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1.
Nat Commun ; 15(1): 1173, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332002

RESUMO

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.


Assuntos
Dibenzocicloeptenos , Piridinas , Infecções por Vírus Respiratório Sincicial , Animais , Feminino , Camundongos , Reposicionamento de Medicamentos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/química
2.
BMC Psychiatry ; 24(1): 81, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291403

RESUMO

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.


Assuntos
Antipsicóticos , Dibenzocicloeptenos , Adulto , Humanos , Antipsicóticos/efeitos adversos , Paladar , Método Simples-Cego , Estudos Cross-Over , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Resultado do Tratamento
3.
J Affect Disord ; 349: 438-451, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38211745

RESUMO

BACKGROUND: The evidence of treatment options' efficacy on acute bipolar manic episodes is relatively less in youths than adults. We aimed to compare and rank the drug's efficacy, acceptability, tolerability, and safety for acute mania in children and adolescents. METHOD: We systematically reviewed the double-blinded, randomized controlled trials (RCTs) comparing drugs or placebo for acute manic episodes of bipolar disorder in children and adolescents using PRISMA guidelines. We searched PubMed/MEDLINE, EMBASE, Web of Science, EBSCO, Scopus, the Cochrane Central Register of Controlled Trials, and https://clinicaltrials.gov from inception until November 20, 2022. Response to treatment was the primary outcome, and random-effects network meta-analyses were conducted (PROSPERO 2022: CRD42022367455). RESULTS: Of 10,134 citations, we included 15 RCTs, including 2372 patients (47 % female), 15 psychotropic drugs, and the placebo. Risperidone 0.5-2.5 mg/day, aripiprazole 30 mg/day olanzapine, quetiapine 400 mg/day, quetiapine 600 mg/day, asenapine 5 mg/day, asenapine 10 mg, ziprasidone, and aripiprazole 10 mg were found to be effective (in comparison with placebo) in children and adolescents, respectively (τ2 = 0.0072, I2 = 10.2 %). The tolerability of aripiprazole 30 mg/day was lower than risperidone 0.5-2.5 mg/day and olanzapine. Oxcarbazepine had the highest discontinuation due to the adverse effects risk ratio. LIMITATIONS: Efficacy ranking of the treatments could be performed by evaluating relatively few RCT results, and only monotherapies were considered. CONCLUSIONS: Efficacy, acceptability, tolerability, and safety are changing with the doses of antipsychotics for children and adolescents with acute bipolar manic episodes. Drug selection and optimum dosage should be carefully adjusted in children and adolescents.


Assuntos
Antipsicóticos , Transtorno Bipolar , Dibenzocicloeptenos , Humanos , Adolescente , Adulto , Criança , Risperidona/uso terapêutico , Olanzapina/uso terapêutico , Aripiprazol/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/induzido quimicamente , Fumarato de Quetiapina/uso terapêutico , Mania/induzido quimicamente , Mania/tratamento farmacológico , Metanálise em Rede , Antipsicóticos/efeitos adversos
4.
Neuropsychopharmacol Rep ; 44(1): 158-164, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38239112

RESUMO

AIM: Patients with cancer often experience nausea and vomiting (N/V), but may have difficulty using olanzapine (OLZ), a common antiemetic. Asenapine (ASE) is a multi-acting receptor-targeted antipsychotic like OLZ, although there is little evidence that ASE serves as an antiemetic. The aim of this study was to evaluate the efficacy and tolerability of ASE compared to those of OLZ for the treatment of N/V in patients with cancer. METHODS: This retrospective study involved patients who received 5 mg ASE, 5 mg OLZ, or 2.5 mg OLZ for 2 days. Daily worst N/V was rated on a scale of 0 (none) to 3 (very much). The primary endpoint was the proportion of patients who had a response, defined as any reduction in N/V score. A complete response (CR) was defined as a score reduction to 0. Secondary endpoints included the proportion of patients with CR and adverse events. RESULTS: Between April 2017 and March 2023, 212 patients were enrolled to receive treatment: 5 mg ASE (n = 34), 5 mg OLZ (n = 102), or 2.5 mg OLZ (n = 76). No significant differences in response rates (52.9% vs. 58.8% vs. 52.6%, p = 0.671) or secondary endpoints were observed between the groups. Patients receiving ASE were more likely to experience oral hypoesthesia (p = 0.004). CONCLUSION: This preliminary study suggests that ASE may be effective for N/V. Further studies are required to confirm these findings.


Assuntos
Antieméticos , Dibenzocicloeptenos , Neoplasias , Humanos , Olanzapina , Antieméticos/efeitos adversos , Estudos Retrospectivos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Neoplasias/induzido quimicamente
6.
Purinergic Signal ; 19(2): 401-420, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36219327

RESUMO

G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y12 receptor antagonist, clopidogrel, P2Y2 receptor (P2Y2R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y2R activity, studies using primarily genetic manipulation have revealed roles for P2Y2R in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2Y2R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y2R function and assess therapeutic effects of P2Y2R antagonism. This review discusses the characteristics of P2Y2R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gαq protein signaling. We also discuss the effects of other P2Y2R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y2Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.


Assuntos
Dibenzocicloeptenos , Transdução de Sinais , Humanos , Pirimidinonas , Fibrose , Receptores Purinérgicos P2Y2
7.
Nutrients ; 16(1)2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38201903

RESUMO

Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with a high mortality rate and refractoriness to chemotherapy. Gemcitabine is an anti-cancer chemotherapeutic agent used for CCA, but the efficacy of gemcitabine in CCA treatment is limited, due to the acquisition of chemoresistance. The present study evaluated the chemosensitizing effects of Amurensin G (AMG), a natural sirtuin-1 inhibitor derived from Vitis amurensis, in the SNU-478 CCA cells. Treatment with AMG decreased the SNU-478 cell viability and the colony formation ability. Annexin V/ Propidium iodide staining showed that the AMG increased apoptotic death. In addition, AMG downregulated anti-apoptotic Bcl-2 expression, while upregulating pro-apoptotic cleaved caspase-3 expression. Treatment with AMG decreased the migratory ability of the cells in a wound healing assay and transwell migration assay. It was observed that AMG decreased the gemcitabine-induced increase in CD44highCD24highCD133high cell populations, and the expression of the Sox-2 protein was decreased by AMG treatment. Co-treatment of AMG with gemcitabine significantly enhanced the production of reactive oxygen species, as observed through mitochondrial superoxide staining, which might be associated with the downregulation of the Sirt1/Nrf2 pathway by AMG. These results indicate that AMG enhances the chemotherapeutic ability of gemcitabine by downregulating cancer stem-like properties in CCA cells. Hence, a combination therapy of AMG with gemcitabine may be an attractive therapeutic strategy for cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Dibenzocicloeptenos , Resorcinóis , Humanos , Gencitabina , Regulação para Baixo , Colangiocarcinoma/tratamento farmacológico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos
9.
Psychopharmacology (Berl) ; 239(10): 3367-3375, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063207

RESUMO

RATIONALE: Mania (or manic episodes) is a common symptom of bipolar disorder and is frequently accompanied by hyperactivity and delusions; given the cost and resources available, there is a paucity of evidence for direct comparison of different drugs. OBJECTIVES: We aimed to provide evidence-based recommendations on the efficacy of overall currently used pharmacological treatments for patients with acute bipolar mania. METHOD: We conducted a systematic review and network meta-analysis (NMA) using a Bayesian network frame. We searched the primary literature databases without language restrictions until Dec 18, 2021, for reports of randomized controlled trials (RCTs) of suspected antimanic drugs used as monotherapy for patients with acute bipolar mania, with the primary outcomes being efficacy (mean difference (MD), standardized mean difference (SMD) in the change of mania score). RESULTS: Eighty-seven studies were included in which 18,724 manic participants (mean age = 34.6 years, with 50.36% males) were allocated at random to one of 25 active medication drug therapies or placebo, resulting in 87 direct comparisons on 192 data points. Tamoxifen (- 22·00 [- 26·00 to - 18·00]) had the best efficacy over the placebo. Meanwhile, risperidone (- 6·60 [- 8·40 to - 4·90]) was substantially more effective than placebo in treating acute mania. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably more effective than placebo. CONCLUSIONS: Overall, tamoxifen appears to be the most effective of the currently known pharmaceutical therapy available to treat acute mania or manic episodes; however, this conclusion is restricted by the scale of RCTs conducted, and risperidone was found to be the most effective medication among antipsychotics. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably effective in treating acute mania or manic episodes.


Assuntos
Antimaníacos , Antipsicóticos , Adulto , Antimaníacos/efeitos adversos , Antipsicóticos/uso terapêutico , Aripiprazol , Benzodiazepinas/uso terapêutico , Carbamazepina , Dibenzocicloeptenos , Haloperidol/uso terapêutico , Humanos , Lítio , Mania , Metanálise em Rede , Olanzapina , Palmitato de Paliperidona , Preparações Farmacêuticas , Piperazinas , Fumarato de Quetiapina , Risperidona/uso terapêutico , Tamoxifeno , Tiazóis , Ácido Valproico/uso terapêutico
10.
J Child Adolesc Psychopharmacol ; 32(7): 374-389, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36074098

RESUMO

Objective: Antipsychotic-related prolactin changes may expose children and adolescents to severe adverse reactions (ARs) related to pubertal development and growth. We therefore aimed to assess the effects of antipsychotics on prolactin levels and associated somatic ARs in children and adolescents. Methods: We systematically searched PubMed and CENTRAL for placebo-controlled randomized trials of antipsychotics in children and adolescents aged ≤18 years, reporting prolactin levels and related ARs. We conducted a random-effect meta-analysis and assessed risk of bias version 2 (ROB2). Results: Thirty-two randomized controlled trials with an average trial duration of 6 weeks, covering 4643 participants with an average age of 13 years and a male majority of 65.3%. Risk of bias across domains was low or unclear. The following antipsychotic compounds: aripiprazole (n = 810), asenapine (n = 506), lurasidone (n = 314), olanzapine (n = 179), paliperidone (n = 149), quetiapine (n = 381), risperidone (n = 609), and ziprasidone (n = 16) were compared with placebo (n = 1658). Compared with placebo, statistically significant higher prolactin increase occurred with risperidone (mean difference [MD] = 28.24 ng/mL), paliperidone (20.98 ng/mL), and olanzapine (11.34 ng/mL). Aripiprazole significantly decreased prolactin (MD = -4.91 ng/mL), whereas quetiapine, lurasidone, and asenapine were not associated with significantly different prolactin levels than placebo. Our results on ziprasidone are based on a single study, making it insufficient to draw strong conclusions. On average, 20.8% of patients treated with antipsychotic developed levels of prolactin that were too high (hyperprolactinemia), whereas only 1.03% of patients reported prolactin-related ARs. Data were highly limited for long-term effects. Conclusions: In children and adolescents, risperidone, paliperidone, and olanzapine are associated with significant prolactin increase, whereas aripiprazole is associated with significant decrease. Despite the significant changes in prolactin level, few ARs were reported. Study protocol on PROSPERO: CRD42018116451.


Assuntos
Antipsicóticos , Hiperprolactinemia , Esquizofrenia , Adolescente , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Criança , Dibenzocicloeptenos/efeitos adversos , Humanos , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/tratamento farmacológico , Cloridrato de Lurasidona/efeitos adversos , Masculino , Olanzapina/efeitos adversos , Palmitato de Paliperidona/efeitos adversos , Piperazinas/efeitos adversos , Prolactina/efeitos adversos , Fumarato de Quetiapina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Risperidona/efeitos adversos , Esquizofrenia/tratamento farmacológico , Tiazóis/efeitos adversos
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 282: 121695, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-35933777

RESUMO

Fluphenazine HCl (FLU) is an anxiolytic, while Nortriptyline HCl (NOR) is an anti-depressant. They are co-formulated together to treat depression and schizophrenia. Perphenazine (PER) and dibenzosuberone (DBZ) are the pharmacopeial impurities of FLU and NOR, respectively. Four spectrophotometric and multivariate chemometric methods were developed to determine the two drugs together or in presence of their two impurities in their bulk and pharmaceutical formulation. Method (A) is the triple divisor-ratio derivative (TDR) method, where the zero order spectrum of each component was divided by a mixture of the other 3 components, then the peak amplitudes of the first derivative spectra of FLU, NOR and DBZ were measured at 265, 245.4 and 283.2 nm, respectively. Method (B) is the double divisor-ratio difference-dual wavelength (DD-RD-DW) method, in which each component spectrum mixture was divided by a binary mixture of 2 of the interfering components. In the resulting ratio spectra, the amplitude difference is calculated between 2 wavelengths at which the third interfering component has zero difference. Methods (C and D) are the principle component analysis (PCA) and partial least squares (PLS) models. Methods (A and B) failed to quantify PER (FLU impurity), while (C and D) succeeded to quantify all components. The four methods have been applied for the prediction of the FLU and NOR in their pharmaceutical formulation with good accuracy and precision. The proposed methods have been validated according to the ICH guidelines and the results were within the acceptable limits.


Assuntos
Nortriptilina , Perfenazina , Dibenzocicloeptenos , Composição de Medicamentos , Flufenazina , Espectrofotometria/métodos
12.
J Clin Psychiatry ; 83(4)2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35687858

RESUMO

Objective: Patients with schizophrenia may exhibit symptoms of hostility. HP-3070 is the first antipsychotic patch approved by the US Food and Drug Administration (FDA) for adults with schizophrenia. Its efficacy was demonstrated in a phase 3 study. This post hoc analysis assessed the efficacy of HP-3070 in treating hostility in schizophrenia.Methods: In the pivotal phase 3 study, conducted between August 2016 and November 2017, adults with schizophrenia (per DSM-5 criteria) were randomized to HP-3070 3.8 mg/24 h, HP-3070 7.6 mg/24 h, or placebo. Least-squares mean (LSM) changes in Positive and Negative Syndrome Scale (PANSS) hostility item and PANSS-Excited Component (PANSS-EC) scores from baseline to week 6 were assessed post hoc using a mixed-effects model for repeated measures adjusted for selected PANSS-Positive symptoms and presence of somnolence or akathisia.Results: Among 442 patients with baseline PANSS hostility item score > 1 (n = 151, HP-3070 7.6 mg/24 h; n = 147, 3.8 mg/24 h; n = 144, placebo), week 6 LSM (95% CI) change from baseline (CFB) in hostility score was superior with HP-3070 versus placebo for 7.6 mg/24 h (-0.4 [-0.6 to -0.2]; P < .001) and 3.8 mg/24 h (-0.3 [-0.6 to -0.1]; P < .01), with similar results for 7.6 mg/24 h after adjusting for covariates (P < .05). For all patients regardless of baseline PANSS hostility item score, PANSS-EC week 6 LSM CFB was greater for HP-3070 7.6 mg/24 h (-1.1 [-1.9 to -0.4]; n = 203; P < .01) and 3.8 mg/24 h (-1.3 [-2.0 to -0.6]; n = 201; P < .001) than for placebo (n = 203), with similar results observed in patients with baseline hostility item score > 1.Conclusions: In this post hoc analysis, HP-3070 was superior to placebo in reducing schizophrenia-associated hostility, even after adjusting for covariates, suggesting these effects are at least partially independent of general antipsychotic effects or effects on sedation or akathisia. These findings suggest HP-3070 has a specific antihostility effect in patients with schizophrenia.Clinical Trials Registration: ClinicalTrials.gov identifier: NCT02876900; EudraCT number: 2015-005134-21.


Assuntos
Antipsicóticos , Esquizofrenia , Adulto , Antipsicóticos/efeitos adversos , Dibenzocicloeptenos , Método Duplo-Cego , Hostilidade , Humanos , Agitação Psicomotora/tratamento farmacológico , Esquizofrenia/diagnóstico , Resultado do Tratamento
13.
Biotechnol Prog ; 38(5): e3284, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35768943

RESUMO

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis. The GBM microenvironment is highly heterogeneous and is composed of many cell types including astrocytes and endothelial cells (ECs) along with tumor cells, which are responsible for heightened resistance to standard chemotherapeutic drugs such as Temozolomide (TMZ). Here, we investigated how drug treatments impact stemness marker expression of GBM cells in multicellular tumor spheroid (MCTS) models. Co- and tri-culture MCTS constructed using U87-MG GBM cells, astrocytes, and/or ECs were cultured for 7 days. At Day 7, 5 µM lonafarnib (LNF), 100 µM TMZ, or combination of 5 µM LNF + 100 µM TMZ was added and the MCTS were cultured for an additional 48 h. We assessed the spheroid sizes and expression of stemness markers- NESTIN, SOX2, CD133, NANOG, and OCT4- through qRT-PCR and immunostaining. Following 48 h treatment with LNF, TMZ or their combination (LNF + TMZ), the spheroid sizes decreased compared to the untreated control. We also observed that the expression of most of the stemness markers significantly increased in the LNF + TMZ treated condition as compared to the untreated condition. These results indicate that drug treatment can influence the stemness marker expression of GBM cells in MCTS models and these aspects must be considered while evaluating therapies. In future, by incorporating other relevant cell types, we can further our understanding of their crosstalk, eventually leading to the development of new therapeutic strategies.


Assuntos
Glioblastoma , Linhagem Celular Tumoral , Dibenzocicloeptenos , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Nestina/uso terapêutico , Piperidinas , Piridinas , Esferoides Celulares/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Microambiente Tumoral
15.
Rheumatol Int ; 42(2): 241-250, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34846554

RESUMO

The COVID-19 pandemic and social distancing restrictions have significantly reduced population-wide physical activity (PA) levels. However, the impact of the pandemic and relevant restrictions on PA participation, and any potential barriers to it, in people with rheumatoid arthritis (RA) are not clear. Furthermore, we are unsure if any such PA changes have affected their body weight, mental wellbeing, and/or quality of life (QoL). Thus, the aim of this study was to examine the impact of the lockdown on PA participation in people with RA, versus people without RA. Participants (n = 128; RA = 27, non-RA = 101) completed a self-administered online survey, which included questions on PA, body weight, mental wellbeing and QoL. PA participation during lockdown was significantly lower among RA versus non-RA participants (p < 0.001). Additionally, a similar profile of results was found where more RA participants vs non-RA participants reported reduced habitual PA (59% vs 33%) and increased body weight (59% vs 35%). Mental wellbeing scores were similarly low in both groups during lockdown (RA: 20.8 ± 4.2; non-RA: 22.2 ± 3.4, p = 0.080). Matched group comparisons identified similar trends to full sample analyses. In the first months of the lockdown, more people with RA reported decreased PA participation and increased body weight than their non-RA counterparts. Access to exercise equipment and facilities appears to be the main cause for these results. Looking beyond COVID-19, specific PA promotion for people with RA will be required to prevent a pandemic of inactivity.


Assuntos
Artrite Reumatoide/fisiopatologia , COVID-19/prevenção & controle , Exercício Físico/estatística & dados numéricos , Quarentena , Adulto , Artrite Reumatoide/psicologia , Peso Corporal , Estudos de Casos e Controles , Dibenzocicloeptenos , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Qualidade de Vida , SARS-CoV-2 , Reino Unido , Adulto Jovem
16.
Curr Drug Deliv ; 19(7): 788-800, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34353260

RESUMO

BACKGROUND: Asenapine maleate, an anti-schizophrenic drug, is a class II drug with low solubility and high permeability. This exerts a rate-limiting effect on drug bioavailability. OBJECTIVE: To improve the solubility/dissolution rate of asenapine maleate and hence the bioavailability using the co-crystal approach. METHODS: Co-crystals were prepared using the solvent evaporation method. Since the drug has Hbond acceptor count of 6, and H-bond donor count of 2, several co-formers (nicotinamide, urea, succinic, benzoic, and citric acid) were investigated in different ratios. The optimized co-crystals (drug-nicotinamide in a ratio of 1:3) were evaluated using PXRD, DSC, FTIR spectroscopy, and SEM. Additionally, in vitro dissolution and stability studies were conducted. RESULTS: Preparation of the co-crystals was successful except when citric and benzoic acids were used. PXRD patterns showed that the co-crystals were crystalline. FTIR spectroscopy confirmed the formation of H-bond between the drug and the co-former. DSC indicated a lower melting point than that of the components followed immediately by an exothermic peak, which confirmed the formation of co-crystals. SEM showed the formation of crystals with different size and habit. The dissolution of the drug from all the prepared co-crystals was almost similar and much enhanced compared to that of the unprocessed drug. The initial dissolution of the drug from the optimized batch was much faster than that from the other co-crystals and the physical mixture with the same ratio. The optimized batch exhibited long term stability. CONCLUSION: Co-crystals with improved solubility/dissolution rate of asenapine maleate were prepared successfully and were expected to enhance the bioavailability of the drug.


Assuntos
Dibenzocicloeptenos , Niacinamida , Varredura Diferencial de Calorimetria , Cristalização/métodos , Solubilidade
17.
CNS Spectr ; 27(3): 369-377, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33461636

RESUMO

BACKGROUND: Differences in psychiatric background and dose-response to asenapine in patients with schizophrenia were examined based on efficacy and safety, using data obtained in a double-blind, placebo-controlled trial. METHODS: Patients with schizophrenia were classified into three clusters by a cluster analysis based on the Positive and Negative Symptom Scale (PANSS) subscores at baseline, using the data from a 6-week, double-blind, placebo-controlled trial. PANSS Marder factor scores were calculated for each cluster. The efficacy of 10 or 20 mg/day of asenapine on PANSS score was used as the primary endpoint, with the incidence of adverse events evaluated as the secondary endpoint. RESULTS: A total of 529 asenapine-treated patients were classified into 3 clusters: Cluster-P with the higher scores in positive symptoms, disorganized thoughts, and hostility/excitement, Cluster-N with higher scores in negative symptoms, and Cluster-L with overall lower scores. In Cluster-N and Cluster-L, both 10 and 20 mg/day groups showed significant improvement in PANSS scores, while only the 20 mg/day group showed a significant difference in Cluster-P. Cluster-N and Cluster-L had differences in the incidence of adverse events, but this was not seen in Cluster-P. CONCLUSIONS: The efficacy and safety of asenapine 10 and 20 mg/day differed between the 3 clusters of patients. This suggests that background information regarding baseline psychiatric symptoms may affect the therapeutic response in patients with schizophrenia.


Assuntos
Antipsicóticos , Antipsicóticos/efeitos adversos , Análise por Conglomerados , Dibenzocicloeptenos , Método Duplo-Cego , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
18.
Crit Rev Anal Chem ; 52(8): 1755-1771, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34061690

RESUMO

Asenapine maleate is a second-generation atypical antipsychotic agent used in the treatment of schizophrenia, a neuropsychiatric disorder. It is available as a fast-dissolving sublingual tablet to avoid extensive first-pass metabolism with higher bioavailability as compared to oral formulations. Although, the established therapeutic solutions do not sufficiently satisfy the patient's safety and efficacy needs. Thus, the core research emphasis is to investigate strategies to produce novel formulations with enhanced safety and efficacy. This necessitates the development of robust, precise, and accurate methods for quantification of asenapine maleate in different sample matrices. Given the foregoing information, the current analysis concentrates on the different analytical techniques used to assess asenapine maleate in bulk, pharmaceutical formulations, and biological specimens. Reverse-phase HPLC coupled with UV detection is a majorly (nearly 50% of papers investigated) used technique for the estimation of asenapine maleate in formulations. On the other hand, for its quantification in the biological matrix, hyphenated techniques using mass spectrometry are widely used. This critical review reveals different analytical methodologies, including spectrophotometric, chromatographic, capillary electrophoresis techniques reported from 2011 to 2020, for the measurement of asenapine maleate in various sample matrices. The information presented in this review would be useful in future research for robust analytical method development for asenapine maleate utilizing a more scientific and risk-based approach. Also, it would aid to minimize analytical failure as well as method fine-tuning throughout the product life cycle. Further, this review may also direct scientists toward the development of methodologies for green research.


Assuntos
Transtorno Bipolar , Humanos , Transtorno Bipolar/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Dibenzocicloeptenos/uso terapêutico , Preparações Farmacêuticas
19.
Pak J Pharm Sci ; 34(4): 1323-1331, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34799304

RESUMO

Nanostructured lipid carriers (NLCs) of asenapine maleate (ASPM) were enteric coated with polymethacrylate polymers (Eudragit®) for oral delivery. The present study aimed to compare the feasibility of direct enteric coating of NLCs and enteric coating of hard gelatin capsules filled with lyophilized ASPM-NLCs. Organic solution of Eudragit® was prepared using acetone containing 3% v/v water, acetone or ethanol. Aqueous dispersion of Eudragit® was obtained by neutralization with base. Capsules were enteric coated by dip-coating method with 3:2 ratio of Eudragit® L100-55:S100 (7.5-12.5% w/v). ASPM-NLCs showed particle size of 84.91±2.14nm, polydispersity index of 0.222±0.026, entrapment efficiency of 86.9±1.8% and zeta potential of -4.83±0.29 mV. TEM images showed good sphericity of the particles with the size of ≈100nm. Non-aqueous enteric coating was not successful as NLCs were precipitated in organic solvent. Aqueous enteric coated ASPM-NLCs (lipid:coat=1:2) showed an increased size (150.8±16.7nm) and zeta potential (-23.5±2.2 mV) revealing the deposition of Eudragit®. However, aqueous enteric coated ASPM-NLCs and uncoated ASPM-NLCs showed higher drug release (18.3±3.1-22.3±3.2%) in HCl solution (pH 1.2) indicating no resistance offered by direct enteric coating of NLCs; whereas enteric coated capsules showed less drug release (4.7±0.8%) in HCl solution indicating sufficient gastric protection.


Assuntos
Cápsulas/administração & dosagem , Sistemas de Liberação de Fármacos por Nanopartículas/administração & dosagem , Administração Oral , Cromatografia Líquida de Alta Pressão , Dibenzocicloeptenos , Estudos de Viabilidade , Gelatina , Microscopia Eletrônica de Transmissão
20.
Neurochem Int ; 151: 105209, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34666077

RESUMO

Neuroleptics have to be used for a long time to produce a therapeutic effect. Cytochrome P450 2D (CYP2D) enzymes mediate alternative pathways of neurotransmitter synthesis (i.e. tyramine hydroxylation to dopamine and 5-methoxytryptamine O-demethylation to serotonin), and metabolism of neurosteroids. The aim of our present study was to examine the influence of chronic treatment with the new atypical neuroleptic asenapine on CYP2D in rat brain. In parallel, liver CYP2D was investigated for comparison. Asenapine added in vitro to microsomes of control rats competitively, but weakly inhibited the activity of CYP2D (brain: Ki = 385 µM; liver: Ki = 36 µM). However, prolonged administration of asenapine (0.3 mg/kg sc. for 2 weeks) significantly diminished the activity and protein level of CYP2D in the frontal cortex, nucleus accumbens, hippocampus and cerebellum, but did not affect the enzyme in the hypothalamus, brain stem, substantia nigra and the remainder of the brain. In contrast, asenapine enhanced the enzyme activity and protein level in the striatum. In the liver, chronically administered asenapine reduced the activity and protein level of CYP2D, and the CYP2D1 mRNA level. In conclusion, prolonged administration of asenapine alters the CYP2D expression in the brain structures and in the liver. Through affecting the CYP2D activity in the brain, asenapine may modify its pharmacological effect. By increasing the CYP2D expression/activity in the striatum, asenapine may accelerate the synthesis of dopamine (via tyramine hydroxylation) and serotonin (via 5-methoxytryptamine O-demethylation), and thus alleviate extrapyramidal symptoms. By reducing the CYP2D expression/activity in other brain structures asenapine may diminish the 21-hydroxylation of neurosteroids and thus have a beneficial influence on the symptoms of schizophrenia. In the liver, by reducing the CYP2D activity, asenapine may slow the biotransformation of concomitantly administered CYP2D substrates (drugs) during continuous treatment of schizophrenia or bipolar disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Dibenzocicloeptenos/farmacologia , Fígado/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dibenzocicloeptenos/administração & dosagem , Dopamina/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/enzimologia , Ratos Wistar , Serotonina/metabolismo
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