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Keywords = antischizophrenic drug

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19 pages, 4297 KiB  
Article
Brain-Targeted Intranasal Delivery of Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics
by Sravanthi Reddy Pailla, Sunitha Sampathi, Vijayabhaskarreddy Junnuthula, Sravya Maddukuri, Sujatha Dodoala and Sathish Dyawanapelly
Pharmaceutics 2022, 14(5), 978; https://doi.org/10.3390/pharmaceutics14050978 - 30 Apr 2022
Cited by 18 | Viewed by 3828
Abstract
The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil [...] Read more.
The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% w/w of Smix (Labrasol and Transcutol HP, and 40% w/w of water resulting in a globule size of 124.6 ± 3.52 nm with low polydispersity index (PDI) (0.212 ± 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug). In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC0–t24 (18.63 ± 1.33 h × µg/g) in the brain by approximately 4.3-fold than oral ME (4.30 ± 0.92 h × µg/g) and 7.7-fold than intravenous drug solutions (2.40 ± 0.36 h × µg/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration. Full article
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16 pages, 2337 KiB  
Article
Fast In Vitro Release and In Vivo Absorption of an Anti-Schizophrenic Drug Paliperidone from Its Soluplus®/TPGS Mixed Micelles
by Ye Zhou, Chenhui Wang, Wenqian Liu, Meiqing Yang, Bohui Xu and Yong Chen
Pharmaceutics 2022, 14(5), 889; https://doi.org/10.3390/pharmaceutics14050889 - 19 Apr 2022
Cited by 17 | Viewed by 3471
Abstract
The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. [...] Read more.
The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10−2 mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: Tmax was 0.83 ± 0.29 h, and Cmax was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer Tmax and lower Cmax. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)
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12 pages, 2863 KiB  
Article
Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia
by Lingzhi Liang, Xia Ren, Junyi Xu, Yurong Ma, Yunlin Xue, Tao Zhuang and Guisen Zhang
Molecules 2022, 27(8), 2550; https://doi.org/10.3390/molecules27082550 - 14 Apr 2022
Cited by 13 | Viewed by 3719
Abstract
Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined [...] Read more.
Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments. Full article
(This article belongs to the Special Issue Novel Compounds in the Treatment of the CNS Disorders)
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19 pages, 4503 KiB  
Article
Utilization of Polymeric Micelles as a Lucrative Platform for Efficient Brain Deposition of Olanzapine as an Antischizophrenic Drug via Intranasal Delivery
by Hadel A. Abo El-Enin, Marwa F. Ahmed, Ibrahim A. Naguib, Shaymaa W. El-Far, Mohammed M. Ghoneim, Izzeddin Alsalahat and Hend Mohamed Abdel-Bar
Pharmaceuticals 2022, 15(2), 249; https://doi.org/10.3390/ph15020249 - 18 Feb 2022
Cited by 19 | Viewed by 3582
Abstract
Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood–brain barrier (BBB) permeability. To direct [...] Read more.
Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood–brain barrier (BBB) permeability. To direct OZ to the brain and to minimize its systemic side effects, the nasal pathway is recommended. OZ-loaded polymeric micelles nano-carriers were developed using suitable biodegradable excipients. The developed micelles were physicochemically investigated to assess their appropriateness for intranasal delivery and the potential of these carriers for OZ brain targeting. The selected formula will be examined in vivo for improving the anti-schizophrenic effects on a schizophrenia rat model. The binary mixture of P123/P407 has a low CMC (0.001326% w/v), which helps in maintaining the formed micelles’ stability upon dilution. The combination effect of P123, P407 and TPGS led to a decrease in micelle size, ranging between 37.5–47.55 nm and an increase in the EE% (ranging between 68.22–86.84%). The selected OZ–PM shows great stability expressed by a suitable negative charge zeta potential value (−15.11 ± 1.35 mV) and scattered non-aggregated spherical particles with a particle size range of 30–40 nm. OZ–PM maintains sustained drug release at the application site with no nasal cytotoxicity. In vivo administration of the selected OZ–PM formula reveals improved CNS targeting and anti-schizophrenia-related deficits after OZ nasal administration. Therefore, OZ–PM provided safe direct nose-to-brain transport of OZ after nasal administration with an efficient anti-schizophrenic effect. Full article
(This article belongs to the Section Pharmaceutical Technology)
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23 pages, 2195 KiB  
Review
Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases
by Dasiel O. Borroto-Escuela, Patrizia Ambrogini, Manuel Narvaez, Valentina Di Liberto, Sarah Beggiato, Luca Ferraro, Ramon Fores-Pons, Jose E. Alvarez-Contino, Alexander Lopez-Salas, Giuseppa Mudò, Zaida Díaz-Cabiale and Kjell Fuxe
Cells 2021, 10(8), 1902; https://doi.org/10.3390/cells10081902 - 27 Jul 2021
Cited by 19 | Viewed by 6993
Abstract
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of [...] Read more.
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder. Full article
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7 pages, 842 KiB  
Proceeding Paper
Formulation, Evaluation, and Pharmacodynamic Investigation of Ziprasidone-b-cyclodextrin In-Situ Nasal Gel
by Vaishali Londhe and Sreevidya Krishnan
Proceedings 2021, 78(1), 42; https://doi.org/10.3390/IECP2020-08699 - 1 Dec 2020
Cited by 2 | Viewed by 1659
Abstract
Ziprasidone hydrochloride is an atypical antipsychotic agent with an anti-schizophrenic activity having less solubility and less bioavailability. The nasal route acts as a promising delivery route for CNS targeting drugs due to improved bioavailability and can reduce peripheral side effects. The main aim [...] Read more.
Ziprasidone hydrochloride is an atypical antipsychotic agent with an anti-schizophrenic activity having less solubility and less bioavailability. The nasal route acts as a promising delivery route for CNS targeting drugs due to improved bioavailability and can reduce peripheral side effects. The main aim of the study is to prepare an in-situ nasal gel of ziprasidone-β-cyclodextrin for improvement in the bioavailability of the drug. The in-situ gel was optimized using box-Behnken design. The optimized formulation was evaluated for homogeneity, viscosity, gelation temperature, mucoadhesive strength, in-vitro permeation studies. The pharmacodynamic activity of in-situ nasal gel was checked using the locomotor activity model. According to the statistical analysis of the design expert software, all the models were found significant. The pharmacodynamic investigation of the cyclodextrin mediated in situ nasal gel showed improvement in drug activity compared to a drug, drug-complex given by oral route indicating the nasal delivery of antipsychotic drug improves its effect. Full article
(This article belongs to the Proceedings of The 1st International Electronic Conference on Pharmaceutics)
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