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3.
Cochrane Database Syst Rev ; 3: CD008591, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661528

RESUMO

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Afetivo Sazonal/tratamento farmacológico , Adulto , Antidepressivos de Segunda Geração/efeitos adversos , Viés , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Cloridrato de Duloxetina/efeitos adversos , Cloridrato de Duloxetina/uso terapêutico , Feminino , Fluoxetina/efeitos adversos , Fluoxetina/uso terapêutico , Humanos , Masculino , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Estudos Observacionais como Assunto , Fototerapia , Placebos/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Reboxetina/uso terapêutico , Transtorno Afetivo Sazonal/terapia , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , Resultado do Tratamento
4.
N Engl J Med ; 384(6): 512-520, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33567191

RESUMO

BACKGROUND: The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma. METHODS: In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm2 contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]). RESULTS: A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved. CONCLUSIONS: In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.).


Assuntos
Acetamidas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Morfolinas/uso terapêutico , Piridinas/uso terapêutico , Acetamidas/efeitos adversos , Administração Tópica , Idoso , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Face/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Pomadas/uso terapêutico , Polimerização/efeitos dos fármacos , Piridinas/efeitos adversos , Couro Cabeludo/patologia , Pele/patologia , Tubulina (Proteína)/metabolismo
5.
Cancer Sci ; 112(3): 1123-1131, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33492746

RESUMO

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Morfolinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Piridonas/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Japão , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridonas/administração & dosagem , Piridonas/farmacocinética , Resultado do Tratamento
7.
Psychopharmacology (Berl) ; 238(3): 867-876, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33433644

RESUMO

RATIONALE: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. OBJECTIVES: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). METHODS: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. RESULTS: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. CONCLUSIONS: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.


Assuntos
Moduladores GABAérgicos/uso terapêutico , Morfolinas/uso terapêutico , Polissonografia/efeitos dos fármacos , Pirimidinas/uso terapêutico , Receptores de GABA-B/metabolismo , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono REM/efeitos dos fármacos , Sono de Ondas Lentas/efeitos dos fármacos , Adulto , Eletroencefalografia/efeitos dos fármacos , Feminino , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Moduladores GABAérgicos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Paroxetina/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Distúrbios do Início e da Manutenção do Sono/psicologia
8.
Br J Anaesth ; 126(5): 940-948, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33454050

RESUMO

BACKGROUND: The observation that patients presenting for bariatric surgery had a high incidence of neuromuscular blocking agent (NMBA) anaphylaxis prompted this restricted case-control study to test the hypothesis that obesity is a risk factor for NMBA anaphylaxis, independent of differences in pholcodine consumption. METHODS: We compared 145 patients diagnosed with intraoperative NMBA anaphylaxis in Western Australia between 2012 and 2020 with 61 patients with cefazolin anaphylaxis with respect to BMI grade, history of pholcodine consumption, sex, age, comorbid disease, and NMBA type and dose. Confounding was assessed by stratification and binomial logistic regression. RESULTS: Obesity (odds ratio [OR]=2.96, χ2=11.7, P=0.001), 'definite' pholcodine consumption (OR=14.0, χ2=2.6, P<0.001), and female sex (OR=2.70, χ2=9.61, P=0.002) were statistically significant risk factors for NMBA anaphylaxis on univariate analysis. The risk of NMBA anaphylaxis increased with BMI grade. Confounding analysis indicated that both obesity and pholcodine consumption remained important risk factors after correction for confounding, but that sex did not. The relative rate of rocuronium anaphylaxis was estimated to be 3.0 times that of vecuronium using controls as an estimate of market share, and the risk of NMBA anaphylaxis in patients presenting for bariatric surgery was 8.8 times the expected rate (74.9 vs 8.5 per 100 000 anaesthetic procedures). CONCLUSIONS: Obesity is a risk factor for NMBA anaphylaxis, the risk increasing with BMI grade. Pholcodine consumption is also a risk factor, and this is consistent with the pholcodine hypothesis. Rocuronium use is associated with an increased risk of anaphylaxis compared with vecuronium in this population.


Assuntos
Anafilaxia/epidemiologia , Codeína/análogos & derivados , Morfolinas/administração & dosagem , Bloqueadores Neuromusculares/efeitos adversos , Obesidade/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anafilaxia/etiologia , Cirurgia Bariátrica/métodos , Estudos de Casos e Controles , Cefazolina/efeitos adversos , Codeína/administração & dosagem , Codeína/efeitos adversos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Bloqueadores Neuromusculares/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Rocurônio/administração & dosagem , Rocurônio/efeitos adversos , Adulto Jovem
9.
Int J Clin Pharmacol Ther ; 59(4): 328-332, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33355084

RESUMO

OBJECTIVE: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine. CASE: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable). CONCLUSION: The drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.


Assuntos
Antieméticos , Bloqueio Atrioventricular , Neoplasias Pulmonares , Idoso , Anlodipino/efeitos adversos , Aprepitanto/uso terapêutico , Bloqueio Atrioventricular/induzido quimicamente , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Morfolinas/efeitos adversos , Vômito
10.
Cells ; 10(1)2020 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-33375410

RESUMO

The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence from both in vitro studies and the clinic that apilimod blocks antiviral immune responses. We therefore warn that the immunosuppression observed in many COVID-19 patients might be aggravated by apilimod.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Hidrazonas/efeitos adversos , Morfolinas/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Pirimidinas/efeitos adversos , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , COVID-19/imunologia , Humanos , Hidrazonas/farmacologia , Morfolinas/farmacologia , Peptídeo Hidrolases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Serina Endopeptidases/metabolismo
11.
Clin Drug Investig ; 40(7): 603-615, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399853

RESUMO

BACKGROUND AND OBJECTIVE: SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H3R) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics. METHODS: A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure. CONCLUSION: SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.


Assuntos
Morfolinas/efeitos adversos , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversos , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Agonismo Inverso de Drogas , Feminino , Voluntários Saudáveis , Histamina , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Piperidinas/farmacocinética
12.
Vasc Health Risk Manag ; 16: 111-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308404

RESUMO

Background: Landiolol hydrochloride, a highly cardio-selective beta-1 blocker with an ultra-short-acting half-life of 4 minutes, was originally approved by Japan for treatment of intraoperative tachyarrhythmias. This review aims to provide an integrated overview of the current state of knowledge of landiolol hydrochloride in the management of arrhythmia in critical settings. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library to retrieve relevant articles with a total of 65 records identified. Results: The high ß1 selectivity (ß1/ß2 ratio of 255:1) of landiolol causes a more rapid heart rate (HR) decrease compared to esmolol while avoiding decreases in mean arterial blood pressure. Recently, it has been found useful in left ventricular dysfunction patients and fatal arrhythmia requiring emergency treatment. Recent random clinical trials (RCT) have revealed therapeutic and prophylactic effects on arrhythmia, and very low-dose landiolol might be effective for preventing postoperative atrial fibrillation (POAF) and sinus tachycardia. Likewise, landiolol is an optimal choice for perioperative tachycardia treatment during cardiac surgery. The high ß1 selectivity of landiolol is useful in heart failure patients as a first-line therapy for tachycardia and arrhythmia as it avoids the typical depression of cardiac function seen in other ß-blockers. Application in cardiac injury after percutaneous coronary intervention (PCI), protection for vital organs (lung, kidney, etc.) during sepsis, and stabilizing hemodynamics in pediatric patients are becoming the new frontier of landiolol use. Conclusion: Landiolol is useful as a first-line therapy for the prevention of POAF after cardiac/non-cardiac surgery, fatal arrhythmias in heart failure patients and during PCI. Moreover, the potential therapeutic effect of landiolol for sepsis in pediatric patients is currently being explored. As positive RCT results continue to be published, new clinical uses and further clinical studies in various settings by cardiologists, intensivists and pediatric cardiologists are being conducted.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/prevenção & controle , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/uso terapêutico , Ureia/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Adulto , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacocinética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Cuidados Críticos , Feminino , Humanos , Masculino , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Fatores de Risco , Resultado do Tratamento , Ureia/efeitos adversos , Ureia/farmacocinética , Ureia/uso terapêutico , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 117(18): 9991-10002, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312805

RESUMO

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.


Assuntos
Comportamento Aditivo/genética , Comportamento Animal/efeitos dos fármacos , Canabinoides/efeitos adversos , Cocaína/efeitos adversos , Adolescente , Animais , Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/patologia , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Canabinoides/farmacologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Cocaína/farmacologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona/genética , Humanos , Proteínas de Membrana/farmacologia , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Fosfoproteínas/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Córtex Pré-Frontal/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Ratos , Transcriptoma/efeitos dos fármacos
14.
Lancet Respir Med ; 8(9): 863-872, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32243865

RESUMO

BACKGROUND: Tachycardia and atrial fibrillation frequently occur in patients being treated for sepsis or septic shock and have a poor prognosis. Treatments for tachyarrhythmias are often ineffective or contraindicated in this setting. We aimed to investigate the efficacy and safety of landiolol, an ultra-short-acting ß-blocker, for treating sepsis-related tachyarrhythmias. METHODS: We did a multicentre, open-label, randomised controlled trial at 54 hospitals in Japan. Patients admitted to the intensive care units who received conventional treatment for sepsis, according to clinical guidelines for the management of sepsis, and who subsequently developed a tachyarrhythmia, were enrolled. The main inclusion criteria were 20 years of age or older, diagnosis of sepsis according to Third International Consensus Definitions for Sepsis and Septic Shock criteria, administration of catecholamine necessary to maintain mean arterial pressure at 65 mm Hg or more for at least 1 h, and heart rate of 100 beats per min (bpm) or more maintained for at least 10 min without a change in catecholamine dose with diagnosis of atrial fibrillation, atrial flutter, or sinus tachycardia. Only patients who developed these symptoms and signs within 24 h before randomisation, and within 72 h after entering an intensive care unit, were prospectively assigned to receive conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group) in an open-label manner. Landiolol hydrochloride was intravenously infused at an initial dose of 1 µg/kg per min within 2 h after randomisation and the dose could be increased per study protocol to a maximum of 20 µg/kg per min. Patients in both groups received conventional therapy (Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2016), including respiratory and fluid resuscitation, antimicrobials, and catecholamines. The treating physicians were required to stabilise the patient's haemodynamic status before randomisation. Randomisation was done using a central randomisation system and dynamic allocation with the minimisation method by institution, heart rate at randomisation (≥100 to <120 bpm or ≥120 bpm), and age (<70 years or ≥70 years). The primary outcome was the proportion of patients with heart rate of 60-94 bpm at 24 h after randomisation. Patients without heart rate data at 24 h after randomisation were handled as non-responders. The primary outcome was analysed using the full analysis set on an as-assigned basis, while safety was analysed using the safety analysis set according to the treatment received. This study was registered with the Japan Pharmaceutical Information Center Clinical Trials Information database, number JapicCTI-173767. FINDINGS: Between Jan 16, 2018 and Apr 22, 2019, 151 patients were randomly assigned, 76 to the landiolol group and 75 to the control group. A significantly larger proportion of patients in the landiolol group had a heart rate of 60-94 bpm 24 h after randomisation than in the control group (55% [41 of 75] vs 33% [25 of 75]), with a between-group difference of 23·1% (95% CI 7·1-37·5; p=0·0031). Adverse events were observed in 49 (64%) of 77 patients in the landiolol group and in 44 (59%) of 74 in the control group, with serious adverse events (including adverse events leading to death) in nine (12%) of 77 and eight (11%) of 74 patients. Serious adverse events related to landiolol occurred in five (6%) of 77 patients, including blood pressure decreases in three patients (4%) and cardiac arrest, heart rate decrease, and ejection fraction decrease occurred in one patient each (1%). INTERPRETATION: Landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia achieving a heart rate of 60-94 bpm at 24 h and significantly reduced the incidence of new-onset arrhythmia. Landiolol was also well tolerated, but it should be used under appropriate monitoring of blood pressure and heart rate owing to the risk of hypotension in patients with sepsis and septic shock. FUNDING: Ono Pharmaceutical Co.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Morfolinas/uso terapêutico , Sepse/complicações , Taquicardia/tratamento farmacológico , Ureia/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Morfolinas/efeitos adversos , Taquicardia/etiologia , Resultado do Tratamento , Ureia/efeitos adversos , Ureia/uso terapêutico
15.
Lancet Oncol ; 21(5): 671-684, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203698

RESUMO

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.


Assuntos
Colangiocarcinoma/tratamento farmacológico , Morfolinas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/genética , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Receptores de Fatores de Crescimento de Fibroblastos/genética
16.
Eur J Pharmacol ; 874: 172911, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32045604

RESUMO

Cannabis and, to a lesser extent, synthetic cannabinoids are used during adolescence, a period in which multiple brain areas are still undergoing development. Among such areas is the hypothalamus, which is implicated in the control of sleep-wake cycle. In the present report, we show that exposing adolescent rats to the cannabinoid receptor agonist WIN 55, 212-2 (0.1, 0.3 or 1.0 mg/kg, i.p) for 14 days during adolescence (i.e., from post-natal day 30-44) resulted in significant sleep disturbances when the animals became adult (post-natal day 80). These included decreased wakefulness and enhanced rapid eye movement sleep. Furthermore, we found that labeling for NeuN, a marker of postmitotic neurons, was significantly increased the dorsomedial hypothalamic nucleus of rats treated with WIN 55, 212-2. The results suggest that excessive cannabinoid receptor activation during adolescence can persistently influence sleep patterns and neuronal activity later in life.


Assuntos
Benzoxazinas/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Morfolinas/efeitos adversos , Naftalenos/efeitos adversos , Transtornos do Sono-Vigília/induzido quimicamente , Animais , Antígenos Nucleares/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ratos Wistar , Sono/efeitos dos fármacos , Transtornos do Sono-Vigília/metabolismo
17.
Zhonghua Nei Ke Za Zhi ; 59(2): 117-123, 2020 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-32074684

RESUMO

Objective: To evaluate the efficacy and safety of Oryz-Aspergillus enzyme and pancreatin tablets (Combizym(®)) in the treatment of postprandial distress syndrome (PDS) in the elderly, compared with gastrointestinal motility drugs. Methods: A prospective randomized controlled trial was designed and registered in the China Clinical Trials Registry (ChiCTR-IPR-16008185). The elderly patients with PDS were randomly divided into three groups, including Mosapride group with Mosapride citrate tablets 5 mg 3 times per day for 2 weeks; Combizym(®) group with Combizym tablets 244 mg 3 times per day for 2 weeks; combined treatment group with both drugs and same doses for 2 weeks. The modified Nepean dyspepsia index (NDSI) score, discomfort intensity score and PDS score were calculated on patients before treatment, at the end of first and second week of treatment, as well as 4 weeks after treatment finished, respectively. Adverse effects were evaluated. Results: A total of 323 patients from 16 tertiary hospitals in China were enrolled in this study. Among them, 105 patients were in Mosapride group, 109 in Combizym(®) group and 109 in combined treatment group. There were 148 males (45.8%) and 175 females (54.2%) with median age 71.4±9.0 years (60-100 years). Baseline characteristics of three groups were comparable. After treatment, the NDSI scores in three groups all decreased significantly (P<0.001), while they were similar between groups (P>0.05). The discomfort intensity score and PDS score in three groups showed a significant reduction after treatment (P<0.001), especially in the combined treatment group. Compared with Mosapride group, the scores in Combizym(®) group decreased significantly after one or two weeks [discomfort intensity score: after one week, 4.0(2.5, 8.0) vs. 6.0(3.0, 10.0); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 6.0); all P<0.05. PDS score: after one week, 6.0(3.0, 9.0) vs. 7.0(3.5, 10.5); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 7.0); all P<0.05]. The efficacy rate in all patients after first week of treatment was over 15.0%. The efficacy rates after two weeks were 55.2%, 68.8% and 73.4% in Mosapride group, Combizym(®) group and combined treatment group, respectively. After two week treatment, the efficacy rates in Combizym(®) group (P=0.041) and combined group (P=0.006) were higher than that of Mosapride group. The recurrence rate of Mosapride group was 9.5%, which was significantly higher than that of Combizym(®) group (1.8%, P<0.05) and combined treatment group (1.8%, P<0.05). There were no serious adverse effects in the three groups. Conclusions: The efficacy of Oryz-Aspergillus enzyme and pancreatin tablets is comparable with that of Mosapride in elderly PDS patients, with fewer adverse effects and low recurrence rate. Combination regimen indicates better efficacy than that of Oryz-Aspergillus enzyme and pancreatin tablets or Mosapride alone.


Assuntos
Benzamidas/uso terapêutico , Dispepsia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Glicosídeo Hidrolases/uso terapêutico , Morfolinas/uso terapêutico , Pancreatina/uso terapêutico , Peptídeo Hidrolases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Benzamidas/efeitos adversos , China , Combinação de Medicamentos , Dispepsia/diagnóstico , Dispepsia/patologia , Feminino , Fármacos Gastrointestinais/efeitos adversos , Glicosídeo Hidrolases/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Pancreatina/efeitos adversos , Peptídeo Hidrolases/efeitos adversos , Período Pós-Prandial , Estudos Prospectivos , Resultado do Tratamento
18.
J Oncol Pharm Pract ; 26(6): 1369-1373, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31955703

RESUMO

INTRODUCTION: At our institution, an increased incidence of hypersensitivity reactions was reported following standardization of fosaprepitant as the preferred agent for the prophylaxis of chemotherapy induced nausea and vomiting (CINV) caused by highly emetogenic therapies. The purpose of this evaluation was to assess the incidence of systemic hypersensitivity reactions (HSRs) to fosaprepitant infusions compared to available literature. METHODS: This evaluation is a retrospective review of electronic health records of adult patients who received their first dose of fosaprepitant for CINV prophylaxis beginning January 1, 2017 through June 30, 2017 at the University of Colorado Cancer Center outpatient infusion center. Subjects were identified using medication administration reports. Individual chart reviews were performed for all patients who received fosaprepitant during the specified timeframe and had a reaction reported on the same date. RESULTS: A total of 868 patients received fosaprepitant in the outpatient infusion center during the study time period. Four patients (0.461%) had a systemic HSR attributed to fosaprepitant. Two of the reactions were reported as HSRs in the adverse reaction reporting system and two were found in provider notes during chart review. Due to the small sample size, risk factors for HSRs to fosaprepitant were not able to be determined. CONCLUSION: The incidence of HSRs to fosaprepitant at our institution was found to be consistent with the <1% incidence currently noted in literature. Based on these findings, opportunities have been identified for education on fosaprepitant-associated HSRs, proper documentation and patient-specific precautions.


Assuntos
Antieméticos/efeitos adversos , Institutos de Câncer , Hipersensibilidade a Drogas/diagnóstico , Morfolinas/efeitos adversos , Neoplasias/tratamento farmacológico , Centros Médicos Acadêmicos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Avaliação de Medicamentos/métodos , Hipersensibilidade a Drogas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/epidemiologia , Neoplasias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/epidemiologia , Adulto Jovem
19.
Medicine (Baltimore) ; 99(2): e18702, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914075

RESUMO

BACKGROUND/AIMS: Old age is a risk factor of suboptimal bowel preparation. This study aimed to evaluate the efficacy of mosapride citrate with a split dose of polyethylene glycol (PEG) plus ascorbic acid for bowel preparation in elderly patients (aged ≥65 years) before they underwent a colonoscopy. MATERIALS AND METHODS: This prospective investigator-blinded randomized study was conducted from November 2017 to October 2018. The patients were randomly divided into 2 groups, a mosapride group (mosapride citrate with a split-dose of PEG plus ascorbic acid) or a non-mosapride group (a split-dose of PEG plus ascorbic acid alone). Mosapride citrate 15 mg (Gastin CR) was administered once with each split-dose of the bowel preparation. The bowel preparation quality was assessed using the Boston Bowel Preparation Scale (BBPS). RESULTS: A total of 257 patients were finally included and analyzed in our study. The total BBPS score was significantly higher in the mosapride group than in the non-mosapride group (8.53 vs 8.24, P = .033). The BBPS scores of the right colon and mid-colon were 2.75 vs 2.61 (P = .044) and 2.89 vs 2.79 (P = .030), respectively. The rate of adequate bowel preparation (BBPS ≥ 6) was similar in both groups (98.4% vs 98.5%, P = .968), while the rate of excellent bowel preparation (BBPS = 9) was higher in the mosapride group than in the non-mosapride group (73.8% vs 61.1%, P = .029). The total incidence of adverse events during the administration of the bowel cleansing agent, particularly abdominal fullness, was lower in the mosapride group (11.9% vs 30.5%, P < .001). CONCLUSION: The administration of mosapride citrate with a split-dose of PEG plus ascorbic acid in elderly patients showed an increase in bowel preparation efficacy and reduced adverse events, particularly abdominal fullness, during the administration of a bowel cleansing agent.


Assuntos
Ácido Ascórbico/uso terapêutico , Benzamidas/uso terapêutico , Catárticos/uso terapêutico , Colonoscopia/métodos , Morfolinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Ácido Ascórbico/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Catárticos/administração & dosagem , Catárticos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Cooperação do Paciente , Satisfação do Paciente , Polietilenoglicóis/administração & dosagem , Cuidados Pré-Operatórios , Estudos Prospectivos , Método Simples-Cego
20.
J Cancer Res Clin Oncol ; 146(2): 503-514, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31745703

RESUMO

PURPOSE: Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present. METHODS: RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes. RESULTS: A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival. CONCLUSIONS: In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.


Assuntos
Cistadenocarcinoma Seroso/genética , Fusão Gênica , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Cistadenocarcinoma Seroso/tratamento farmacológico , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , RNA-Seq/métodos , Proteínas Repressoras/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
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