Nose-to-brain delivery of paliperidone palmitate poloxamer-guar gum nanogel: Formulation, optimization and pharmacological studies in rats.

Oral delivery of paliperidone palmitate (PPD), a potent antipsychotic agent, has been reported with a potential risk of very serious drug-induced adverse events such as tachycardia, hyperprolactinemia, sexual dysfunction, and neutropenia. Alternatively, the potential of nasal delivery has also been explored to treat CNS complications by delivering the medicines directly to the brain bypassing the blood-brain barrier. Hence, the objectives of current work were to formulate, design, optimize, and investigate the therapeutic potency of PPD-loaded intranasal in-situ gel (PPGISG) in the treatment of schizophrenia. PPD-nanoemulsion (PNE) was fabricated using water titration technique, was further optimized via Box-Behnken design. Furthermore, the optimized PNE was evaluated for parameters such as globule size, polydispersity index, zeta potential, and % entrapment efficiency were found to be 21.44±1.58nm, 0.268±0.02, -25.56±1.6mV, and 99.89±0.25%, respectively. PNE was further converted to PPGISG utilizing two polymers, poloxamer, and guar gum. Simultaneously, ex-vivo permeation for PNE, PPGISG, and PPD-suspension was found to be 211.40±4.8, 297.89±3.9 and 98.66±1.6µg/cm2, respectively. While PPGISG nanoparticles showed 1.58 and 5.65-folds more Jss than PNE and PPD-suspension. Behavioral studies confirmed that no extrapyramidal symptoms were observed in experimental animals post intranasal administration. Finally, the outcomes of the in-vivo hemato-compatibility study proved that intranasal formulation did not cause any alteration in leukocytes, RBCs, and neutrophils count. Therefore, intranasal delivery of PPGISG can be considered a novel tool for the safe delivery of PPD in schizophrenic patients.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.

Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent.

A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole.

Quetiapine Albumin Nanoparticles as an Efficacious Platform for Brain Deposition and Potentially Improved Antipsychotic Activity.

Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Therefore, this study aimed to develop an intravenous QP albumin nanoparticles (NPs) system for improving QP antipsychotic activity and brain targeting. QP-loaded albumin NPs were prepared by the desolvation method. The fabricated NPs were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. In vivo pharmacokinetics and biodistribution in rats were studied. In addition, the antipsychotic activity of the optimized platform was also investigated. Human serum albumin (HSA) concentration, pH, and stirring time were modulated to optimize QP albumin NPs with a particle size of 103.54 ± 2.36 nm and a QP EE% of 96.32 ± 3.98%. In addition, the intravenous administration of QP albumin NPs facilitated QP brain targeting with a 4.9-fold increase in targeting efficiency compared to the oral QP solution. The QP albumin NPs improved the QP antipsychotic activity, indicated by suppressing rats' hypermobility and reducing the QP's extrapyramidal side effects. The obtained results proposed that intravenous QP- NPs could improve QP brain targeting and its antipsychotic efficiency.

Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: In vitro and in vivo pharmacological studies.

Unfavorable side effects of available antipsychotics limit the use of conventional delivery systems, where limited exposure of the drugs to the systemic circulation could reduce the associated risks. The potential of intranasal delivery is gaining interest to treat brain disorders by delivering the drugs directly to the brain circumventing the tight junctions of the blood-brain barrier with limited systemic exposure of the entrapped therapeutic. Therefore, the present research was aimed to fabricate, optimize and investigate the therapeutic efficacy of amisulpride (AMS)-loaded intranasal in situ nanoemulgel (AMS-NG) in the treatment of schizophrenia. In this context, AMS nanoemulsion (AMS-NE) was prepared by employing aqueous-titration method and optimized using Box-Behnken statistical design. The optimized nanoemulsion was subjected to evaluation of globule size, transmittance, zeta potential, and mucoadhesive strength, which were found to be 92.15 nm, 99.57%, -18.22 mV, and 8.90 g, respectively. The AMS-NE was converted to AMS-NG using poloxamer 407 and gellan gum. Following pharmacokinetic evaluation in Wistar rats, the brain Cmax for intranasal AMS-NG was found to be 1.48-folds and 3.39-folds higher when compared to intranasal AMS-NE and intravenous AMS-NE, respectively. Moreover, behavioral investigations of developed formulations were devoid of any extrapyramidal side effects in the experimental model. Finally, outcomes of the in vivo hematological study confirmed that intranasal administration of formulation for 28 days did not alter leukocytes and agranulocytes count. In conclusion, the promising results of the developed and optimized intranasal AMS-NG could provide a novel platform for the effective and safe delivery of AMS in schizophrenic patients.

Antipsychotic Potential and Safety Profile of TPGS-Based Mucoadhesive Aripiprazole Nanoemulsion: Development and Optimization for Nose-To-Brain Delivery.

Delivering therapeutics to the brain using conventional dosage forms is always a challenge, thus the present study was aimed to formulate mucoadhesive nanoemulsion (MNE) of aripiprazole (ARP) for intranasal delivery to transport the drug directly to the brain. Therefore, a TPGS based ARP-MNE was formulated and optimized using the Box-Behnken statistical design. The improved in vitro release profile of the formulation was in agreement to enhanced ex vivo permeation through sheep mucous membranes with a maximum rate of permeation co-efficient (62.87  cm h-1 × 103) and flux (31.43  µg cm-2.h-1). The pharmacokinetic profile following single-dose administration showed the maximum concentration of drug in the brain (Cmax) of 15.19 ± 2.51  µg mL-1 and Tmax of 1 h in animals with ARP-MNE as compared to 10.57 ± 1.88  µg mL-1 and 1 h, and 2.52 ± 0.38  µg mL-1 and 3 h upon intranasal and intravenous administration of ARP-NE, respectively. Further, higher values of % drug targeting efficiency (96.9%) and % drug targeting potential (89.73%) of ARP-MNE through intranasal administration were investigated. The studies in Wistar rats showed no existence of extrapyramidal symptoms through the catalepsy test and forelimb retraction results. No ex vivo ciliotoxicity on nasal mucosa reflects the safety of the components and delivery tool. Further, findings on locomotor activity and hind-limb retraction test in ARP-MNE treated animals established its antipsychotic efficacy. Thus, it can be inferred that the developed ARP-MNE could effectively be explored as brain delivery cargo in the effective treatment of schizophrenia without producing any toxic manifestation.

[The peptide analogue of neurotensin with antipsychotic and pro-cognitive effects: results of the pilot clinical trial]. / Peptidnyi analog neirotenzina s antipsikhoticheskimi i prokognitivnymi svoistvami: rezul'taty pilotnogo klinicheskogo issledovaniia.

OBJECTIVE: To evaluate the psychotropic specific spectrum activity of the novel peptide drug dilept and to find its effective doses in patients with schizotypal disorder. MATERIAL AND METHODS: The effects of dilept were studied in 25 patients (33.4±10.0 years old) with schizotypal disorder (F21.3) with predominance of obsessive-compulsive, hypochondriac, phobic symptoms, mild cognitive impairment and negative symptoms. Patients were treated with dilept 60, 120 and 200 mg daily for 14 days as monotherapy (with allowance of phenazepam up to 2 mg single doses for insomnia and anxiety) followed by combined treatment with phenazepam in the case of insufficient effectiveness of dilept monotherapy. The Positive and Negative Syndrome scale (PANSS), Psychopathological Symptom Severity scale, Clinical Global Impression scale (CGI) and Wechsler Adult Intelligence scale (WAIS-R) were used as outcome measures. RESULTS AND CONCLUSION: Dilept demonstrated the unique spectrum of psychotropic activity: antipsychotic with stimulating action, favorable effect on negative symptoms and cognitive dysfunction. Treatment action was the most evident when dilept was used in the dose 200 mg/day. There was no evidence of any side-effects known to be typical for antipsychotics. The efficacy of dilept and phenazepam combination is dependent on dilept's antipsychotic and pro-cognitive effects, while benzodiazepine lacks these effects.

Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting.

The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders.

ASP2905, a specific inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3 gene, is psychoactive in mice.

Schizophrenia is a major psychiatric disorder associated with positive and negative symptoms and cognitive impairments. In this study, we used animal models of behavior to evaluate the antipsychotic activity of ASP2905, a potent and selective inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3/BEC1 gene. ASP2905 inhibited hyperlocomotion induced by methamphetamine and by phencyclidine. In contrast, ASP2905 did not affect spontaneous locomotion, suggesting that ASP2905 selectively inhibits abnormal behaviors induced by stimulants. Chronic infusion of ASP2905 significantly ameliorated phencyclidine-induced prolongation of immobility time in mice subjected to the forced swimming test. These findings suggest that ASP2905 potentially mitigates symptoms of schizophrenia, such as apathy. The antipsychotic clozapine also reversed phencyclidine-induced prolonged immobility, while risperidone and haloperidol had no effect. Assessment of the effects of ASP2905 on latent learning deficits in mice treated with phencyclidine as neonates subjected to the water-finding task showed that ASP2905 significantly ameliorated phencyclidine-induced prolongation of finding latency, which reflects latent learning performance. These findings suggest that ASP2905 potentially mitigates cognitive impairments caused by schizophrenia, such as attention deficits. In contrast, administration of clozapine did not ameliorate phencyclidine-induced prolongation of finding latency. Therefore, ASP2905 may alleviate the broad spectrum of symptoms of schizophrenia, including positive and negative symptoms and cognitive impairments, which is in contrast to currently available antipsychotics, which are generally only partially effective for ameliorating these symptoms.

Advances in the Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia.

Schizophrenia is a debilitating mental disorder with relatively high prevalence (~1%), during which positive manifestations (such as psychotic states) and negative symptoms (e.g., a withdrawal from social life) occur. Moreover, some researchers consider cognitive impairment as a distinct domain of schizophrenia symptoms. The imbalance in dopamine activity, namely an excessive release of this neurotransmitter in the striatum and insufficient amounts in the prefrontal cortex is believed to be partially responsible for the occurrence of these groups of manifestations. Second-generation antipsychotics are currently the standard treatment of schizophrenia. Nevertheless, the existent treatment is sometimes ineffective and burdened with severe adverse effects, such as extrapyramidal symptoms. Thus, there is an urgent need to search for alternative treatment options of this disease. This review summarizes the results of recent preclinical and clinical studies on phosphodiesterase 10A (PDE10A), which is highly expressed in the mammalian striatum, as a potential drug target for the treatment of schizophrenia. Based on the literature data, not only selective PDE10A inhibitors but also dual PDE2A/10A, and PDE4B/10A inhibitors, as well as multifunctional ligands with a PDE10A inhibitory potency are compounds that may combine antipsychotic, precognitive, and antidepressant functions. Thus, designing such compounds may constitute a new direction of research for new potential medications for schizophrenia. Despite failures of previous clinical trials of selective PDE10A inhibitors for the treatment of schizophrenia, new compounds with this mechanism of action are currently investigated clinically, thus, the search for new inhibitors of PDE10A, both selective and multitarget, is still warranted.

3-month parenteral PLGA microsphere formulations of risperidone: Fabrication, characterization and neuropharmacological assessments.

The study aims at formulation and characterization of three months parenteral risperidone loaded polymeric microspheres (p-RLPMs) as a sustained delivery system and established their in vitro and in vivo assessments. The p-RLPMs formulations were prepared by solvent extraction and diffusion method. The optimized p-RLPMs (batch RPLGA-1) formulation demonstrated favorable different physicochemical properties such as mean particle size (104±5.34µm), percent porosity (44.56±3.11%) and percent drug loading (38.42±2.67%). The physical state characterization, Fourier transformed infrared spectroscopy analysis showed no changes in the chemical structure of risperidone (RPD) in the batch RPLGA-1 formulation and differential scanning calorimetry study confirmed, pure RPD retained its crystallinity in the batch RPLGA-1 formulation. The SEM micrographs of the all p-RLPMs formulations revealed the irregular shapes and indentations. The GC/MS results showed that the residual organic solvent content in the batch RPLGA-1 formulation was below the limits. Pharmacokinetic parameters revealed that optimized RPLGA-1 formulation exhibited an initial burst followed by an excellent sustained release as compared to pure RPD as well as other formulations. Furthermore, in vivo studies of the batch, RPLGA-1 formulation showed an antipsychotic effect that was significantly prolonged over that of pure RPD solution for up to 72h with fewer extrapyramidal side effects. Thus, results of this study prove the suitability of using poly(lactic-co-glycolic acid) copolymer to develop sustained release p-RLPMs formulations that can tailor in vivo behavior and enhance the pharmacological effectiveness of the RPD.

The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.

Mechanism based neurotoxicity of mGlu5 positive allosteric modulators--development challenges for a promising novel antipsychotic target.

Previous work has suggested that activation of mGlu5 receptor augments NMDA receptor function and thereby may constitute a rational approach addressing glutamate hypofunction in schizophrenia and a target for novel antipsychotic drug development. Here, we report the in vitro activity, in vivo efficacy and safety profile of 5PAM523 (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), a structurally novel positive allosteric modulator selective of mGlu5. In cells expressing human mGlu5 receptor, 5PAM523 potentiated threshold responses to glutamate in fluorometric calcium assays, but does not have any intrinsic agonist activity. 5PAM523 acts as an allosteric modulator as suggested by the binding studies showing that 5PAM523 did not displace the binding of the orthosteric ligand quisqualic acid, but did partially compete with the negative allosteric modulator, MPyEP. In vivo, 5PAM523 reversed amphetamine-induced locomotor activity in rats. Therefore, both the in vitro and in vivo data demonstrate that 5PAM523 acts as a selective mGlu5 PAM and exhibits anti-psychotic like activity. To study the potential for adverse effects and particularly neurotoxicity, brain histopathological exams were performed in rats treated for 4 days with 5PAM523 or vehicle. The brain exam revealed moderate to severe neuronal necrosis in the rats treated with the doses of 30 and 50 mg/kg, particularly in the auditory cortex and hippocampus. To investigate whether this neurotoxicity is mechanism specific to 5PAM523, similar safety studies were carried out with three other structurally distinct selective mGlu5 PAMs. Results revealed a comparable pattern of neuronal cell death. Finally, 5PAM523 was tested in mGlu5 knock-out (KO) and wild type (WT) mice. mGlu5 WT mice treated with 5PAM523 for 4 days at 100 mg/kg presented significant neuronal death in the auditory cortex and hippocampus. Conversely, mGlu5 KO mice did not show any neuronal loss by histopathology, suggesting that enhancement of mGlu5 function is responsible for the toxicity of 5PAM523. This study reveals for the first time that augmentation of mGlu5 function with selective allosteric modulators results in neurotoxicity.