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Pharmacology of ‘Seroquel’ (ICI 204,636): An atypical clozapine-like antipsychotic
598
Abstrllcts
DlOl PSYCIUATRY 19%;39:500- 666
!ichilophrcnill. In Phase II lrials, lei 2o.t,636 was effective ill treating positivc and negative symptoms and W3!' well tolerated. In two multicenler, plaeebo.comrolledlrials, the incidence of e~urJp)'mmidal symp· toms (EPSj was no srealer wilh ICI 204,636 than with placebo. Similarly, prolaclin levels were no greater than with placebo. A 6·week, muhicenler, ....lOdomized. double-blind, placebo·controlled trial cvalualed the efficacy, silfcty, ami optimal dose range of lei 204,636 in paticnlS wilh acUle exacerbation of schizophrenia. In 0111, 361 paticnts from Nonh America received one of live fixed duses of ICI 204,636 (75,150. 300, 600, or 750 mg daily), hnlopcridol (12 mg daily), or placebo. Paticnts were assessed wcekly using the BPRS. eGl, uml SANS for cfficacy :lnd Simpson Scale for EPS. Significant end point differenccs (p
334, 'SEROQUEL' (ICI 204,636): NOT DIFFERENT FROM PLACEBO FOR EPS OF PROLACTIN
W.W. Hong, L.A, Arvanitis, & B.a. Miller Zenccll Phannaceuticllls, Wilmington, DE 19850-5437
TIle ~Iypicill antipsychotic, CI07.11pinc. has minimal cXlmpyrmllidal symptom (EPS) liability :md docs nol cause sustained hyperprolactincmia. These fenturcs of atypical nnrips)'chotics nrc expected to improvc compliance, reduce hospitalizations. and enhance Ihe qualily of lives of patients with schil.Ophrcnia. 'Seroqucl' (ICI 2()..J,636) i!i tl promising new antipsychotic wilh an atypical profile. In Phase II ciiniclil trials there were no differences between ICI 204.636 nnd plucebo groups in EPS as tlssessed by the Simpson Scale IOlal score. usc of concomitant anticholinergic mcdicUlions, llmllhc incidence of molor system adverse events. Acute d)'~lonic reactions were not rcport~d. Funher. there were no difference~. between Ihe lei 204.636 llnd placebo groups in change from baselinc ill prolactin levels (PRL) after 6 weeks of trcntmcnt. EPS and PRL were also assessed in a 6·weck, multicenter, placebo-controlled, doubh:-bliml, ramlomized, Phuse III clinical trial. This lrial evalualed the eflil:acy, tolerability, amI optimal dose range of ICI 204,636 in lhe trealmcnl of patients wilh aCUle cXllcerbation of schizophrenia (n:::361) With live fixed doses of leI 204,636 (75, ISO, 300, 600, 750 mg daily), one Iixed dose of hulopcridol (12 mg L1aily), anLl plucebo. EPS was ussesscll weekly using the Simpson SellIe. and PRL wus assessed at baseline (following u I week placebo phase) untl ufter 4 weeks of treulmenl. Blood samples for flRL were drawn prior 10 Ihe moming dose of slurJy medication. Mean Simpson Scalc lolal score1t decreased in all ICI 204.636 groups (-1.010 -1.8) lind Ihe pillcebo group (-0.6), with the l~lr8est decrca.~es in tt1c 600 and 7S0 mg leI 204.636 groups, whereas (h~ mean Simpson Scale lotal score in lhc haloperidol group increased (+ 1.1). There were no significant differences belween any ICI 204,636 group nnd the placebo group in Simpson Scale total score grouped responses lit end point. There were no signifiennt differences \)(:Iwcen
,my lei 2O-t,636 group nnd the placcbo group in mean change from baseline in PRL levels at the final observation, w!u~rcas the difference belween Ihe haloperidol and placebo groups in respect of PRL was significant (p
335. PHARMACOLOGY OF 'SEROQUEL' (leI 204,636): AN ATYPICAL CLOZAPINE-LIKE ANTIPS YCHOTIC J.M. Goldstein Zenccn Phamtaceuticals, Wilmington, DE 19850-S437 'Scroquel' (lei 204,636) is a new antipsychotic drug thal rcs~mbles eloznpinc in a hro:ld nlOge of phannncologic tests prediclive of antipsychotic activilY und cxtfllpyrllmidal side effecls (EPS) or tardive dysktnesia (TD). In receplor binding. leJ 204,636 interacls wilh multiple ncurolrunsmiucr receplors including dopamine (DA) D1 and O2 (Ie:\()::: 1243 and 329 nM rcspcelively). serotonin 5-HT 1A and S-HT2A (IC:lll:::720 and 148 nM. respectively). adrenergic QI and (l:! (lC50 :::90 lind 270 nM. respectively), and hislamine HI receptors (IC Sll =3D nM). ICI 204,636 has no appreciable affinity for muscarinic and bcnzodiazcpine receptors (each IC511> 5000 nM). In behavioral lesls, lei 204,636 blocks conditioned avoiuunee in primatcs wilh polency greater lhan c1ozapinc, and reverses the bchaviornl effects induced by dopamine agonist!> in mice. rats, cut!'. nnd monkeys. Like c1Qzapine. it produces only weak catalepsy at doses that antngonize olher dopamine ngonistinduced behaviors. In cleclrophysiologic lests, leI 204,636 reverses the inhibitory effects of amphelamine on midbrain DA cell firing with limbic selectivity. Neurochemical indices of D2 receptor blockade, eg, increase in DA melabolitcs in brain, could also be t1emonstrulcd.ICI2Q.t,636 also meets Olher pharmacologic criu:ria that indicate clolapinelike pro:Jcrties. These include low affinity for the D! Sill.' and gremer S·HT;/5-HT() relalive 10 D:! C'Jtios, limbic selectivity as evidenced by depolarization blockade of AID but not A9 DA-contllining cells ufter 28 days' mfrninislrntion, a tendency 10 produce lIonsuitlaincd elevations in plasma prolllclin levels. minimal dyslonic liability in hflloperitlol·scnsitized lind drug-naive monkeys, full subSlilulion for eto1.apine in drug discrimination tesls in squirrel monkeys, seleclive limbic expression of the early gene pcodUCIS c·Fos nnd FosD, reversal of apomorphine and pcp. inducetl disruplion of prepulsc inhibition, reversal of social isolation induced by amphetamine in monkeys, and c10zapinclikc actions in the Paw Test. The phannacologic prolilc of lei 204,636 predicts that Ibis lIgent shoulll have atypical antipsychotic actions including enhunced efficacy, compared with standard agents, and minimal EPS and TD liobility. 'Seroquel' is a trademark, the property of ZeneclI Limited.
Abstrllcts
DlOl PSYCIUATRY 19%;39:500- 666
!ichilophrcnill. In Phase II lrials, lei 2o.t,636 was effective ill treating positivc and negative symptoms and W3!' well tolerated. In two multicenler, plaeebo.comrolledlrials, the incidence of e~urJp)'mmidal symp· toms (EPSj was no srealer wilh ICI 204,636 than with placebo. Similarly, prolaclin levels were no greater than with placebo. A 6·week, muhicenler, ....lOdomized. double-blind, placebo·controlled trial cvalualed the efficacy, silfcty, ami optimal dose range of lei 204,636 in paticnlS wilh acUle exacerbation of schizophrenia. In 0111, 361 paticnts from Nonh America received one of live fixed duses of ICI 204,636 (75,150. 300, 600, or 750 mg daily), hnlopcridol (12 mg daily), or placebo. Paticnts were assessed wcekly using the BPRS. eGl, uml SANS for cfficacy :lnd Simpson Scale for EPS. Significant end point differenccs (p
334, 'SEROQUEL' (ICI 204,636): NOT DIFFERENT FROM PLACEBO FOR EPS OF PROLACTIN
W.W. Hong, L.A, Arvanitis, & B.a. Miller Zenccll Phannaceuticllls, Wilmington, DE 19850-5437
TIle ~Iypicill antipsychotic, CI07.11pinc. has minimal cXlmpyrmllidal symptom (EPS) liability :md docs nol cause sustained hyperprolactincmia. These fenturcs of atypical nnrips)'chotics nrc expected to improvc compliance, reduce hospitalizations. and enhance Ihe qualily of lives of patients with schil.Ophrcnia. 'Seroqucl' (ICI 2()..J,636) i!i tl promising new antipsychotic wilh an atypical profile. In Phase II ciiniclil trials there were no differences between ICI 204.636 nnd plucebo groups in EPS as tlssessed by the Simpson Scale IOlal score. usc of concomitant anticholinergic mcdicUlions, llmllhc incidence of molor system adverse events. Acute d)'~lonic reactions were not rcport~d. Funher. there were no difference~. between Ihe lei 204.636 llnd placebo groups in change from baselinc ill prolactin levels (PRL) after 6 weeks of trcntmcnt. EPS and PRL were also assessed in a 6·weck, multicenter, placebo-controlled, doubh:-bliml, ramlomized, Phuse III clinical trial. This lrial evalualed the eflil:acy, tolerability, amI optimal dose range of ICI 204,636 in lhe trealmcnl of patients wilh aCUle cXllcerbation of schizophrenia (n:::361) With live fixed doses of leI 204,636 (75, ISO, 300, 600, 750 mg daily), one Iixed dose of hulopcridol (12 mg L1aily), anLl plucebo. EPS was ussesscll weekly using the Simpson SellIe. and PRL wus assessed at baseline (following u I week placebo phase) untl ufter 4 weeks of treulmenl. Blood samples for flRL were drawn prior 10 Ihe moming dose of slurJy medication. Mean Simpson Scalc lolal score1t decreased in all ICI 204.636 groups (-1.010 -1.8) lind Ihe pillcebo group (-0.6), with the l~lr8est decrca.~es in tt1c 600 and 7S0 mg leI 204.636 groups, whereas (h~ mean Simpson Scale lotal score in lhc haloperidol group increased (+ 1.1). There were no significant differences belween any ICI 204,636 group nnd the placebo group in Simpson Scale total score grouped responses lit end point. There were no signifiennt differences \)(:Iwcen
,my lei 2O-t,636 group nnd the placcbo group in mean change from baseline in PRL levels at the final observation, w!u~rcas the difference belween Ihe haloperidol and placebo groups in respect of PRL was significant (p
335. PHARMACOLOGY OF 'SEROQUEL' (leI 204,636): AN ATYPICAL CLOZAPINE-LIKE ANTIPS YCHOTIC J.M. Goldstein Zenccn Phamtaceuticals, Wilmington, DE 19850-S437 'Scroquel' (lei 204,636) is a new antipsychotic drug thal rcs~mbles eloznpinc in a hro:ld nlOge of phannncologic tests prediclive of antipsychotic activilY und cxtfllpyrllmidal side effecls (EPS) or tardive dysktnesia (TD). In receplor binding. leJ 204,636 interacls wilh multiple ncurolrunsmiucr receplors including dopamine (DA) D1 and O2 (Ie:\()::: 1243 and 329 nM rcspcelively). serotonin 5-HT 1A and S-HT2A (IC:lll:::720 and 148 nM. respectively). adrenergic QI and (l:! (lC50 :::90 lind 270 nM. respectively), and hislamine HI receptors (IC Sll =3D nM). ICI 204,636 has no appreciable affinity for muscarinic and bcnzodiazcpine receptors (each IC511> 5000 nM). In behavioral lesls, lei 204,636 blocks conditioned avoiuunee in primatcs wilh polency greater lhan c1ozapinc, and reverses the bchaviornl effects induced by dopamine agonist!> in mice. rats, cut!'. nnd monkeys. Like c1Qzapine. it produces only weak catalepsy at doses that antngonize olher dopamine ngonistinduced behaviors. In cleclrophysiologic lests, leI 204,636 reverses the inhibitory effects of amphelamine on midbrain DA cell firing with limbic selectivity. Neurochemical indices of D2 receptor blockade, eg, increase in DA melabolitcs in brain, could also be t1emonstrulcd.ICI2Q.t,636 also meets Olher pharmacologic criu:ria that indicate clolapinelike pro:Jcrties. These include low affinity for the D! Sill.' and gremer S·HT;/5-HT() relalive 10 D:! C'Jtios, limbic selectivity as evidenced by depolarization blockade of AID but not A9 DA-contllining cells ufter 28 days' mfrninislrntion, a tendency 10 produce lIonsuitlaincd elevations in plasma prolllclin levels. minimal dyslonic liability in hflloperitlol·scnsitized lind drug-naive monkeys, full subSlilulion for eto1.apine in drug discrimination tesls in squirrel monkeys, seleclive limbic expression of the early gene pcodUCIS c·Fos nnd FosD, reversal of apomorphine and pcp. inducetl disruplion of prepulsc inhibition, reversal of social isolation induced by amphetamine in monkeys, and c10zapinclikc actions in the Paw Test. The phannacologic prolilc of lei 204,636 predicts that Ibis lIgent shoulll have atypical antipsychotic actions including enhunced efficacy, compared with standard agents, and minimal EPS and TD liobility. 'Seroquel' is a trademark, the property of ZeneclI Limited.