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1.
PLoS One ; 15(8): e0235676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32746451

RESUMO

Breast cancer is the second leading cause of death among women globally. The existing treatment options for breast cancer are largely associated with severe toxicities, and lower efficacies. Therefore, there is an urgent need for the development of non-toxic effective drugs against breast cancer. For this purpose, drug repositioning strategy was used to evaluate the anti-cancer potential of a library of heterocyclic drugs. The major advantage of drug repurposing is that the pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs are well documented. In the current study, we screened 97 drugs of different chemical classes, and among them aripiprazole, an antipsychotic drug, was found to be sufficiently active against breast cancer cell line MCF-7. Aripiprazole showed a cytotoxicity (IC50 = 12.1 ± 0.40 µM) to MCF-7 cells, comparable to the standard anticancer drug doxorubicin (IC50 = 1.25 ± 0.34 µM). Aripiprazole was also found to be active against other cancer cell lines, including MDA-MB-231 (IC50 = 19.83 ± 0.27 µM), AU565 (IC50 = 18.02 ± 0.44 µM), and BT-474 (IC50 = 36.42 ± 0.12 µM). Aripiprazole significantly inhibited the cell cycle progression at subG0G1 phase, and enhanced apoptosis in MCF-7 breast cancer cells. The drug was also able to significantly increase the nuclear condensation, and modulated the expression of certain genes involved in breast cancer, such as caspases 3, and 9, BAK-1, C-MYC, BCL2L1, BCL-10, and BCL-2. Further studies are needed to explore the effect of aripiprazole on intrinsic and extrinsic pathways of apoptosis in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Neoplasias da Mama/tratamento farmacológico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7
3.
J Clin Psychiatry ; 81(4)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609960

RESUMO

OBJECTIVE: INP105 is a drug-device combination of olanzapine and technology that delivers a powder formulation of olanzapine to the vascular-rich upper nasal space. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single ascending doses of INP105, olanzapine intramuscular (OLZ IM), and olanzapine oral disintegrating tablet (OLZ ODT). METHODS: This was a phase 1, active and double-blind placebo comparator-controlled, ascending-dose, 2-period, incomplete-block, 1-way crossover study in 40 healthy subjects, randomized to single doses of OLZ IM (5 or 10 mg) or OLZ ODT (10 mg) in Period 1 and then 1 of 3 doses (5 mg, 10 mg, or 15 mg) of INP105 or placebo in Period 2 between July and October 2018. Sedation and attention were evaluated by visual analog scale (VAS), the Agitation/Calmness Evaluation Scale (ACES), and the Digit Symbol Substitution Test (DSST). RESULTS: At equivalent doses, INP105 provided similar area under the drug concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity, and maximum observed concentration (Cmax) as OLZ IM and greater Cmax than but similar AUCs to OLZ ODT. Median time to maximum concentration was less for INP105 (15, 10, and 9.5 min for 5 mg, 10 mg, and 15 mg, respectively) than for OLZ IM (20 and 15 min for 5 mg and 10 mg, respectively) or OLZ ODT (120 min). Effects as measured with the VAS, ACES, and DSST with INP105 5 mg were comparable to those with OLZ IM 5 mg, with earlier onset for INP105 10 mg and 15 mg and greater effects than placebo and OLZ ODT. The incidence of treatment-emergent adverse events with INP105 5 mg, 10 mg, and 15 mg was 80%, 66.7%, and 75%, respectively, compared to 90% and 100% for OLZ IM 5 mg and 10 mg, respectively, and 83.3% for OLZ ODT; most common were dizziness, hypotension, and orthostatic symptoms. CONCLUSIONS: INP105 has rapid absorption and pharmacodynamic effects and may represent an effective, convenient, noninvasive, and well-tolerated alternative for treating acutely agitated patients by self- or caregiver administration in the home, community, or hospital environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03624322.


Assuntos
Olanzapina/efeitos adversos , Olanzapina/farmacocinética , Administração Intranasal , Administração Oral , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Olanzapina/administração & dosagem , Olanzapina/farmacologia , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-32479008

RESUMO

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.


Assuntos
Clozapina/farmacologia , Maleato de Dizocilpina/toxicidade , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/induzido quimicamente
5.
PLoS Negl Trop Dis ; 14(3): e0008220, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226018

RESUMO

Human clonorchiasis, caused by Clonorchis sinensis, is endemic in East Asian countries. C. sinensis metacercariae excyst in the duodenum of mammalian hosts, migrate to the intrahepatic bile duct, and mature into adults in the milieu of bile. We have previously shown that newly excysted juvenile C. sinensis move chemotactically toward bile and bile acids. Here, the chemotactic behavior of adult C. sinensis (CsAd) toward bile and bile acids was investigated. CsAds moved toward 0.05-5% bile and were most attracted to 0.5% bile but moved away from 10% bile. Upon exposure to 1-10% bile, CsAds eventually stopped moving and then died quickly. Among bile acids, CsAds showed strong chemotaxis toward cholic acid (CA) and deoxycholic acid. On the contrary, CsAds repelled from lithocholic acid (LCA). Moreover, at higher than 10 mM LCA, CsAds became sluggish and eventually died. Dopamine D1 receptor antagonists (LE-300 and SKF-83566), D2/3 receptor antagonists (raclopride and its derivative CS-49612), and a dopamine re-uptake inhibitor inhibited CA-induced chemotaxis of CsAds almost completely. Clinically used antipsychotic drugs, namely chlorpromazine, haloperidol, and clozapine, are dopaminergic antagonists and are secreted into bile. They completely inhibited chemotaxis of CsAds toward CA. At the maximum doses used to treat patients, the three tested medicines only expelled 2-12% of CsAds from the experimentally infected rabbits, but reduced egg production by 64-79%. Thus, antipsychotic medicines with dopaminergic antagonism could be considered as new anthelmintic candidates for human C. sinensis infections.


Assuntos
Anti-Helmínticos/farmacologia , Antipsicóticos/farmacologia , Quimiotaxia/efeitos dos fármacos , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Antagonistas de Dopamina/farmacologia , Animais , Anti-Helmínticos/administração & dosagem , Antipsicóticos/administração & dosagem , Bile/metabolismo , Fatores Quimiotáticos/metabolismo , Ácido Cólico/metabolismo , Clonorquíase/tratamento farmacológico , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Ácido Litocólico/metabolismo , Coelhos , Análise de Sobrevida , Resultado do Tratamento
6.
Life Sci ; 249: 117535, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151688

RESUMO

AIM: Schizophrenia is a chronic, disabling and one of the major neurological illnesses affecting nearly 1% of the global population. Currently available antipsychotic medications possess limited effects. The current research aimed at investigating potential therapeutic add-on benefit to enhance the effects of clozapine anti-schizophrenic. MAIN METHODS: To induce schizophrenia, ketamine was administered at a dose of 25 mg/kg i.p. for 14 consecutive days. Naringin was administered to Wistar rats at a dose of 100 mg/kg orally, alone or in combination with clozapine 5 mg/kg i.p from day 8 to day 14. Furthermore, behavioral tests were conducted to evaluate positive, negative and cognitive symptoms of schizophrenia. In addition, neurotransmitters' levels were detected using HPLC. Moreover, oxidative stress markers were assessed using spectrophotometry. Furthermore, apoptotic and wnt/ß-catenin pathway markers were determined using western blotting (Akt, GSK-3ß and ß-catenin), colorimetric methods (Caspase-3) and immunohistochemistry (Bax, Bcl2 and cytochrome c). KEY FINDINGS: Ketamine induced positive, negative and cognitive schizophrenia symptoms together with neurotransmitters' imbalance. In addition, ketamine treatment caused significant glutathione depletion, lipid peroxidation and reduction in catalase activity. Naringin and/or clozapine treatment significantly attenuated ketamine-induced schizophrenic symptoms and oxidative injury. Additionally, ketamine provoked apoptosis via increasing Bax/Bcl2 expression, caspase-3 activity, and Cytochrome C and Akt protein expression while naringin/clozapine treatment significantly inhibited this apoptotic effect. Moreover, naringin activated the neurodevelopmental wnt/ß-catenin signaling pathway evidenced by increasing pGSK-3ß and reducing pß-catenin protein expression. SIGNIFICANCE: These findings may suggest that naringin possesses a potential therapeutic add-on effect against ketamine-induced schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ketamina/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Clozapina/administração & dosagem , Clozapina/farmacologia , Clozapina/uso terapêutico , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Flavanonas/uso terapêutico , Masculino , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente
7.
J Clin Psychiatry ; 81(2)2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32141721

RESUMO

OBJECTIVE: Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). DATA SOURCES: Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. STUDY SELECTION: Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). DATA EXTRACTION: Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. RESULTS: Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. CONCLUSIONS: The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.


Assuntos
Antipsicóticos/farmacologia , Estudos Multicêntricos como Assunto , Avaliação de Resultados em Cuidados de Saúde , Efeito Placebo , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/tratamento farmacológico , Humanos , Estados Unidos , United States Food and Drug Administration
8.
J Clin Psychiatry ; 81(2)2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32141723

RESUMO

OBJECTIVE: To assess the antipsychotic efficacy and safety of a combination of olanzapine and samidorphan (OLZ/SAM). METHODS: This 4-week, phase 3, randomized, double-blind, placebo- and olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation. Patients were randomized 1:1:1 to OLZ/SAM, olanzapine monotherapy, or placebo. The primary and key secondary efficacy endpoint assessed was the change in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness Scale (CGI-S) score between baseline and week 4, respectively, for OLZ/SAM versus placebo. Safety monitoring occurred throughout. RESULTS: 401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: -6.4 ± 1.8 [P < .001] and -0.38 ± 0.12 [P = .002], respectively). Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of -5.3 ± 1.84 [P = .004] and -0.44 ± 0.12 [P < .001], respectively). Adverse events (AEs) occurred in 54.5%, 54.9%, and 44.8% of patients on OLZ/SAM, olanzapine, and placebo, respectively. Weight gain, somnolence, dry mouth, anxiety, and headache were the most common AEs (ie, ≥ 5%) with active treatment. CONCLUSIONS: OLZ/SAM treatment resulted in statistically and clinically significant efficacy improvements over 4 weeks versus placebo in adults with acutely exacerbated schizophrenia. Improvements were similar to those observed with olanzapine. OLZ/SAM was well tolerated, with a safety profile similar to that of olanzapine. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT02634346; EudraCT number: 2015-003373-15​​.


Assuntos
Antipsicóticos/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Olanzapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Esquizofrenia/tratamento farmacológico , Exacerbação dos Sintomas , Doença Aguda , Adulto , Antipsicóticos/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Olanzapina/administração & dosagem
9.
J Clin Psychiatry ; 81(2)2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160422

RESUMO

OBJECTIVE: Alcohol use disorder (AUD) is a common comorbidity of schizophrenia. No effective pharmacologic treatment is available for both disorders to date. METHODS: In a phase 2, double-blind study, patients with schizophrenia and AUD experiencing ≥ 10 drinking and ≥ 2 heavy-drinking days in the previous month and recent (≤ 6 mo) disease symptom exacerbation were recruited between June 2014 and March 2017. DSM-IV-TR and DSM-5 criteria were used to assign the diagnoses of schizophrenia and AUD, respectively. After a 6-week lead-in period, 234 eligible patients were randomized (1:1) to olanzapine + 10 mg samidorphan tablets (OLZ/SAM) or olanzapine + placebo tablets (olanzapine) for 36-60 weeks of treatment. The primary outcome of time to the first event of exacerbation of disease symptoms (EEDS) was evaluated using the log rank test for treatment comparison, and the Cox proportional-hazards model was used to estimate hazard ratio. Safety was assessed as adverse events and laboratory measures. RESULTS: No significant difference was observed between groups in the time to first EEDS (hazard ratio = 0.91; 95% CI, 0.53-1.56; P = .746). Patients treated with OLZ/SAM vs olanzapine had numerically lower rates in 6 of 8 criteria to evaluate EEDS. Change from baseline in percentage of heavy-drinking days during the double-blind treatment period was similar in OLZ/SAM- vs olanzapine-treated patients. OLZ/SAM was generally well tolerated with a safety profile similar to olanzapine. CONCLUSIONS: OLZ/SAM was not superior to olanzapine in the time to EEDS and was well tolerated in patients with schizophrenia and AUD. Further research is needed to identify effective treatments for this difficult-to-treat population. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT02161718; EudraCT number: 2014-001211-39 ​.


Assuntos
Alcoolismo/tratamento farmacológico , Antipsicóticos/farmacologia , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Olanzapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Esquizofrenia/tratamento farmacológico , Adulto , Alcoolismo/epidemiologia , Antipsicóticos/administração & dosagem , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Olanzapina/administração & dosagem , Esquizofrenia/epidemiologia
10.
J Clin Psychiatry ; 81(2)2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32220153

RESUMO

OBJECTIVE: Patients with schizophrenia and comorbid alcohol use disorder remain understudied. This post hoc analysis evaluated data from Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study (January 2001-December 2004). METHODS: Patients without substance abuse (except marijuana use) in the month before study entry were categorized into those with a history of alcohol use disorder (SZ + AUD) within 5 years before study entry and those without alcohol use disorder (SZ-only) per DSM-IV criteria. Time to first and recurrent exacerbations and hospitalizations were compared between disease states and between olanzapine and perphenazine, quetiapine, risperidone, and ziprasidone. RESULTS: A total of 1,338 patients (SZ + AUD = 22.6%; SZ-only = 77.4%) were included. Time to first exacerbation of SZ was significantly shorter in the SZ + AUD versus SZ-only population (median = 5.4 vs 6.4 months; hazard ratio [HR] = 1.20 [95% CI, 1.01-1.42]; P = .039). Similar findings were observed for first hospitalization (HR = 1.63 [95% CI, 1.20-2.22]; P = .002) and recurrent hospitalizations (HR = 1.60 [95% CI, 1.18-2.15]; P = .002). The most common reasons leading to exacerbation in both groups were an increase in symptom severity and lack of efficacy. In patients with SZ + AUD related or unrelated to marijuana, perphenazine, quetiapine, risperidone, and ziprasidone were associated with significantly shorter time to first exacerbation versus olanzapine. CONCLUSIONS: This post hoc analysis confirmed that patients with SZ + AUD had a worse illness course than patients with SZ-only and suggests that olanzapine may be associated with a longer time to first and recurrent exacerbations versus other antipsychotics in this difficult-to-treat population. Further research is needed to identify effective treatments for this important yet understudied patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001.


Assuntos
Alcoolismo , Antipsicóticos/farmacologia , Hospitalização , Olanzapina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Exacerbação dos Sintomas , Adulto , Alcoolismo/epidemiologia , Comorbidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Perfenazina/farmacologia , Piperazinas/farmacologia , Transtornos Psicóticos/epidemiologia , Fumarato de Quetiapina/farmacologia , Risperidona/farmacologia , Esquizofrenia/epidemiologia , Índice de Gravidade de Doença , Tiazóis/farmacologia , Fatores de Tempo
11.
PLoS One ; 15(3): e0230051, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155207

RESUMO

Schizophrenia poses a significant economic burden on the healthcare system as well as it has a significant impact on society at large. Reasons for such a high economic burden of schizophrenia include the frequent relapses and hospitalizations occurring in this disorder. We analyze the effectiveness of long-acting injectable antipsychotics (LAIs) compared to oral medications, in terms of "clinical process management" in a sample of patients with a diagnosis of schizophrenia spectrum disorder treated in community mental health centers. An observational, retrospective, mirror-image study was carried out to evaluate the effectiveness of LAIs compared to oral medications in terms of number of hospitalizations, emergency visits and planned visits on a 10-year period (from July 2007 to June 2017). Differences between first and second generation LAIs were also explored. Our findings show that hospitalization and emergency visits are significantly decreased with the use of LAIs, while planned visits are increased in patients treated with LAIs. Our results suggest that LAIs, in particular, second generation ones, reduce hospitalization rates and emergency visits, improving the economic burden of schizophrenia. Therefore, LAIs should be considered a cost-effective treatment in the management of schizophrenia under routine conditions.


Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/farmacocinética , Serviços Comunitários de Saúde Mental , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Feminino , Hospitalização , Humanos , Injeções , Masculino , Qualidade da Assistência à Saúde , Estudos Retrospectivos , Esquizofrenia/metabolismo , Resultado do Tratamento
12.
PLoS One ; 15(2): e0228648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017792

RESUMO

BACKGROUND: Antipsychotic medication, stress, gender, and age are factors that influence prolactin levels in patients with psychosis. The aim of the study was to investigate the level of prolactin response to antipsychotic treatment in acute patients, taking into account the total duration of psychosis. METHODS AND FINDINGS: The study was conducted on 170 acute patients with schizophrenia spectrum disorders and bipolar disorder. Subjects were divided into three subgroups according to the duration of the psychosis (less than 5 years, between 5 and 10 years and more than 10 years of disorder duration). The initial prolactin response under antipsychotic treatment was measured, while the severity of the psychiatric symptoms was assessed with the BPRS (Brief Psychiatric Rating Scale). Hyperprolactinemia was found in 120 (70.6%) patients, amongst which 80 (66.7%) were females and 40 (33.3%) were males. The average increase in prolactinemia was 2.46 times the maximum value in women, and 1.59 times in men. Gender (ß = 0.27, p<0.0001), type of antipsychotic medication according to potency of inducing hyperprolactinemia (ß = -0.23, p<0.003), and the duration of psychosis over 10 years (ß = -0.15, p = 0.04) significantly predicted prolactin levels, when age, diagnosis, antipsychotic category (conventional/atypical/combinations of antipsychotics), and BPRS total scores were controlled for. CONCLUSIONS AND RELEVANCE: Prolactin levels in patients treated with antipsychotic medication appeared to depend on patients' gender, on the type of antipsychotic medication according to potency of inducing hyperprolactinemia, and on the duration of the psychosis. An increase in prolactin levels was associated with female gender, while the use of prolactin sparing antipsychotics and a duration of psychosis over 10 years were associated with lower prolactin levels.


Assuntos
Antipsicóticos/farmacologia , Hiperprolactinemia/etiologia , Prolactina/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Hiperprolactinemia/diagnóstico , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Prolactina/sangue , Transtornos Psicóticos/complicações , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Fatores Sexuais , Fatores de Tempo
13.
Rev Med Suisse ; 16(681): 314-317, 2020 Feb 12.
Artigo em Francês | MEDLINE | ID: mdl-32049453

RESUMO

Suicide is a common cause of death in Switzerland. It often occurs during a period of crisis marked by a disruption of the subject's intrapsychic, interpersonal or social balance. The management of this crisis is crucial and essentially psychotherapeutic. Drug therapy may be necessary for the management of acute symptoms or for the prevention of long-term suicidal risk. Benzodiazepines and atypical antipsychotics are often used for acute symptoms such as anxiety or sleep disorders while other molecules are recognized in reducing long-term suicidal risk. Some disorders, such as borderline personality disorder, account for more frequent suicidal behaviors. The pharmacological management of these specific situations is discussed.


Assuntos
Antipsicóticos/farmacologia , Suicídio/prevenção & controle , Suicídio/psicologia , Benzodiazepinas/farmacologia , Transtorno da Personalidade Borderline/psicologia , Humanos , Fatores de Risco , Ideação Suicida , Suíça
14.
Nat Commun ; 11(1): 1074, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103023

RESUMO

The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.


Assuntos
Antipsicóticos/farmacologia , Haloperidol/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/ultraestrutura , Cristalografia por Raios X , Humanos , Conformação Proteica/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Risperidona/metabolismo , Risperidona/farmacologia
15.
J Clin Psychiatry ; 81(2)2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32074412

RESUMO

OBJECTIVE: The aim of the present study was to identify individual symptoms whose early improvements contributed to subsequent treatment response to antipsychotics for neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) using the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD). METHODS: The CATIE-AD study was conducted between April 2001 and November 2004 at 45 sites in the United States. Data for 421 patients with DSM-IV AD with NPSs treated with antipsychotics were analyzed in the present study. Treatment response was defined as a reduction of ≥ 9 points in the Neuropsychiatric Inventory (NPI) score or a reduction of ≥ 25% from baseline in Brief Psychiatric Rating Scale (BPRS) total score at week 8. Logistic regression analyses were performed to examine associations between response and clinical and demographic characteristics, including each total or individual symptom score reduction at week 2. RESULTS: Reduction in NPI or BPRS total score at week 2 and several individual symptom score reductions (euphoria/elation, irritability, hallucinations, anxiety, agitation, apathy, disinhibition, and depression among NPI subitems; excitement, suspiciousness, disorientation, hostility, depressive mood, and emotional withdrawal among BPRS subitems) at week 2 were significantly associated with subsequent treatment response at week 8 (all P values < .05); Early non-improvements of irritability and suspiciousness were shown to be especially influential clinical markers in predicting subsequent treatment nonresponse. Furthermore, healthier condition at baseline was significantly associated with treatment response at week 8 (P < .05). CONCLUSIONS: Although further research to validate these preliminary findings is needed, focusing on early improvements of individual symptoms could help identify subsequent treatment responders to antipsychotics in AD patients with NPSs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00015548.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/farmacologia , Sintomas Comportamentais/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Sintomas Comportamentais/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
16.
Psychopharmacology (Berl) ; 237(6): 1577-1593, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076746

RESUMO

RATIONALE: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.


Assuntos
Ketamina/toxicidade , Atividade Motora/efeitos dos fármacos , Nootrópicos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/análogos & derivados , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Microdiálise , Atividade Motora/fisiologia , Nootrópicos/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tetra-Hidroisoquinolinas/farmacologia , Resultado do Tratamento
17.
FASEB J ; 34(1): 1182-1197, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914658

RESUMO

d-Amino acids are the "wrong" enantiomers of amino acids as they are not used in proteins synthesis but evolved in selected functions. On this side, d-aspartate (d-Asp) plays several significant roles in mammals, especially as an agonist of N-methyl-d-aspartate receptors (NMDAR), and is involved in relevant diseases, such as schizophrenia and Alzheimer's disease. In vivo modulation of d-Asp levels represents an intriguing task to cope with such pathological states. As little is known about d-Asp synthesis, the only option for modulating the levels is via degradation, which is due to the flavoenzyme d-aspartate oxidase (DASPO). Here we present the first three-dimensional structure of a DASPO enzyme (from human) which belongs to the d-amino acid oxidase family. Notably, human DASPO differs from human d-amino acid oxidase (attributed to d-serine degradation, the main coagonist of NMDAR) showing peculiar structural features (a specific active site charge distribution), oligomeric state and kinetic mechanism, and a higher FAD affinity and activity. These results provide useful insights into the structure-function relationships of human DASPO: modulating its activity represents now a feasible novel therapeutic target.


Assuntos
Encéfalo/metabolismo , D-Aspartato Oxidase/química , D-Aspartato Oxidase/metabolismo , Ácido D-Aspártico/análise , Animais , Antipsicóticos/farmacologia , Sítios de Ligação , Bovinos , Cristalografia por Raios X , Dimerização , Desenho de Fármacos , Humanos , Cinética , Ligantes , Camundongos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo , Especificidade por Substrato , Suínos
18.
Sci Rep ; 10(1): 1219, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988392

RESUMO

This study aimed to identify if antipsychotic exposure in offspring is associated with psychiatric and non-psychiatric healthcare service use and work disability of their parents. This Swedish population-based cohort study was based on data comprising 10,883 individuals with schizophrenia, who had at least one identifiable parent in the nationwide registers, and their parents (N = 18,215). The register-based follow-up during 2006-2013 considered the level of antipsychotic exposure and persistence of use of the offspring, further categorized into first (FG) and second generation (SG) antipsychotics, and orals versus long-acting injections (LAIs). The main outcome measure was parental psychiatric healthcare service use, secondary outcomes were non-psychiatric healthcare use and long-term sickness absence. SG-LAI use was associated with a decreased risk (relative risks [RR] 0.81-0.85) of parental psychiatric healthcare use compared with not using SG-LAI, whereas oral antipsychotics were associated with an increased risk (RRs 1.10-1.29). Both FG- and SG-LAI use by the offspring were associated with a lower risk of long-term sickness absence (range of odds ratios 0.34-0.47) for the parents, compared with non-use of these drugs. The choice of antipsychotic treatment for the offspring may have an impact on work disability and healthcare service use of their parents.


Assuntos
Pais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Esquizofrenia/epidemiologia , Adolescente , Adulto , Antipsicóticos/farmacologia , Cuidadores/psicologia , Estudos de Coortes , Assistência à Saúde/métodos , Feminino , Custos de Cuidados de Saúde , Hospitalização/economia , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/economia , Sistema de Registros , Fatores de Risco , Esquizofrenia/tratamento farmacológico , Suécia
19.
Psychopharmacology (Berl) ; 237(4): 957-966, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897573

RESUMO

RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Comportamento Alimentar/fisiologia , Motivação/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores 5-HT1 de Serotonina/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/psicologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Antagonistas da Serotonina/farmacologia , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia
20.
J Pharm Pharmacol ; 72(1): 149-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31713882

RESUMO

OBJECTIVES: A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia-like behaviours induced by MK-801. METHODS: HCE (30, 100 or 300 mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia-like animal model induced by MK-801. We conducted an acoustic startle response task, an open-field task, a novel object recognition task and a social novelty preference task. KEY FINDINGS: We found that a single administration of HCE (100 or 300 mg/kg) ameliorated MK-801-induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK-801-induced increases in phosphorylated Akt and GSK-3ß expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300 mg/kg). CONCLUSIONS: These results imply that HCE ameliorates MK-801-induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK-3ß signalling pathways.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Transtornos Neurológicos da Marcha/prevenção & controle , Extratos Vegetais/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/prevenção & controle , Filtro Sensorial/efeitos dos fármacos , Animais , Clematis , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Maleato de Dizocilpina , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/psicologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Fosforilação , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Prunella , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Psicologia do Esquizofrênico , Comportamento Social , Trichosanthes
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