Valuable interaction with cognitive remediation and optimal antipsychotics for recovery in schizophrenia (VICTORY-S): study protocol for an interventional, open-label, randomized comparison of combined treatment with cognitive remediation and lurasidone or paliperidone.

Background: Cognitive impairment, a core feature of schizophrenia, is associated with poor outcomes. Pharmacotherapy and psychosocial treatment, when used alone, have inadequate effect sizes for cognitive impairment, leading to recent interest in combination interventions. A previous study examined the additive effect of cognitive remediation on lurasidone in patients with schizophrenia, which was negative. Although improvement in cognitive function was suggested for lurasidone, it was inconclusive because there was no antipsychotic control in the study. To clarify whether lurasidone has a meaningful impact on cognitive function in combination with cognitive remediation, we use paliperidone as a control antipsychotic in this study. We hypothesize that combination with lurasidone will improve cognitive and social function to a greater extent than paliperidone. Methods: The valuable interaction with cognitive remediation and optimal antipsychotics for recovery in schizophrenia study is a multicenter, interventional, open-label, rater-blind, randomized comparison study, comparing the effect of lurasidone plus cognitive remediation with that of paliperidone plus cognitive remediation in patients with schizophrenia. The Neuropsychological Educational Approach to Remediation (NEAR) is used for cognitive remediation. Eligible patients will be randomized 1:1 to receive lurasidone or paliperidone combined with NEAR (6 weeks antipsychotic alone followed by 24 weeks combination antipsychotic plus NEAR). The primary endpoint is the change from baseline in the tablet-based Brief Assessment of Cognition in Schizophrenia composite T-score at the end of the NEAR combination treatment period. Secondary endpoints will include change from baseline in social function, schizophrenia symptoms, and quality of life at the end of the NEAR combination treatment period. Furthermore, change from baseline to the end of the pharmacotherapy period and change from the end of the pharmacotherapy period to the end of the NEAR combination treatment period will be assessed for all endpoints. Safety will also be evaluated. Discussion: Achievement of adequate cognitive function is central to supporting social function, which is a key treatment goal for patients with schizophrenia. We think this study will fill in the gaps of the previous study and provide useful information regarding treatment decisions for patients with schizophrenia. Clinical trial registration: Japan Registry of Clinical Trials ID, jRCTs031200338.

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia.

In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT: This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.

Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028--for human safety in clinical study.

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies.

Effect of SMP-028 on steroidogenesis in rats; mechanism of toxicological events on endocrine organs of rats.

SMP-028 is a new compound for treatment of asthma. Oral administration of SMP-028 to rats was associated with toxicological events in endocrine organs. These events mainly consisted of pathological changes in the adrenal gland, testis, prostate, seminal vesicle, ovaries, and uterus. In this study, we set to clarify whether SMP-028 inhibits steroidogenesis in primary culture cells obtained from rat endocrine organs in vitro. Adrenal cells, testicular cells, and ovarian cells were treated with SMP-028 and the production of steroid hormones, i.e., progesterone, aldosterone, corticosterone, total testosterone, and estradiol from these cells was measured by radioimmunoassay. We found that the production of progesterone from these cells treated with SMP-028 at 1 µM decreased to 16-67% that of the control. These findings indicate that SMP-028 inhibits steroidogenesis in rat endocrine organs in vitro. Considering that free maximum concentration in rats treated with SMP-028 are higher than the IC50 values for the inhibition of steroidogenesis in vitro, it is therefore believed that the toxicological events seen in rats following treatment with SMP-028 are due to inhibition of steroidogenesis in vivo.

Development of relevant assay system to identify steroidogenic enzyme inhibitors.

Steroidogenesis in the adrenals, testes, and ovaries plays an important roles in hormonal homeostasis in vivo and is mediated by various enzymes, such as acid cholesterol esterase (CEase), neutral CEase, CYP11A, 3beta-hydroxysteroid dehydrogenase (HSD), CYP21, CYP11B, CYP17, CYP19 and 17beta-HSD. Compounds that are potent inhibitors of one or more steroidogenic enzymes can thus cause serious endocrine toxicity so that relevant assay systems for detecting such enzyme inhibition are useful for safety assessment. Methods already reported involve incubation of radiolabeled steroid precursors with enzyme sources followed by separation of products by TLC or other methods. However, it is unclear whether the systems in use are kinetically-optimized (i.e., reactions performed in the linear range in terms of both reaction time and substrate concentrations), so that they might not be applicable for appropriate inhibition studies. The purpose of this present study was to establish kinetically-optimized methods for rat adrenal, testis, and ovary tissues with radio-HPLC. After development of HPLC methods for separation of precursor substrates and derived metabolites, we investigated the time course and substrate concentration dependence of individual reactions, using radiolabeled substrates and enzyme sources (mitochondria-lysosomal, microsomal, and cytosolic fractions from rat adrenal, testis and ovary tissues). Linearity of metabolism was confirmed in terms of both reaction time and substrate concentrations, and we conclude that this approach can be utilized to assess the inhibition profiles of compounds impacting on steroidogenic enzyme activity.

Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects.

To assess the contribution of OATP-C to the hepatobiliary transport of bilirubin, a pharmacogenomic evaluation with regard to polymorphisms of three candidate genes, OATP-C, MRP2, and UGT1A1, was performed. Serum total and direct (conjugated) bilirubin levels were used as phenotypic indexes. Pharmacokinetic variables of pravastatin, a typical substrate for OATP-C, were obtained from our previous study. Among 23 volunteers, two variants (Val417Ile and Ser789Phe) were observed in the MRP2 gene. While there was no apparent effect of these two variants and the UGT1A1*28 on direct bilirubin levels, the OATP-C variants were associated with differences in unconjugated bilirubin levels. Subjects with the OATP-C*15 allele had higher bilirubin levels; unconjugated bilirubin levels in *1b/*1b (n = 3), *1b/*15 (n= 7), and *15/*15 (n = 1) subjects were 0.40 +/- 0.10, 0.77 +/- 0.35, and 0.70 (mg/dL), respectively. In addition, the correlation between unconjugated bilirubin levels and pharmacokinetic parameters of pravastatin revealed that the subjects with higher bilirubin levels had lower non-renal clearance values, and then higher serum concentrations of pravastatin. Large clinical studies are needed to confirm a role of OATP-C in the carrier-mediated uptake of bilirubin in the human liver.

Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.

OBJECTIVE: Our objective was to quantitate the contribution of the genetic polymorphisms of the genes for 2 human organic anion transporters-organic anion transporting polypeptide C (OATP-C) and organic anion transporter 3 (OAT3)-to the pharmacokinetics of pravastatin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformation polymorphism analysis, after sequencing with deoxyribonucleic acid obtained from 120 healthy volunteers. To examine whether polymorphisms in these 2 genes of interest alter transport activity, we conducted a clinical study (n = 23) with pravastatin as a selective probe drug. RESULTS: Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively. The polymorphisms in the OAT3 gene did not appear to be associated with changes in renal and tubular secretory clearance. In contrast, the OATP-C variants were associated with differences in the disposition kinetics of pravastatin. Subjects with the OATP-C*15 allele (Asp130Ala174) had a reduced total and nonrenal clearance, as compared with those with the OATP-C*1b allele (Asp130Val174); nonrenal clearance values in *1b/*1b (n = 4), *1b/*15 (n = 9), and *15/*15 (n = 1) subjects were 2.01 +/- 0.42 L. kg(-1). h(-1), 1.11 +/- 0.34 L. kg(-1). h(-1), and 0.29 L. kg(-1). h(-1), respectively, and the difference between *1b/*1b and *1b/*15 subjects was significant (P <.05). CONCLUSION: Certain commonly occurring single-nucleotide polymorphisms in OATP-C, such as T521C (Val174Ala), are likely to be associated with altered pharmacokinetics of pravastatin. Large clinical studies are needed to confirm these observations.