RESUMEN
Importance: Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. Objective: To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. Interventions: Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. Main Outcomes and Measures: The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression-Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. Results: The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], -4.2; 95% CI, -7.8 to -0.6; P = .02; effect size [ES], -0.3) and the CGI-S (LSMD, -0.3; 95% CI, -0.5 to -0.1; P = .003; ES, -0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was -2.6 (95% CI, -6.2 to 1.1; P = .16; ES, -0.2) on the PANSS total score and -0.2 (95% CI, -0.5 to 0.0; P = .02; ES, -0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. Conclusions and Relevance: Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. Trial Registration: ClinicalTrials.gov identifier: NCT02282761.
Asunto(s)
Antipsicóticos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/efectos adversos , Método Doble Ciego , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , MasculinoRESUMEN
Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.
Asunto(s)
Antipsicóticos/farmacocinética , Butirofenonas/farmacocinética , Neostriado/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Adulto , Radioisótopos de Carbono , Antagonistas de los Receptores de Dopamina D2/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neostriado/diagnóstico por imagen , Tomografía de Emisión de Positrones , Racloprida/farmacocinética , Esquizofrenia/diagnóstico por imagenRESUMEN
OBJECTIVE: Findings from epidemiologic studies of trichloroethylene (TCE) exposure and liver cancer have been inconsistent. To quantitatively evaluate this association and to examine sources of heterogeneity, we conducted a meta-analysis of occupational studies of TCE exposure and liver/biliary tract cancer. METHODS: We identified 14 occupational cohort studies of TCE exposed workers and one case-control study that met our inclusion criteria. Nine studies specifically identified TCE as a workplace exposure, and were classified as Group I cohort studies. Subcohorts of workers, identified within eight of these studies as more likely exposed to TCE than the total cohort, were analyzed separately. RESULTS: The combined liver/biliary cancer summary relative risk estimate (SRRE) for all studies was 1.08 (95% CI 0.91-1.29; heterogeneity (H)-P-value=0.12). For the total study populations in the Group I cohorts, the SRRE was 1.14 (95% CI 0.93-1.39; H-P-value=0.05) and for the subcohorts, the SRRE was 1.30 (95% CI 1.09-1.55). Within this subcohort analysis, the association for the European studies of workers from various industries (SRRE=1.38; based on four studies) was higher than the association for the US studies of aerospace and aircraft workers (SRRE=0.97, based on four studies). CONCLUSION: Although positive associations were observed for some analyses, results were inconsistent across occupational groups (aerospace/aircraft vs. other industries combined), study location, and incidence versus mortality endpoints. In addition, exposure-response trends were not observed consistently across studies. Interpretation is also limited by the potential impact of uncontrolled confounding by other occupational or lifestyle exposures such as smoking or alcohol consumption. Given these limitations, the currently available epidemiologic data are not sufficient to support a causal relation between occupational TCE exposure and liver/biliary cancer.
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Neoplasias Hepáticas/inducido químicamente , Exposición Profesional/efectos adversos , Tricloroetileno/envenenamiento , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Tricloroetileno/farmacologíaRESUMEN
Six cases of coagulase-negative staphylococcal mediastinitis were identified in the latter half of 1999. A new preoperative cleansing solution was suspected by hospital staff to be a factor in the outbreak. We evaluated this possible risk factor along with other known and suspected surgical site infection risk factors in this case-control study.
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Coagulasa/aislamiento & purificación , Brotes de Enfermedades , Mediastinitis/microbiología , Anciano , Estudios de Casos y Controles , Coagulasa/efectos adversos , Femenino , Cardiopatías/cirugía , Humanos , Masculino , Mediastinitis/etiología , Persona de Mediana Edad , Complicaciones Posoperatorias , Factores de Riesgo , Piel/microbiologíaRESUMEN
Analysis of settled dust collected from carpeting and furnishings is occasionally used by investigators to determine whether an environment contains unusual fungi. Little information is available concerning the types and concentrations of culturable fungi present on textile surfaces in normal residential settings not affected by unusual mold reservoirs, such as from fungal growth sites within the built environment. This study presents the results of the collection and analysis of surface dust from 26 residential environments that were prescreened by interview, physical inspection, and air sampling to limit the surface dust collection to structures in which there was no history of water intrusion, flooding, plumbing leaks, signs of mold growth, or evidence of unusual airborne fungal spore types or concentrations. In those structures found to have no history or indications of water events or unusual fungi, surface dust was vacuumed from prescribed horizontal areas on carpet and textile-covered furnishings. These samples were then subjected to fungal culture, from which viable colonies were enumerated and identified. Based on the study results, it does not appear reasonable that the frequently quoted total fungi concentration exceeding 10(5) CFU/g is definitive evidence that a residential surface is contaminated with unusual amounts of culturable fungi. Collocated samples collected from eight side-by-side carpets sections revealed poor reproducibility. While settled dust sampling may be appropriate for determining the fungal status of a localized area, or as a gross screening tool, using settled dust results alone to establish the presence of unusual fungal types or concentrations within a structure appears to be inappropriate, and using settled dust results with other investigative methods, such as visual observations and air sampling, requires cautious interpretation.