Y-931, a Novel Atypical Antipsychotic Drug, Is Less Sensitive to Oxidative Phenomena

Abstract

Clozapine (Fig. 1) is a dibenzodiazepine atypical antipsychotic drug whose main advantages include a lack of extrapyramidal side effects (EPS) such as tardive dyskinesia 1) and its effectiveness in otherwise "typical antipsychotic drugs treatment-resistant" patients. 2) Despite these advantages, the use of clozapine is restricted because of a relatively high incidence (0.8%) of lethal agranulocytosis. 3,4) The exact mechanism of this adverse reaction is not known, yet clinical observations suggest an immune-mediated hypersensitivity reaction. 5) In general, drug-induced hypersensitivity reactions appear to be linked to the metabolic activation of the drug by reactive metabolites. A good correlation exists between the incidence of agranulocytosis and drug activation by myeloperoxidase (MPO) or horseradish peroxidase, which is present in both polymorphonucleocytes and bone marrow cells. 6) Olanzapine, which is a thienobenzodiazepine derivative structurally related to clozapine, is an effective antipsychotic agent. 7) Interestingly, despite the structural similarity between clozapine and olanzapine, no cases of agranulocytosis have been reported with the clinical use of olanzapine. 8) Recently, we reported that Y-931 (8-fluoro-12-(4-meth- [9][10][11] which was developed in our laboratory, showed a pattern of interaction with various neurotransmitter receptors similar to that of clozapine. In addition, Y-931 did not cause catalepsy (a correlate of EPS), despite its potent antagonistic activity of apomorphine-induced hyperlocomotion or conditioned avoidance response (a correlate of antipsychotic effects). Furthermore, Y-931 more potently prevented neurotoxicity (neuronal vacuolization) induced by MK-801, a non-competitive NMDA antagonist, in the rat retrosplenial cortex (a correlate of blockade ability for the NRH (NMDA receptor hypofunction)) than did clozapine or haloperidol. These findings suggest that Y-931 would be a novel antipsychotic drug not only with the potential to ameliorate NRH, but also with a low risk of EPS.Recently, with investigations into the oxidability and the toxicity of antipsychotic agents, exciting progress has been made in anticipating drug-induced agranulocytosis. In 1991, Fischer and coworkers proposed a correlation between the oxidability of clozapine through the formation of free radicals and its agranulocytosis potential. 12) Furthermore, the redox potential values for clozapine, JL13 and loxapine were in accord with spectrophotometric and electron paramagnetic resonance (EPR) results. 13) In this paper, we report on the oxidability of Y-931, clozapine and olanzapine. ExperimentalChemicals Horseradish peroxidase (HRP), glutathione (GSH) and dimethylsulfoxide (DMSO) were obtained from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Diethylpentaactic acid (DTPA) was purchased from Tokyo Chemical Industry Co. (Tokyo, Japan). 5,5-Dimethyl-1-pyrroline Noxide (DMPO) was obtained from Tokyo Chemical Industry Co. (Tokyo, Japan) and purified with activated charcoal as previously described. 14) Phos...

Clozapine repackaged into dose administration aids: a common practice in Australian hospitals

“…For light-sensitive drugs such as frusemide and prochlorperazine, the pharmacist's role in minimising light exposure during repackaging and counselling the patient on the storage of the DAA, in terms of protection from light, was confirmed. Since the literature has shown the susceptibility of clozapine to oxidation, [18] it is assumed that an oxidative process in part played a role in the discoloration of these tablets.…”

“…[16,17] The only difference between the storage conditions of the two brands outlined is that the Clopine® CMI indicates that packaging also requires protection from light. [16] Because of reports received from hospital pharmacists about discoloration of returned clozapine tablets that have been repackaged into DAAs, and the evidence in the literature that it is susceptible to oxidation, [18] the aim of this study was to evaluate the chemical, physical and light stability of these tablets when repackaged into a DAA.…”

In vitroevaluation of glutathione peroxidase (GPx)-like activity and antioxidant properties of some Ebselen analogues

“…18,19 With this EPR method, we tested diselenide [3,4] and selenide [1,2] compounds and could monitor the ability of these compounds to prevent the formation of thiyl radical species (GS • ) formed from the HRP/GSH/H 2 O 2 system in the presence of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap. Only diselenide [3] and Ebselen prevented the generation of oxidized glutathione (GSSG) through its thiyl radical form.…”

Quality Assurance of Medicines in Practice

“…A study by Perks and colleagues (Perks, Robertson et al, 2011) was prompted due to anecdotal reports from hospital pharmacy practice about discolouration of returned clozapine tablets that were repackaged into DAAs, and the known susceptibility of clozapine to oxidation (Kohara, Koyama et al, 2002). The study evaluated both the chemical content and physical stability of clozapine tablets (Clopine, Hospira, and Clozaril, Novartis) repackaged into a DAA (WebsterPak®) over a six week period.…”