RESUMEN
Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Administración Oral , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Antígenos T-Independientes/química , Antígenos T-Independientes/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Sitios de Unión , Dominio Catalítico , Perros , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/metabolismo , Pirimidinas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
AIMS: Stereotactic ablative body radiotherapy doses for peripheral lung lesions caused high toxicity when used for central non-small cell lung cancer (NSCLC). To determine a safe stereotactic ablative body radiotherapy dose for central tumours, the phase I/II Radiation Therapy Oncology Group RTOG 0813 trial used 50 Gy/five fractions as a baseline. From 2013, 50 Gy/five fractions was adopted at the Beatson West of Scotland Cancer Centre for inoperable early stage central NSCLC. We report our prospectively collected toxicity and efficacy data. MATERIALS AND METHODS: Patient and treatment characteristics were obtained from electronic medical records. Tumours were classed as moderately central or ultra-central tumours using published definitions. Toxicity was assessed in a centralised follow-up clinic at 2 weeks, 6 weeks, 3 months, 6 months, 1 year and 2 years after treatment. RESULTS: Fifty patients (31 women, 19 men, median age 75.1 years) were identified with T1-2N0M0 moderately central NSCLC; one patient had both an ultra-central and a moderately central tumour. Eighty-four per cent were medically unfit for surgery. Forty per cent had biopsy-proven NSCLC and 60% were diagnosed radiologically using 18-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Fifty-six per cent of patients were Eastern Cooperative Oncology Group (ECOG) performance status 2 or worse. All patients received 50 Gy/five fractions on alternate days on schedule. Two patients died within 90 days of treatment, one from a chest infection, the other cause of death was unknown. There was one episode of early grade 3 oesophagitis and one grade 3 late dyspnoea. There was no grade 4 toxicity. Over a median follow-up of 25.2 months (range 1-70 months), there were 34 deaths: 18 unrelated to cancer and 16 due to cancer recurrence. The median overall survival was 27.0 months (95% confidence interval 20.6-35.9) and cancer-specific survival was 39.8 months (95% confidence interval 28.6, not reached). CONCLUSION: This study has shown that 50 Gy/five fractions is a safe dose and fractionation for early stage inoperable moderately central NSCLC, with outcomes comparable with other series, even with patients with a poor performance status.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiocirugia/métodos , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50=24µm) and particle engineered wet milled API (D50=70µm and 90µm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc<4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc>10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.
Asunto(s)
Polvos/química , Carboximetilcelulosa de Sodio/química , Celulosa/química , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Reología , Dióxido de Silicio/química , Ácidos Esteáricos/química , Comprimidos/química , Tecnología FarmacéuticaRESUMEN
Pancreas disease (PD) of farmed Atlantic salmon Salmo salar L., which is caused by an alphavirus known as salmon pancreas disease virus (SPDV), can have serious economic consequences. An epidemiological survey carried out in Ireland in 2003 indicated that within individual farms there were significant differences in the susceptibility of different strains of farmed Atlantic salmon to infection with SPDV, as measured by levels of clinical disease and mortality. The aim of this preliminary study was to investigate this field observation by comparing lesion development, viraemia and serological responses of 3 commercial strains of Atlantic salmon (A, B and C) experimentally infected with SPDV. Highly significant differences in the severity of lesions in the pancreas at Day 21 post-infection (pi) were detected (p < 0.01), with Group B being more severely affected. There were also significant differences in the prevalence and severity of lesions in heart and skeletal muscle at Day 21 and 35 pi respectively, with Group B results again significantly higher than those from both Groups A and C (p < 0.05). There was no overlap between viraemia and the presence of specific SPDV antibody. Some fish in all groups had no viraemia, lesions or evidence of seroconversion. There were no significant differences seen between the challenged groups in relation to the percentage of viraemic fish at each time point. Viral loads were not determined. Differences between the number of antibody-positive fish in each challenge group were found at Days 28 and 35 pi (p < 0.1). Highly significant differences (p < 0.01) in the geometric mean titres of seropositive fish were detected at Day 28. These results, obtained using a challenge model, confirm that there are strain differences in the susceptibility to experimental SPDV infection in commercial farmed Atlantic salmon.
Asunto(s)
Infecciones por Alphavirus/veterinaria , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/virología , Salmo salar , Alphavirus/inmunología , Alphavirus/aislamiento & purificación , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/patología , Análisis de Varianza , Animales , Anticuerpos Antivirales/sangre , Encéfalo/patología , Susceptibilidad a Enfermedades/veterinaria , Susceptibilidad a Enfermedades/virología , Enfermedades de los Peces/patología , Músculo Esquelético/patología , Miocardio/patología , Pruebas de Neutralización/veterinaria , Páncreas/patología , Análisis de SupervivenciaRESUMEN
Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.
Asunto(s)
Antifúngicos/química , Ácidos Dicarboxílicos/química , Itraconazol/química , Cristalización , Cristalografía por Rayos X , Cinética , Modelos Moleculares , SolubilidadRESUMEN
BACKGROUND: Hepatic support systems that provide detoxification without biliary secretion (i.e., isolated hepatocyte systems) are sufficient to improve encephalopathy and bridge patients to transplantation. However, biliary secretion may be critical when hepatic support attempts to restore function and regeneration of the host liver. The purpose of these studies was to optimize the support liver secretory response to bile acid by either single-vessel (portal vein; PV) or dual-vessel (hepatic artery [HA] + PV) perfusions during extracorporeal porcine liver perfusion. METHODS: Extracorporeal porcine liver perfusion of anesthetized pigs was developed using support porcine livers perfused through the PV (n=4) alone and through the HA + PV (n=4) via a venovenous circuit. Support livers were provoked with taurocholate (TC) to enhance bile aqueous and hydrophobic outputs. RESULTS: After cold preservation and reperfusion, both PV and HA + PV livers had initial 1-hr bile aqueous outputs < 15% of in vivo flow, with cholesterol (C) and phospholipid (PC) outputs <25% of in vivo flow. Bile flow was significantly greater for recovered HA + PV livers (3.0+/-0.01 ml/15 min) than PV livers (1.9+/-0.01 ml/15 min). Despite this, PC output was significantly greater for PV than HA + PV livers. The C/PC ratio of PV livers was twice that of HA + PV livers. TC infusion (48 micromol/kg/15 min) of HA + PV livers demonstrated significantly greater increments in bile flow, PC output, and C output than PV livers. CONCLUSION: In the unstimulated state, porcine support livers with dual-vessel perfusion generated greater aqueous and C outputs despite diminished PC output than in those with single-vessel perfusion. TC stimulation increased bile flow, PC output, and C output in dual-perfused livers more than in PV livers. HA + PV perfusion of support livers is the preferred technique for removing hydrophobic compounds that require PC transport for excretion or exist in the aqueous phase.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Arteria Hepática , Perfusión/métodos , Vena Porta , Animales , Colesterol/metabolismo , Circulación Extracorporea , Hígado , Fosfatidilcolinas , Fosfolípidos/metabolismo , PorcinosRESUMEN
An epidemic of hepatitis B occurring in 1988 and 1989 in Cape Breton brought to light the existence of a group of "buddies" who engaged in injection drug use. Interviewing was conducted by Public Health in 82% of the 186 IDU contacts named. In comparison with published reports of contact-tracing efforts for viral hepatitis among IDUs, the Cape Breton experience seems successful. This article describes the approach used by Public Health. Aspects of the management of the epidemic and the interview technique which may have contributed to the comparative success of contact-tracing include collaboration with family physicians and laboratories; collaboration among public health investigators; and a nonjudgemental interview technique with 6 "golden rules".