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Phase I trials of BMY 14802, a potential antipsychotic with affinity for sigma binding sites
327
binding site in vivo. Both typical and atypical APD displaced 5HT-2 binding in vivo in cortex with similar affinities. There were significant positive correlations between the ability of the APD to displace DA-2 receptor binding in vitro and in vivo, and to displace 5HT-2 receptor binding in vitro and in vivo. The typical APD loxapine was more potent in vivo than in vitro in competing for 5HT-2 or DA-2 binding sites. These results indicate that the ratio of potency of APD in displacing DA-2 and 5HT-2 receptor binding both in vivo and in vitro discriminates between typical and atypical APD. The atypical APD may achieve their antischizophrenic action without blocking DA-2 receptors in vivo.
Phase I trials of BMY 14802, a potential antipsychotic sigma binding sites
with affinity for
D.P. Taylor*‘, U.A. Shukla2, S.A. Wolfe, Jr.4, P.Q. Owen3, R. Pyke3, E.B. DeSouza4 ‘CNS Drug Discovery, ‘Metabolism and Pharmacokinetics, and 3CNS Clinical Development, Bristol-Meyers Squibb Pharmaceutical Research Institute, Wallingforrl, CT 06492-7660, U.S.A., and 4AaUiction Research Center, National Institate on DragAbuse, Baltimore, MD 21224, U.S.A.
BMY 14802 has emerged as a potential antipsychotic with a preclinical profile consistent with efficacy comparable to available antipsychotics and with greater apparent safety. It is active in traditional models of antipsychotic efficacy as well as newer models such as the attenuation of behaviors elicited by chronic amphetamine intoxication in monkeys. Its potential for safety in long-term use is suggested by its lack of effect on D-2 dopamine receptors or neuronal activity in the substantia nigra after chronic administration to rats. BMY 14802 exhibits selective affinity for the limbic system in its effects on dopamine and its metabolites, but it does not bind to D-2 or D-l dopamine receptors in vitro or in vivo. BMY 14802 exhibits potent, steroselective competitive inhibition of binding to u sites. The R( + ) enantiomer is more potent at the u site and the 5-HTlA receptor than the S(-) enantiomer. Phase I trials of BMY 14802 have been completed. The first single dose study was carried out in 109 healthy male volunteers. Oral doses ranging from 2 to 800 mg were administered with 6 subjects in each dose group except 4 at 700 and 2 at 800 mg. A safety endpoint was reached at the 800 mg dose. A second 28 day multiple dose, double-blind, placebo-controlled safety, tolerance, and pharmacokinetic study was carried out in 22 healthy volunteers. Oral doses of 200,300,400 and 500 mg were administered on a q.i.d. schedule. The drug was well tolerated with no reportable side effects. In particular, no signs of movement disorders were observed. Subjects receiving BMY 14802 had elevated levels of u binding on peripheral blood leucocytes compared to subjects receiving placebo. Leucocyte binding was not correlated with Cm, or AUC values for blood levels of BMY 14802. If BMY 14802 were au “antagonist”, it might be expected that long-term administration of the drug would result in u “supersensitivity.” In fact, Bremer et al. (Sot. Neurosci. Abst. 15: 1216, 1989) have observed this phenomenon with BMY 14802 in the rat. Should future well-controlled clinical trials demonstrate clinical efficacy, BMY 14802 may act by a novel mechanism to treat the symptoms of schizophrenia with reduced liability for the side effects (extrapyramidal side effects, cardiotoxicity, agranulocytosis) of currently-available drugs.
Initial experience with clozapine in Oregon’s State Hospitals W.H. Wilson Department of Psychiatry, Oregon Health Sciences Universily, 3181 S. W. Sam Jackson Park Road, OPO2, Portlanti, OR 97201-3098, USA.
Controlled clinical trials and compassionate use protocols have indicated that clozapine is of significant therapeutic benefit to many individuals with otherwise treatment-resistant schizophrenia, at least when used in these carefully controlled circumstances. Clozapine therapy has been associated with troublesome side-effects including sedation, seizures, and a small but significant rate of agranulocytosis. These side effects might limit the efficacy when used in routine clinical settings by physicians who have only limited experience with the medication. Dammasch State Hospital has treated 39 patients and provided follow-up data after 10 weeks of treatment. Thirteen patients had BPRS improvement of more than 30%. Oregon State Hospital reported the outcome of 45 patients at 16 weeks, with 9 patients showing “excellent” therapeutic results. Eastern Oregon
binding site in vivo. Both typical and atypical APD displaced 5HT-2 binding in vivo in cortex with similar affinities. There were significant positive correlations between the ability of the APD to displace DA-2 receptor binding in vitro and in vivo, and to displace 5HT-2 receptor binding in vitro and in vivo. The typical APD loxapine was more potent in vivo than in vitro in competing for 5HT-2 or DA-2 binding sites. These results indicate that the ratio of potency of APD in displacing DA-2 and 5HT-2 receptor binding both in vivo and in vitro discriminates between typical and atypical APD. The atypical APD may achieve their antischizophrenic action without blocking DA-2 receptors in vivo.
Phase I trials of BMY 14802, a potential antipsychotic sigma binding sites
with affinity for
D.P. Taylor*‘, U.A. Shukla2, S.A. Wolfe, Jr.4, P.Q. Owen3, R. Pyke3, E.B. DeSouza4 ‘CNS Drug Discovery, ‘Metabolism and Pharmacokinetics, and 3CNS Clinical Development, Bristol-Meyers Squibb Pharmaceutical Research Institute, Wallingforrl, CT 06492-7660, U.S.A., and 4AaUiction Research Center, National Institate on DragAbuse, Baltimore, MD 21224, U.S.A.
BMY 14802 has emerged as a potential antipsychotic with a preclinical profile consistent with efficacy comparable to available antipsychotics and with greater apparent safety. It is active in traditional models of antipsychotic efficacy as well as newer models such as the attenuation of behaviors elicited by chronic amphetamine intoxication in monkeys. Its potential for safety in long-term use is suggested by its lack of effect on D-2 dopamine receptors or neuronal activity in the substantia nigra after chronic administration to rats. BMY 14802 exhibits selective affinity for the limbic system in its effects on dopamine and its metabolites, but it does not bind to D-2 or D-l dopamine receptors in vitro or in vivo. BMY 14802 exhibits potent, steroselective competitive inhibition of binding to u sites. The R( + ) enantiomer is more potent at the u site and the 5-HTlA receptor than the S(-) enantiomer. Phase I trials of BMY 14802 have been completed. The first single dose study was carried out in 109 healthy male volunteers. Oral doses ranging from 2 to 800 mg were administered with 6 subjects in each dose group except 4 at 700 and 2 at 800 mg. A safety endpoint was reached at the 800 mg dose. A second 28 day multiple dose, double-blind, placebo-controlled safety, tolerance, and pharmacokinetic study was carried out in 22 healthy volunteers. Oral doses of 200,300,400 and 500 mg were administered on a q.i.d. schedule. The drug was well tolerated with no reportable side effects. In particular, no signs of movement disorders were observed. Subjects receiving BMY 14802 had elevated levels of u binding on peripheral blood leucocytes compared to subjects receiving placebo. Leucocyte binding was not correlated with Cm, or AUC values for blood levels of BMY 14802. If BMY 14802 were au “antagonist”, it might be expected that long-term administration of the drug would result in u “supersensitivity.” In fact, Bremer et al. (Sot. Neurosci. Abst. 15: 1216, 1989) have observed this phenomenon with BMY 14802 in the rat. Should future well-controlled clinical trials demonstrate clinical efficacy, BMY 14802 may act by a novel mechanism to treat the symptoms of schizophrenia with reduced liability for the side effects (extrapyramidal side effects, cardiotoxicity, agranulocytosis) of currently-available drugs.
Initial experience with clozapine in Oregon’s State Hospitals W.H. Wilson Department of Psychiatry, Oregon Health Sciences Universily, 3181 S. W. Sam Jackson Park Road, OPO2, Portlanti, OR 97201-3098, USA.
Controlled clinical trials and compassionate use protocols have indicated that clozapine is of significant therapeutic benefit to many individuals with otherwise treatment-resistant schizophrenia, at least when used in these carefully controlled circumstances. Clozapine therapy has been associated with troublesome side-effects including sedation, seizures, and a small but significant rate of agranulocytosis. These side effects might limit the efficacy when used in routine clinical settings by physicians who have only limited experience with the medication. Dammasch State Hospital has treated 39 patients and provided follow-up data after 10 weeks of treatment. Thirteen patients had BPRS improvement of more than 30%. Oregon State Hospital reported the outcome of 45 patients at 16 weeks, with 9 patients showing “excellent” therapeutic results. Eastern Oregon