Effects of Seroquel® and other atypical antipsychotics in primate models of EPS

Goldstein, Jonathan; Snyder, Dean H.

doi:10.1016/0006-3223(95)94605-v

Cited by 2 publications

(4 citation statements)

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“…Chronic (four-week, once-daily) oral administration of ICI 204,636 (20 mg/kg) produced a significant decrease in the number of spontaneously active dopamine cells; this was in the same dopamine cell region in which acute administration of ICI 204,636 had caused a significant increase of spontaneously active dopamine cells -the limbicrelated A10 area (Goldstein et al, 1993). This decrease was reversed by subsequent intravenous injection of a low dose (0.063 mg/kg) of apomorphine, which suggests that the decrease in active dopamine cells was due to depolarisation block.…”

Section: Chronic Effectsmentioning

confidence: 87%

“…The highest oral dose that produced a significant increase in the number of spontaneously active Al 0 cells (20 mg/kg) did not produce such an increase in the number of spontaneously active A9 cells. Thus, following acute administration, ICI 204,636 has a selective effect on A10 dopamine cells (Goldstein et al, 1993). The doses of ICI 204,636 and clozapine that produce equivalent effects, and the magnitude of these effects, are similar.…”

Section: Acute Effectsmentioning

confidence: 90%

“…One such compound is Seroquel" (ICI 204,636) (Zeneca Limited, Macclesfield, UK), which is currently in phase III development. A synopsis of the pre-clinical pharmacological studies describing the properties oflCI 204,636 is presented here, but more detailed accounts of its biochemical, behavioural, and electrophysiological properties have previously been reported (Migler et al, 1993;Goldstein et al, 1993;Saller & Salama, 1993;Goldstein, 1995a,b;Goldstein & Snyder, 1995). ICI 204,636 has a pharmacological profile that is similar to that of other atypical antipsychotic drugs (APDs) (represented by clozapine) and different from classic APDs (such as haloperidol and chlorpromazine).…”

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confidence: 99%

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ICI 204, 636: A New Atypical Antipsychotic Drug

et al. 1996

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The therapeutic effects of ‘classic’ (typical) antipsychotic agents lie in their ability to block central dopaminergic receptors – a property that is also responsible for the frequent occurrence of undesirable extrapyramidal side-effects (EPS). In contrast to these typical agents, clozapine alone has distinguished itself in humans – by virtue of its enhanced antipsychotic action and lack of concurrent EPS – as an atypical antipsychotic. However, the use of clozapine has been limited by the occurrence of agranulocytosis and, to a lesser extent, seizures (Alvir et al, 1993; Haring et al, 1994). The mechanism underpinning the atypical profile of clozapine remains elusive. One hypothesis suggests that it lies in clozapine's higher serotonin 5-HT2: D2 binding ratio, when compared with typical agents – a factor being considered as a predictor of atypicality (Meltzer, this issue; Meltzer et al, 1989). However, an emerging view is that it is not a single pharmacological action, but rather multiple properties that may define an atypical, clozapine-like compound (Lieberman, 1993).

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Section: Chronic Effectsmentioning

confidence: 87%

Section: Acute Effectsmentioning

confidence: 90%

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confidence: 99%

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ICI 204, 636: A New Atypical Antipsychotic Drug

et al. 1996

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“…In addition JNJ‐37822681‐treated monkeys elicited hypoactivity, apathy, hunched posture, recumbency and inability to hold on to the cage. These motor disorders were consistent with reports of dyskinesias and locomotor depressant changes occurring in monkeys with various other antipsychotics (Casey, ; Fukuoka et al ., ; Goldstein & Snyder, ; Liebman & Neale, ; Peacock & Gerlach, ; Porsolt & Jalfre, ; Rehm et al ., ; Varty et al ., ; Weiss et al ., ). Catalepsy‐associated behavior in monkeys reflected by static postures and unusual positions occurring for prolonged periods of time have been described as well (Auclair et al ., ; Kumar et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

Waal

Desmidt

Korte

et al. 2013

J of Applied Toxicology

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JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat.

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Effects of Seroquel® and other atypical antipsychotics in primate models of EPS

Cited by 2 publications

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ICI 204, 636: A New Atypical Antipsychotic Drug

ICI 204, 636: A New Atypical Antipsychotic Drug

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

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