chronic refractory para• noid IChlzOPhrenlc in patients (OSM IV), (duration of Illness 6 to 25 years).

Treatment started In our hospitalization unit with Cloza up to a maximum of

eoo mgfday. Clinical evaluations (BPRS, Quality of Ufe Scale), regular blood

rnonltOriflg were conducted at the same time, (6 to 24 months). All of them ~ ~ery quickly. Some of them develop a depression, treated with

tIlloxetin8 (20 mglday). For therapeutic response without risk of side effects and withOUt agranulocytosis we preconlzed for P Cloza 200 to 700 nglml and lot RBC Cloza 100 to 400 nglml. We noticed an Important Increase (> 100%) tor whole bloOd 5 HT, about 4 weeks after Cloza. May such an Increase be representative of therapeutic effect? And Is there a threshold before toxical manifestation?

~ Effects of clozaplne and rlsperldone on noradrenaline transporter In cultured adrenal medullary cells R. YQ&himura. N. Yanaglhara 1, T. Terao, K. Abe, F. Izumi 1. Dept. of Psychiatry. University of OCCupational & Environmental Health, SChool of I.fBc:IiCin« KItakYushu 807, Japan, 1Dept. of Pharmacology. University of & Environmental Health. School of Medicine. Kitakyushu 807.

OCcupational

Japan ApproxJmately 30% of schizophrenic patients do not respond to conventional ~cs. Clozapine and risperidone are new drugs with antagonistic properties to 02 and 5-HT2 receptors and demonstrate superiority over other entional antipsychotics In the treatment of refractory schizophrenic pa• We examined the effects of these two new drugs on noradrenaline er In adrenal medullary cells. (1) Clozapine at therapeutic con· (30-1000 nglml) suppressed desipramine-sensitive [3Hj nora· chnaIine uptake In a doslHlependent manner, while risperidone at upper limil of therapeutic concentrations (100 nglml) did not. (2) Clozapine (1000 deCr88Sed both Bmu and Kct value in [SHjdesipramlne binding to the ~~. These results suggest that clozapine but not risperidone i'1lIuenC8S noradrenaline transporter in adrenal medullary cells.

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165-64] Effects of centrally acting drugs on PI response and C-klnase activation of human platelets t TIIJkah8t8. H. Wakatabe, K. Hieda. Y. Ohnuki, J. Ishlgooka, M. Murasaki, Miura. Department of psychiatry. Kitasato University School of Medicine. S4gamihafB. Japa!I Thrombin stimulation of platelets Is known to result In phosphatldyllnositol er (PI response), the activation of protein kinase C (C-klnase). and ea2+ mobilization. We studied the effects of centrally acting ........ on these responses. .. ~ • platelets were obtained from a healthy volunteer and Incubated ·PI The labeled platelets suspension was Incubated with the WIlh stimulated with thrombin until 180 sec. The radioactivities drugS. eln PI PI-4 monophosphate (PIP), PI-4. 5 bisphosphate (PIP2), : = t e (PA) were measured. Then, the concentrations of intracell~lar eaz. e also measured. The drugs were as follows: chlorpromazine w~ ridol (HPO), SCH23390 (SCH), ritanserin (RTS), prazosin (CPZ). ~loI (PPL). scopolamine (SCP), chlorphenilamine (CPH). ~Following thrombin stimulation, a timlHlependent intensification oIlhe ~p/lOrylation In 40 K protein and PA. and a reduction of PIP were Cpz. SCH, PAZ. CPH Inhibited 40 Kprotein phosphorylation, and CPH Inhibited PA phosphorylation. CPZ, RTS. PPL Inhibited the

S.

:UUIaf

[32.% then

=.

IIduclion of PIP.

165-6~ Effect of SM-13496, a novel antipsychotic agent, on

the central dopamlnerglc system IIhlb85hI Yo Ohno, K. Tokuda, R. Tojlma, T. Horizawa, M. Nakamura. ~ Cs~ter, sumitomo Pharmaceuticals Co.. Ltd.• Osaka. Japan 96 Is a novel antipsychotic candidate that preferentially acts on SM-134 D2 and 5-HT2 receptors. SM·13496 (0.3-10 mglkg, p.o.) in• clcJpamineariOU& behaviors Induced by dopamine agonlsts. but It had only hbted v ctlons In Inducing catalepsy and bradykinesia (E050 > 1000 nr.f9~':'13496 showed high affinities for 02 (K, = 1.68 nM), 5-HT2 (K, ~). and 5-HT1A (K, • 6.75 nM) receptors in rat brain membrane. ~;~h-30 mglkg, p.o.) Increased the levels of dopamine metabolites,

1997:42:15-2975

175S

OOPAC and HVA, in the frontal cortex, striatum, thalamus, hypothalamus and hippocampus. SM·13496-lnduced Increase of dopamine tumover, as Indexed by OOPACIdopamine and HVAldopamlne ratios, was compatible in the striatum and frontal cortex or slightly higher in the latter structure whereas haloperidol predominantly increased the striatal dopamine tumover: Furthermore, SM·13496 showed a very weak activity for Induction of the stri· atal Oofos mRNA expression, which was markedly enhanced by haloparidol. These findings suggest that SM-1349Bls a novel atypical antipsychotic with preferential action on the mesocortical (versus nigrostriatal) dopamlnergic system.

I65-66 ! Inhibition by arlpiprazole, a novel antipsychotic, on dopamlnergic excitatory transmission In striatal neurons M. Sass, H. Matsubayashl. T. Amano. Department of Pharmacology. Hiroshima University School of Medicine. Hiroshima 734. Japan Aripiprazole Is a unique antipsychotic drug that Inhibits dopamine (OA) neurons In the ventral segmental area as a OA agonist and suppresses dopamlnerglc transmission of postsynaptic nucleus accumbens neurons as a OA antagonist. The present study was performed to determine If arlplprazole acted on striatal neurons as an agonist or an antagonist. Methods: Single neuronal activities were recorded In the striatum of chloral hydrate-anesthetized rats using a glass mlcroelectrode attached along a seven-barreled micropipette. Each barrele of the micropipette was filled with aripiprazole. domperidone (02 antagonist), quinpirole (02 agonist), glutamate and 3 M NaCI accordingly. These drugs were microlontophoretically applied to the Immediate vicinity of the target neuron being recorded. A bipolar stimulating electrode was Inserted In the substantia nigra pars compacta (SN) for evoking spikes. Results: Microlontophoretic application of ariplprazole Inhibited spike generation Induced by SN stimulation In the striatal neurons. where the stimulus·induced spike was blocked by domperidone. Qulnpirole-lnduCed firing was also Inhibited by ariplprazole and domperidone, whereas gluta• mate-induced firing was not affected by either drug. These results suggest that aripiprazole acts on striatal neurons as a OA antagonist

165-671 Amlsulprlde Is a preferential D3 dopamine receptor antagonist Gh. Perrault. H. Schoemaker, R. Oepoortere. Y. Claustre, O.J. Sanger, B. SCatton. CNS Research Department. Synthelabo Recherche. Bagneux. France Amisulpride, a benzamlde derivative. which displays a unique pharmacolog• Ical profile, binds selectively to recombinant human 03 and 02 dopamine (OA) receptors with high and similar affinity (KI-3 nM) Ex vivo. amisulpride preferentially displaced [1 25 1]iodosulprlde in rat brain areas enriched In 03 receptors (lobule 10 of the cerebellum, Islands of calleja) as compared to the striatum (area enriched In O2receptors). In vivo In mice, amisulpride reversed dopamine agonlst·induced hypothermia (a 03 receptor mediated effect) at doses 10 times lower than those required to Inhibit apomorphine-Induced climbing (an effect Involving 01 and O2 receptors). In rats, Its ability to coun• teract the Inhibition by 7-QH-OPAT of OA synthesis after blockade of nerve impulse flow, may be related to its preferential affinity for presynaptic 0 3 receptors. Similarly, the selectivity of amisulpride for limbic structures as indio cated by a preferential displacement of In vivo [3Hjraclopride In rats In these brain regions as compared to the striatum (limbic selectivity ratio. 3) In rats and by its preferential blockade of hypermotility produced by d-amphetamlne or apomorphine In comparison to the lack of (d-amphetamine) or weak (apo• morphine) antagonism of drug-Induced stereotypies, may also be associated with its selectivity for 03 receptors. Thus. amisulpride is a preferential 03 dopamine antagonist, Which may account for Its clinical efficacy as an antipsychotic without the motor side effects associated with 02 receptor blockade.

165-681 Zoteplne: Preclinical support for antidepressant activity P.L Needham. M.J. Skill, S.C. Cheetham. O.J. Heal. Knoll Pharmaceuticals Research and Development. Nottingham, NGt tGF, UK Zotepine, an atypical antipsychotic, efficacious against positive and negative symptoms of schizophrenia, with low extrapyramidal side-effect potential