Design of long acting invasomal nanovesicles for improved transdermal permeation and bioavailability of asenapine maleate for the chronic treatment of schizophrenia.

Asenapine Maleate (ASPM) is a second generation antipsychotic used for the management of schizophrenia but with very limited oral bioavailability due to its extensive first pass metabolism. Transdermal administration of ASPM using nanocarriers like invasomes might offer an excellent alternative to its oral administration with enhanced bioavailability and a sustained action. ASPM-loaded invasomes were successfully prepared by thin film hydration technique; meanwhile the penetration enhancing effect of terpenes (cineole and limonene) was compared to hydromiscible cosolvent (Transcutol®). Soft nanovesicles containing Transcutol® displayed smaller particle sizes than invasomes containing limonene and cineole while invasomes showed higher efficiency to encapsulate asenapine. Ex- vivo skin permeation revealed that invasomes with limonene are more efficient than those with cineole for the transdermal delivery of asenapine. The optimum nano-invasomes formulation contained 1% Limonene and showed particle size of 82 ± 0.6 nm, entrapment efficiency of 56.6 ± 1.5 % and transdermal flux of 3401.6 ± 604.2 (µg/h.cm2). Transmission electron microscopy of the selected formulation showed uniform spherical vesicles with intense outline and lighter core and FTIR study emphasized that ASPM was completely incorporated within the vesicles. The in- vivo pharmacokinetic study revealed that transdermal invasomes achieved 2 folds higher Cmax compared to oral suspension and delayed the Tmax from 1.5 h to around 4 h. The bioavailability of asenapine loaded invasomes after transdermal application was significantly improved to 54.5% compared to the 3.6 % achieved with the oral administration and exceeding the bioavailability of sublingual tablets currently available in the market and exhibited sustained release kinetics over 72 h which permits reduction of dosing frequency to increase patient adherence to medication.

Osteopathy students profile in Italy: A cross sectional census.

INTRODUCTION: The Osteopathy Students Analysis (OSA) aims to profile osteopathy students in Italy as a target population in terms of sociodemographic characteristics, geographical distribution, health status, and previous and ongoing education specifications. MATERIALS AND METHODS: The OSA used a cross-sectional design. A Web-based survey was distributed to the Italian Osteopathic Education Institutions (OEIs). The OSA survey was composed of items organised into four sections: 1. Sociodemographic characteristics (11 items); 2. Geographical distribution (5 items); 3. Health status (3 items); 4. Previous and ongoing education specifications (16 items). A descriptive sample population analysis was performed. Dichotomous and categorical variables were presented as frequencies and percentages, and continuous variables were displayed as means and standard deviations. Some variables were analysed using a pentenary distribution. RESULTS: 49 out of the 61 OEIs identified matched the inclusion criteria, and among these, 22 accepted to propose the enrolment of their students into the study. The survey was administered to 4,720 students from all the participant OEIs. A total of 3,762 students responded to the survey, accounting for an estimated response rate of 53.7%. The majority of respondents were men (54%), with an average age of 26.9 ± 6.5 years. Almost the totality of the sample was composed of the European ethnic group (99.1%). Respondents were predominantly born in Italy (97.2%). The majority of the sample reported being in good (49.5%) to excellent (38.6%) health. To date, osteopathy students are almost evenly distributed between the two types of curricula (T1 = 46.6%; T2 = 53.4%). CONCLUSIONS: The OSA is the first study that aims to profile Italian osteopathy students as a target population in terms of sociodemographic characteristics, geographical distribution, health status, and previous and ongoing education specifications. Future studies should focus on investigating the correlation between the sociodemographic characteristics of students and their academic performance.

Surface-engineered nanoliposomes with lipidated and non-lipidated peptide-dendrimeric scaffold for efficient transdermal delivery of a therapeutic agent: Development, characterization, toxicological and preclinical performance analyses.

The current study aimed to develop novel peptide dendrimer (PD)-conjugated nanoliposomal formulations of asenapine maleate (ASP) for improvement in the transdermal delivery and pharmacokinetic profile of the drug. Novel arginine-terminated PDs (+/-lipidation) were prepared by solid phase peptide synthesis, followed by conjugation onto ASP nanoliposomes. The nanoliposomes were characterized for particle size (and polydispersity index), zeta potential (ZP), drug entrapment efficiency, shape and morphology, differential scanning calorimetry and FT-IR spectroscopy. Ex vivo skin permeation and retention studies demonstrated considerably higher percutaneous permeation of ASP from the developed nanoliposomes (Q24 = 794.31 ± 54.89 µg/cm2, Jss = 105.40 ± 4.8 µg/cm2/h, ER = 36.85 ± 2.89 for liposomes with lipidated peptide dendrimer (Lipo-PD2)) in comparison with passive diffusion studies (Q24 = 63.09 ± 3.56 µg/cm2, Jss = 3.01 ± 0.23 µg/cm2/h). Confocal Laser Scanning Microscopy (CLSM) confirmed the higher percutaneous penetration of Lipo-PD2 in comparison with liposomes without the dendrimer. In vitro cytotoxicity determined on HaCaT cell line demonstrated CTC50 of >1000 µg/mL for both the synthesized PDs and Lipo-PD2. Pharmacokinetic studies in male Sprague Dawley rats revealed considerably and significantly higher t1/2 = 82.32 ± 14.48 h and AUC0-t = 4403.34 ± 367.10 h.ng/mL, from the developed formulation, compared to orally administered ASP (t1/2 = 21.64 ± 2.53 h and AUC0-t = 2303.55 ± 444.5 h.ng/mL), demonstrating higher bioavailability and longer retention in vivo. Additionally, in vivo skin retention, brain uptake studies and pharmacodynamics of the developed formulations were investigated. Stability studies indicated that the formulations were stable up to relatively stable with respect to size, ZP and drug content for 4 months at the tested conditions. This study demonstrates that the developed PD-conjugated nanoliposomal formulations can effectively serve as a transdermal delivery strategy for ASP.

Characterization and Validation of Canine P-Glycoprotein-Deficient MDCK II Cell Lines for Efflux Substrate Screening.

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.

Impact of P-Glycoprotein-Mediated Active Efflux on Drug Distribution into Lumbar Cerebrospinal Fluid in Nonhuman Primates.

Estimation of unbound drug concentration in the brain (Cu,brain) is an essential part of central nervous system (CNS) drug development. As a surrogate for Cu,brain in humans and nonhuman primates, drug concentration in cerebrospinal fluid (CCSF) collected by lumbar puncture is often used; however, the predictability of Cu,brain by lumbar CCSF is unclear, particularly for substrates of the active efflux transporter P-glycoprotein (P-gp). Here, we measured lumbar CCSF in cynomolgus monkey after single intravenous administration of 10 test compounds with varying P-gp transport activities. The in vivo lumbar cerebrospinal fluid (CSF)-to-plasma unbound drug concentration ratios (Kp,uu,lumbar CSF) of nonsubstrates or weak substrates of P-gp were in the range 0.885-1.34, whereas those of good substrates of P-gp were in the range 0.195-0.458 and were strongly negatively correlated with in vitro P-gp transport activity. Moreover, concomitant treatment with a P-gp inhibitor, zosuquidar, increased the Kp,uu,lumbar CSF values of the good P-gp substrates, indicating that P-gp-mediated active efflux contributed to the low Kp,uu,lumbar CSF values of these compounds. Compared with the drug concentrations in the cisternal CSF and interstitial fluid (ISF) that we previously determined in cynomolgus monkeys, the lumbar CCSF were more than triple for two and all of the good P-gp substrates examined, respectively. Although lumbar CCSF may overestimate cisternal CSF and ISF concentrations of good P-gp substrates, lumbar CCSF allowed discrimination of good P-gp substrates from the weak and nonsubstrates and can be used to estimate the impact of P-gp-mediated active efflux on drug CNS penetration. SIGNIFICANCE STATEMENT: This is the first study to systematically evaluate the penetration of various P-glycoprotein (P-gp) substrates into lumbar cerebrospinal fluid (CSF) in nonhuman primates. Lumbar CSF may contain >3-fold higher concentrations of good P-gp substrates than interstitial fluid (ISF) and cisternal CSF but was able to discriminate the good substrates from the weak or nonsubstrates. Because lumbar CSF is more accessible than ISF and cisternal CSF in nonhuman primates, these findings will help increase our understanding of drug central nervous system penetration at the nonclinical stage.

Patterns of comorbidity and sociodemographic and psychosocial correlates among people living with HIV in South Carolina, USA.

OBJECTIVES: Prevention of comorbidity with HIV infection warrants more attention as people living with HIV (PLWH) tend to live longer in the era of effective antiretroviral therapy (ART). This study aimed to investigate the associations between various psychosocial variables and different comorbid conditions in South Carolina (SC), USA. METHODS: A cross-sectional survey was conducted among PLWH from May to September 2018 in SC. Comorbid conditions were based on self-report data and grouped into sexually transmitted infection (STI) comorbidities, noninfectious chronic comorbidities or any comorbidity. Multivariate logistic regression models were used to analyse the relevant associations. RESULTS: Among 402 participants, the prevalence of STI comorbidities, noninfectious chronic comorbidities, and any comorbidity was 61.7%, 21.9% and 69.4%, respectively. The multivariate analysis showed that higher depression scores were associated with an increased risk of any comorbidity, while higher anxiety scores were associated with an increased risk of STI comorbidities or any comorbidity. Higher resilience scores were associated with a decreased risk of noninfectious chronic comorbidities or any comorbidity. CONCLUSIONS: The association between psychosocial factors and different types of comorbidity could inform holistic interventions, such as providing integrated mental health services (e.g. treating mental health problems or building resilience), to effectively cope with and manage the co-existing medical conditions of PLWH.

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design, characterization, in vitro, ex vivo and in vivo appraisal.

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES4) were found to be 137.9 nm and -28.8 mV respectively. A maximum of 99.64 ± 0.16% of ASM was released from SES4 in 60 minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES4 showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the tmax determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55 ± 3.11% as extend of lymphatic absorption (r = 0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.

From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y2 receptor.

The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point.

Effects of a detergent micelle environment on P-glycoprotein (ABCB1)-ligand interactions.

P-glycoprotein (P-gp) is a multidrug transporter that uses energy from ATP hydrolysis to export many structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs from cells. Several structural studies on purified P-gp have been reported, but only limited and sometimes conflicting information is available on ligand interactions with the isolated transporter in a dodecyl-maltoside detergent environment. In this report we compared the biochemical properties of P-gp in native membranes, detergent micelles, and when reconstituted in artificial membranes. We found that the modulators zosuquidar, tariquidar, and elacridar stimulated the ATPase activity of purified human or mouse P-gp in a detergent micelle environment. In contrast, these drugs inhibited ATPase activity in native membranes or in proteoliposomes, with IC50 values in the 10-40 nm range. Similarly, a 30-150-fold decrease in the apparent affinity for verapamil and cyclic peptide inhibitor QZ59-SSS was observed in detergent micelles compared with native or artificial membranes. Together, these findings demonstrate that the high-affinity site is inaccessible because of either a conformational change or binding of detergent at the binding site in a detergent micelle environment. The ligands bind to a low-affinity site, resulting in altered modulation of P-gp ATPase activity. We, therefore, recommend studying structural and functional aspects of ligand interactions with purified P-gp and other ATP-binding cassette transporters that transport amphipathic or hydrophobic substrates in a detergent-free native or artificial membrane environment.

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155µM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30µM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100µM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10µM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.

Effect of Asenapine on the Activity of Hypocretin Neurons in Normal and Unpredictable Mild Stress Preconditioned Rats.

Asenapine (ASE) is a novel atypical antipsychotic used in schizophrenia treatment. Here, the effect of ASE on Fos expression in hypocretin (Hcrt) neurons in medial and lateral portions of the lateral hypothalamus (LH) and the effect of chronic unpredictable variable mild stress (CMS) preconditioning were studied. CMS consisted of restraint, social isolation, crowding, swimming, and cold and lasted 21 days. The rats were sacrificed on day 22, 90 min after a single injection of vehicle (saline 300 µl/rat subcutaneously--s.c.) or ASE (0.3 mg/kg s.c.). Control (CON), ASE, CMS, and CMS+ASE groups were used. Fos protein was visualized by the avidin biotin peroxidase technique, while Hcrt perikarya by fluorescent dye. Fos/Hcrt co-localizations were evaluated under parallel light and fluorescent illuminations. In the single Fos expression assessment, the Fos number was significantly higher in the medial in comparison with the lateral LH portion in each group. No differences in Fos amount were observed between the individual groups within the medial and lateral LH portions. In the Fos/Hcrt co-localization assessments, ASE significantly reduced the number of Fos/Hcrt neurons in the medial, but not lateral, LH portion in ASE and CMS+ASE groups. CMS only slightly contributed to the inhibitory effect of ASE in the CMS+ASE groups. The present data show as the first that ASE may reduce the activity of Hcrt cells in the medial LH portion, which might correspond with the relatively low weight gain liability of ASE. CMS preconditioning did not significantly interfere with this impact of ASE.

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity.

Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms--two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2-3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.

Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties.

Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest. Among them, their antioxidant, anti-aging and anti-angiogenesic properties are well established and subjects of numerous research endeavors. This mini-review aspires to account and present the literature reports published on research concerning various natural and synthetic stilbenes, such as trans-resveratrol. Special focus was given to most recent research findings, while the mechanisms underlying their anti-aging and anti-angiogenic effects as well as the respective signaling pathways involved were also presented and discussed.

Amurensin G induces autophagy and attenuates cellular toxicities in a rotenone model of Parkinson's disease.

Although Parkinson's disease is a common neurodegenerative disorder its cause is still unknown. Recently, several reports showed that inducers of autophagy attenuate cellular toxicities in Parkinson's disease models. In this report we screened HEK293 cells that stably express GFP-LC3, a marker of autophagy, for autophagy inducers and identified amurensin G, a compound isolated from the wild grape (Vitis amurensis). Amurensin G treatment induced punctate cytoplasmic expression of GFP-LC3 and increased the expression level of endogenous LC3-II. Incubation of human dopaminergic SH-SY5Y cells with amurensin G attenuated the cellular toxicities of rotenone in a model of Parkinson's disease. Amurensin G inhibited rotenone-induced apoptosis and interfered with rotenone-induced G2/M cell cycle arrest. In addition, knockdown of beclin1, a regulator of autophagy, abolished the effect of amurensin G. These data collectively indicate that amurensin G attenuates cellular toxicities through the induction of autophagy.

The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania.

INTRODUCTION: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. AREAS COVERED: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations. EXPERT OPINION: Asenapine exhibits a broad pharmacological profile that targets a wide range of neurotransmitter receptors with variable affinities. The drug preferentially increases dopamine, norepinephrine, and acetylcholine levels in cortical and limbic brain areas. It also potentiates cortical glutamatergic neurotransmission, and is active in behavioral animal models predictive of antipsychotic, antidepressant, and pro-cognitive activities. Chronic administration of asenapine alters the abundance of dopamine, serotonin, glutamate, adrenergic, and cholinergic receptor subtypes in different brain regions. These action mechanisms of asenapine might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia and other psychotic disorders.

Leaf and stem of Vitis amurensis and its active components protect against amyloid ß protein (25-35)-induced neurotoxicity.

This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid ß protein (Aß) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 µM Aß (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 µg/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of which were induced by Aß (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol Aß (25-35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans-ɛ-viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i) and the generation of ROS induced by Aß (25-35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against Aß (25-35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer's disease.

Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1.

The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many anticancer agents. We recently showed that a Forkhead box-containing protein of the O subfamily 1 (FoxO1) is a key regulator of MDR1 gene transcription. Because nuclear localization of FoxO1 is regulated by silent information regulator two ortholog 1 (SIRT1) deacetylase, we wondered whether SIRT1 dominates MDR1 gene expression in breast cancer cells. Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. In addition, SIRT1 inhibition reduced both nuclear FoxO1 levels and MDR1 expression in doxorubicin-resistant breast cancer cells (MCF-7/ADR) cells. A potent SIRT1 inhibitor, amurensin G (from Vitis amurensis), was identified by screening plant extracts and bioassay-guided fractionation. The compound suppressed FoxO1 activity and MDR1 expression in MCF-7/ADR cells. Moreover, pretreatment of MCF-7/ADR cells with 1 µg/ml amurensin G for 24 h increased cellular uptake of doxorubicin and restored the responsiveness of MCF-7/ADR cells to doxorubicin. In xenograft studies, injection of 10 mg/kg i.p. amurensin G substantially restored the ability of doxorubicin to inhibit MCF-7/ADR-induced tumor growth. These results suggest that SIRT1 is a potential therapeutic target of MDR1-mediated chemoresistance and that it may be possible to develop amurensin G as a useful agent for chemoresistance reversal.

Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation.

An exposure-response (E-R) analysis using linear mixed effects modeling was conducted on data from a thorough QTc trial for asenapine in 148 patients with schizophrenia. In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10 days (10d) followed by 10 mg BID (6d), asenapine 15 mg BID (10d) followed by 20 mg BID (6d), quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1 (baseline), 1, 10, and 16 at 8 scheduled times on each day. At mean C(max) for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International Conference on Harmonisation-established threshold for clinical concern. The model predicted a mean increase of 7 to 8 milliseconds for quetiapine. The corresponding upper bounds of the 95% confidence intervals were 7.5 milliseconds and 11.2 milliseconds for asenapine and quetiapine, respectively.

Asenapine maleate: a new drug for the treatment of schizophrenia and bipolar mania.

Schizophrenia and bipolar disorder are serious neuropsychiatric disorders with substantial health risks for patients that result in major socioeconomic burdens on society. Current therapeutic agents fail to adequately address patient needs in terms of efficacy, tolerability and treatment-related adverse events. Consequently there is an urgent need to develop more effective and better tolerated pharmacotherapies for improved treatment of these illnesses. Asenapine maleate is a novel drug recently approved by the Food and Drug Administration for treatment of acute schizophrenia and for manic or mixed episodes of bipolar I disorder with or without psychotic features in adults. It has a unique pharmacologic profile as it targets multiple dopamine, serotonin and adrenergic receptor subtypes with variable affinities. Such drug/receptor interactions contribute to the antipsychotic and antimanic efficacy of asenapine. Asenapine was effective in animal models predictive of antipsychotic activity and clinical trials indicate that it improves the symptoms of acute schizophrenia and bipolar mania, is well tolerated and has a favorable safety profile. This monograph provides an up to date review of the preclinical and clinical profiles of asenapine, including new clinical data in patients with schizophrenia and bipolar mania.

New bioactive prenylflavonoids and dibenzocycloheptene derivative from roots of Dendrolobium lanceolatum.

Two new flavanones (1 and 2), a new flavan (3), and a new rare dibenzocycloheptene derivative (4) together with a known flavan, 4'-hydroxy-2' ',2' 'dimethyl-pyranoflavan (5), were isolated from the roots of Dendrolobium lanceolatum. Their structures were established on the basis of spectral evidence, and an X-ray analysis was performed to confirm the structure of 4. Compounds 1-3 exhibited antimalarial activity with IC50 values of 2.6, 3.3, and 3.1 microg/mL, respectively. Compounds 1-5 showed moderate antimycobacterial activity with MIC values of 6.3, 12.5, 25, 25, and 50 microg/mL, respectively. In addition, 1 showed strong cytotoxicity against cancer cell lines KB, BC, and NCI-H187 with IC50 values of 1.2, 1.6, and 0.6 microg/mL, respectively, while 2 showed moderate cytotoxicity against the NCI-H187 cell line with an IC50 value of 8.1 microg/ mL.