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Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, ß-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the ß-catenin protein expression was also determined by immunocytochemistry. ILO (p < 0.05) and TMZ (p < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment (p < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups (p < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression (p < 0.001). The expressions of ß-catenin (p < 0.001), Dvl2 (p < 0.001), Twist (p < 0.001), and Slug (p < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and ß-catenin expression and has the potential to be repurposed against GBM.

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Background: Among antipsychotics, sialorrhea is most associated with clozapine, and when it occurs, it is uncomfortable, socially stigmatizing, and can contribute to medication non-adherence. Risperidone has a generally negligible muscarinic activity compared to clozapine, and yet, multiple reports of severe sialorrhea associated with risperidone have been reported. Case presentation: This case report describes risperidone-induced sialorrhea that was unintentionally masked by simultaneous clonidine administration that was intended to treat hypertension. Interestingly, sialorrhea was present but mild when clonidine was present; however, when risperidone was further titrated and clonidine removed, a significant worsening of sialorrhea developed. Sialorrhea did not respond to treatment with anticholinergic medication. Conclusion: The pathophysiology of antipsychotic-induced sialorrhea is complex and varies between antipsychotics. Risperidone-induced sialorrhea is suspected of having prominent adrenergic pathophysiology that is likely composed of highly viscoelastic saliva (high protein content), differing from the more commonly encountered clozapine-induced sialorrhea. Risperidone-induced sialorrhea is reported as more likely to respond to dose reduction and treatment with α2-adrenergic receptor agonists or ß-adrenergic receptor antagonists and less likely to respond to anticholinergic (antimuscarinic) medications.

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Iloperidone (ILO) is a poorly soluble and bioavailable WHO-approved schizophrenia drug. Microneedles are a revolutionary delivery technology that overcomes many of the issues associated with traditional drug administration. The current research aimed to compare the antipsychotic activity and pharmacokinetics of ILO-loaded dissolving microneedles (DMNs) and transdermal film with a solid microneedle (STF). The DMNs were fabricated using the micromolding process, while the transdermal film was created using the solvent casting approach. Furthermore, an in vivo pharmacokinetic, pharmacodynamic, and skin irritation study was performed on Wistar rats. Studies were compared with transdermal film (TF) on untreated skin as a passive control. STF and DMNs had considerably greater AUC and Cmax (p ≤ 0.001) than transdermal film. In pharmacodynamic tests, STF and DMNs demonstrated significant (p ≤ 0.001) forelimb retraction time (FRT) and hindlimb retraction time (HRT) delay responses as compared to control and TF. In the skin irritation test, no adverse effects such as erythema or edema were observed at the end of the 48 h. Thus, antipsychotic activity (paw test) and pharmacokinetics studies revealed sustained action of DMN and STF. This research revealed that improved efficacy of DMN and STF for antipsychotic drug delivery may be an alternative to the existing dosage form.

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PURPOSE: Iloperidone (IP) is an antipsychotic drug which belongs to Biopharmaceutical Classification System (BCS) II exhibiting poor aqueous solubility. The current investigation explores the possibility of enhancement of solubility and dissolution characteristics of IP by formulation of liquid self-nano emulsifying drug delivery system (L-SNEDDS) utilizing Box-Behnken Design (BBD) and desirability function. METHODS: The oils, surfactants and co-surfactants used in the study were selected based on solubility of the drug and their emulsification ability. Optimization of the formulation was performed using BBD by employing four response variables such as globule size (nm), percentage transmittance (%), self-emulsification time (sec) and percent drug released in 15min. 2D contour plots and 3D response surface plots were constructed using Design Expert software. RESULTS: The developed optimal L-SNEDDS of IP through BBD approach resulted in improvement of solubility and dissolution rate as compared with the pure drug. Based on desirability function, optimized formulation was prepared and was assessed for response variables (globule size, percentage transmittance, self-emulsification time and percent drug dissolved in 15min). The characterization studies revealed droplet size to be 21.80±2.41nm, 99.584±0.65% transmittance, 24.43±2.12sec emulsification time and 95.31±1.57% cumulative drug release in 15min. CONCLUSION: The results conclude the potentiality of prepared L-SNEDDS in improving solubility and dissolution rate of IP.

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The transient receptor potential cation channel, subfamily M, members 6 and 7 (TRPM6 and TRPM7) are homologous membrane proteins encompassing cation channel units fused to cytosolic serine/threonine-protein kinase domains. Clinical studies and experiments with animal disease models suggested that selective inhibition of TRPM6 and TRPM7 currents might be beneficial for subjects with immune and cardiovascular disorders, tumours and other pathologies, but the suitable pharmacological toolkit remains underdeveloped. The present study identified small synthetic molecules acting specifically on the channel moieties of TRPM6 and TRPM7. Using electrophysiological analysis in conjunction with Ca2+ imaging, we show that iloperidone and ifenprodil inhibit the channel activity of recombinant TRPM6 with IC50 values of 0.73 and 3.33 µM, respectively, without an impact on the TRPM7 channel. We also found that VER155008 suppresses the TRPM7 channel with an IC50 value of 0.11 µM but does not affect TRPM6. Finally, the effects of iloperidone and VER155008 were found to be suitable for blocking native endogenous TRPM6 and TRPM7 in a collection of mouse and human cell models. Hence, the identification of iloperidone, ifenprodil, and VER155008 allows for the first time to selectively manipulate TRPM6 and TRPM7 currents.

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CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 µM and Ki = 462 µM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.

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In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients' lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T3 increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.

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Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

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Iloperidone (IL) is practically insoluble in water and has significant first-pass metabolism, resulting in low oral bioavailability in humans (36%). IL lipid nanoemulsions (IL-LNEs) were prepared to improve oral bioavailability. IL-LNEs were formulated by hot homogenization and ultrasonication method. Soybean oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. Dynamic light scattering technique was used for globule size analysis. All LNE formulations showed narrow size distribution and the average globule size and Poly Dispersity Index (PDI) were found to be in between 182.2 ± 2.8 to 222.3 ± 1.9 nm and 0.200 ± 0.004 to 0.274 ± 0.005 respectively. Zeta potential values varied from -20.0 ± 0.15 to -28.9 ± 0.30 mV which indicated stability of prepared LNEs. All formulations showed good entrapment efficiency ranging from 99.07 ± 0.01 to 99.28 ± 0.01% when separated using centrisart tubes and the drug content varied from 96.99 ± 0.94 to 99.06 ± 0.36%. Physical stability testing indicated the stability of all LNEs and optimized LNE-IL4 was found stable for 3 months at both refrigerated (4 °C) and room temperature (25 °C). During in vivo studies in wistar rats, the optimized LNE showed 2.47-fold improvement in the oral bioavailability and superior (1.22-fold) pharmacodynamic activity when compared to marketed tablet suspension (Ilosure-4®) in suppressing the hyperlocomotor activity, being induced by MK-801 (Dizocilpine).

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α1-Adrenoceptor is implicated in numerous neuronal diseases. The development of new modulators targeting this receptor as well as the investigation of the role of α1-adrenoceptor in healthy and disease conditions, however, is hindered by the lack of specific positron emission tomography (PET) radiotracers. Iloperidone shows a high binding affinity to α1-adrenoceptor and moderate selectivity over other brain receptors. We report herein the synthesis and characterization of carbon-11 labeled iloperidone for imaging of α1-adrenoceptor in brain. The radiolabeling of [11C]iloperidone was carried out conveniently in one step by treating precursor with [11C]CH3I in DMF in the presence of K2CO3. Then, [11C]iloperidone was purified by semi-preparative HPLC, and characterized in C57BL/6 mice using PET/CT scanning. The desired product [11C]iloperidone was obtained in an average decay corrected radiochemical of 12% (n = 3) and over 99% radiochemical purity. The average molar radioactivity was 357 GBq/µmol with total synthetic time of 35-40 min. PET/CT scanning in C57BL/6 mice showed favorable pharmacokinetic properties and high brain exposure of [11C]iloperidone. Blocking experiments by pretreatment with the unlabeled iloperidone showed the significant blocking effects with about 25% reduction in brain uptake. These results suggested that [11C]iloperidone can serve as a lead compound for the further development of specific radiotracers for PET imaging of α1-adrenoceptor in brain clinically.

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Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver. The study was carried out on cryopreserved human hepatocytes. The hepatotoxicity of the tested drugs was assessed after exposure to the neuroleptics (LDH cytotoxicity assay). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6ß-hydroxylation (CYP3A4). Parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Asenapine significantly decreased the mRNA level and activity of CYP1A2, while iloperidone potently diminished the mRNA level and activity of CYP3A4 in the cultures of human hepatocytes. Lurasidone did not affect the expression and activity of any of the investigated human CYP enzymes. The presented findings may have clinical implications for the prediction of potential drug-drug interactions involving the asenapine-induced inhibition of metabolism of CYP1A2 substrates (e.g. caffeine, theophylline, melatonin, tricyclic antidepressants, phenacetin, propranolol) and iloperidone-induced inhibition of CYP3A4 substrates (e.g. antidepressants, benzodiazepines, atorvastatin, macrolide antibiotics, calcium channel antagonists).

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INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

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BACKGROUND: The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). METHODS: The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4'-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1'-hydroxylation/CYP2D6 and testosterone 6ß-hydroxylation/CYP3A4, respectively, using HPLC. RESULTS: Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes). CONCLUSION: The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

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Iloperidone, a second-generation atypical antipsychotic drug, is widely used in the treatment of schizophrenia. However, the side-effects of iloperidone on vascular K+ channels remain to be determined. Therefore, we explored the effect of iloperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Iloperidone inhibited vascular Kv channels in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 2.11 ± 0.5 µM and a Hill coefficient of 0.68 ± 0.03. Iloperidone had no effect on the steady-state inactivation kinetics. However, it shifted the steady-state activation curve to the right, indicating that iloperidone inhibited Kv channels by influencing the voltage sensors. Application of 20 repetitive depolarizing pulses (1 and 2 Hz) progressively increased the inhibition of the Kv current in the presence of iloperidone. Furthermore, iloperidone increased the recovery time constant from Kv channel inactivation, suggesting that iloperidone-induced inhibition of Kv channels is use (state)-dependent. Pretreatment with a Kv1.5 inhibitor (diphenyl phosphine oxide 1 [DPO-1]) inhibited the Kv current to a level similar to that with iloperidone alone. However, pretreatment with a Kv2.1 or Kv7.X inhibitor (guangxitoxin or linopirdine) did not affect the inhibitory effect of iloperidone on Kv channels. Therefore, iloperidone directly inhibits Kv channels in a concentration- and use (state)-dependent manner independently of its antagonism of serotonin and dopamine receptors. Furthermore, the primary target of iloperidone is the Kv1.5 subtype.

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Iloperidone (ILO) is an anti-psychotic, used in schizophrenia. It has low bioavailability (36%) due to low solubility and first pass effect. Oral solid self microemulsifying drug delivery system (SMEDDS) and liquisolid compact (LSC) of ILO were developed. The hypothesis is to test in vivo performance (PK and PD effects) of these delivery systems, as both systems improve dissolution. Based on solubility Capmul MCM, Labrafac WL 1349 were selected as oils, Lauroglycol 90 and PEG 600 were selected as surfactant and cosurfactant. Syloid XDP was optimized for adsorption of liquid SMEDDS. Syloid XDP and Aerosil 200 were optimized as carrier and coating material in the ratio of 15:1 w/w for liquisolid formulation. SEM and PXRD studies indicated no specific crystallinity due to bulkiness in both formulations, which showed similar flow and release behavior. Pharmacokinetic studies were performed for ILO Coarse suspension (CS), Tablet suspension (TS), optimized solid SMEDDS (A1X) and liquisolid compact (S3) in wistar rats. About 3.80 and 2.19-fold improvements in relative bioavailabilty were found for A1X and S3, respectively, when compared to CS. In comparison to TS, 2.61 and 1.51 fold improvements in bioavailability were found for A1X and S3, respectively. Further, Pharmacodynamic activity was studied by reversal of MK-801 induced hyperlocomotion in rats. A1X and S3 formulations showed maximum reversal after 15 min when compared to CS and found to have similar performance. Thus, in comparison to S3, A1X showed significant difference in pharmacokinetic effects but similar pharmacodynamic effects.

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PURPOSE: Iloperidone, second generation antipsychotic drug, reported in clinical trial to produce orthostatic hypotension as side effect. It was claimed to be antagonistic at alpha adrenergic receptor in central nervous system. We evaluated effect of Iloperidone on peripheral alpha 1 adrenoreceptor by in silico and in vitro methods while in vivo hypotensive, antihypertensive and ocular hypotensive activity was evaluated in animals. METHODS: Pharmacological activity prediction of Iloperidone was done using PASSOnline and SwissTargetPrediction softwares and molecular docking with Alpha 1A adrenoreceptor using AutoDock Vina. Hypotensive activity in normotensive and antihypertensive activity against DOCA-salt induced hypertension in rats were evaluated at doses 0.03 mg/Kg and 0.1 mg/Kg, i.p of Iloperidone. Blood pressure was measured by invasive blood pressure measurement technique using PowerLab 4/30 and intraocular pressure was measured using digital tonometer. RESULTS: Iloperidone (0.1 mg/Kg) showed significant decrease in blood pressure (38.96 ± 1.1%) in normotensive rats, while in DOCA salt induced hypertensive rats, systolic blood pressure was found to be decreased by 29.04 ± 1.45% and 31.43 ± 1.21% in 0.03 mg/Kg and 0.1 mg/Kg treated rats respectively. Iloperidone prevented rise in systolic BP with adrenaline. Intraocular pressure was found to be decreased by 36.66 ± 3.15% in rabbits after 1 h of instillation of 0.1% Iloperidone. CONCLUSION: Iloperidone exerted hypotensive and/or anti-hypertensive activity in rats and ocular hypotensive activity in rabbits.

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The objective of present study was to develop and evaluate lipid vesicular transdermal system of iloperidone. Liposomes were prepared successfully using thin film hydration method. With aim of enhancing permeation, cholesterol from liposomes was replaced with transcutol to give PEVs. Liposomes and PEVs were evaluated for particle size, shape, entrapment efficiency, viscosity and release study. The vesicles were incorporated in 0.5% of Carbopol gel and evaluated. Particle size of liposomes and PEVs was found between 200-300 nm and entrapment efficiency was found 80-90%w/w. The transdermal gels were homogeneous, spreadable having acceptable pH and drug content between 90-100%.In ex vivo studies, both liposomes and PEVs showed relatively higher skin deposition and permeation of Iloperidone than the plain drug without vesicles. The in vivo pharmacokinetics studies showed relative bioavailability of the PEV loaded gel as 62% and 166% when compared to the oral drug and gel without vesicles respectively. Pharmacodynamic studies showed FRT and HRT delay responses of the transdermal gel systems were significant[p < 0.05] as compared to control at the end of 24 hs. Thus, it can be concluded that transdermal delivery system can be a promising approach for sustained delivery of Iloperidone.

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BACKGROUND: The signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously". OBJECTIVE: To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). METHODOLOGY: The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. RESULTS: The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. CONCLUSION: Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

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The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including serotonin and adrenoceptors. We examined the long-term effects of multiple doses of iloperidone (0.5, 1.5, or 5 mg/kg) on serotonin (5-HT) 5-HT1A, 5-HT2A receptor subtypes, and adrenoceptors α1 and α2 subtypes. Rats received daily intraperitoneal injections of different doses of iloperiodone or vehicle for 4 weeks. Receptor autoradiography quantified the levels of 5-HT and adrenoceptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampal CA1 (HIP-CA1) and CA3 (HIP-CA3) regions. Four weeks of iloperidone treatment significantly and dose-dependently increased 5-HT1A and decreased 5-HT2A receptors in the MPC and DFC. Higher doses of iloperidone (1.5 and 5 mg/kg) increased 5-HT1A and decreased 5-HT2A receptors in HIP-CA1 and HIP-CA3 regions. In addition, repeated iloperidone treatment produced significant increases in α1- and α2-adrenoceptors in MPC, DFC, HIP-CA1, and HIP-CA3 regions. No changes in 5-HT and adrenoceptors were observed in other brain regions examined. These results suggest that long-term iloperidone treatment exerts region- and dose-specific effects on forebrain 5-HT and adrenoceptors, which may contribute to its therapeutic benefits in improving positive and negative symptoms of schizophrenia as well as maintaining a benign safety profile.

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