RESUMEN
BACKGROUND: Total knee replacement (TKR) or total hip replacement (THR) are common and effective procedures in patients with osteoarthritis (OA) to restore physical function and reduce joint related pain. Patient education plays an important role in the treatment process aiming to develop necessary self-management skills to facilitate recovery and ensure long-term success. We have developed a mobile app (RECOVER-E) for iOS and Android smartphones which provides important information on the preoperative phase, surgery and recovery. The concomitant study will determine the efficacy of RECOVER-E on patients' surgical outcomes. METHODS/DESIGN: This study is a non-randomized, multi-centre (4 sites), double-arm, controlled trial with 1:1 assignment. 160 patients undergoing primary TKR or THR will be recruited from January until October 2019 in 4 German hospitals. Both groups will receive standard care. Additionally, the intervention group will use the app RECOVER-E. Measurements will be taken 4-6 weeks before surgery, on the day of admission to the hospital, on the first and 7th postoperative day and 3 months post-surgery. Primary outcome will be self-reported physical function measured on the activities of daily living (ADL) subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Hip disability and Osteoarthritis Outcome Score (HOOS) for patients with knee and hip osteoarthritis, respectively. Secondary outcomes include the subscales for pain, symptoms, function in sport and recreation and knee/hip-related quality of life of the HOOS and KOOS, preoperative anxiety, measured by the Hospital Anxiety and Depression Scale (HADS), as well as, pain at rest and pain during activity measured by a numerical rating scale (NRS). Primary endpoint is 3 months post-surgery. DISCUSSION: Mobile Health (mHealth) has become increasingly important in patient-centred health care aiming to enhance patient involvement and self-management capabilities. To our knowledge this is the first study to investigate the effect of an evidence-based mobile app on patient reported outcomes after joint replacement. This study should provide evidence supporting the use of mHealth to facilitate recovery and open up new possibilities for patient care in joint replacement. TRIAL REGISTRATION: DRKS Data Management retrospectively registered. DRKS-ID: DRKS00012744.
Asunto(s)
Artralgia/terapia , Aplicaciones Móviles , Osteoartritis de la Cadera/terapia , Osteoartritis de la Rodilla/terapia , Educación del Paciente como Asunto/métodos , Atención Perioperativa/métodos , Actividades Cotidianas , Adulto , Ansiedad/etiología , Ansiedad/prevención & control , Artralgia/diagnóstico , Artralgia/etiología , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Cadera/psicología , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/psicología , Ensayos Clínicos Controlados como Asunto , Terapia por Ejercicio/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Multicéntricos como Asunto , Osteoartritis de la Cadera/complicaciones , Osteoartritis de la Rodilla/complicaciones , Medición de Resultados Informados por el Paciente , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Calidad de Vida , Automanejo/métodos , Resultado del TratamientoRESUMEN
A humanized monoclonal antibody targeting transforming growth factor ß1 (TGF-ß1 mab) has been used in development for the treatment of chronic kidney disease. Embryo-fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF-ß1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated. There was no indication of maternal or embryo-fetal toxicity in the rat. Effects in the rabbit were limited to the fetus where the 30 mg/kg TGF-ß1 mab dose produced a slight decrease in fetal weight and an increase in the incidence of retrocaval ureter and an absent and/or malpositioned kidney/ureter in two fetuses. In conclusion, TGF-ß1 mab produced no adverse maternal or embryo-fetal findings in rats when administered ≤50 mg/kg on GDs 6, 10, and 14. TGF-ß1 mab did not demonstrate maternal toxicity or embryo-fetal lethality at doses as high as 30 mg/kg when administered on GDs 7, 12, 14, 16, and 18 in rabbits. Fetal growth and morphology were affected only at 30 mg/kg; thus, the no observed adverse effect level was 3 mg/kg in rabbits. The margin of safety for both rats and rabbits was ≥37-fold the clinical exposure level.
Asunto(s)
Anticuerpos Monoclonales Humanizados/toxicidad , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales Humanizados/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Feto/efectos de los fármacos , Masculino , Nivel sin Efectos Adversos Observados , Conejos , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Pruebas de Toxicidad , ToxicocinéticaRESUMEN
At least seven distinct epidermal growth factor (EGF) ligands bind to and activate the EGF receptor (EGFR). This activation plays an important role in the embryo and in the maintenance of adult tissues. Importantly, pharmacologic EGFR inhibition also plays a critical role in the pathophysiology of diverse disease states, especially cancer. The roles of specific EGFR ligands are poorly defined in these disease states. Accumulating evidence suggests a role for transforming growth factor α (TGFα) in skin, lung, and kidney disease. To explore the role of Tgfa, we generated a monoclonal antibody (mAb41) that binds to and neutralizes human Tgfa with high affinity (KD = 36.5 pM). The antibody also binds human epiregulin (Ereg) (KD = 346.6 pM) and inhibits ligand induced myofibroblast cell proliferation (IC50 values of 0.52 and 1.12 nM for human Tgfa and Ereg, respectively). In vivo, a single administration of the antibody to pregnant mice (30 mg/kg s.c. at day 14 after plug) or weekly administration to neonate mice (20 mg/kg s.c. for 4 weeks) phenocopy Tgfa knockout mice with curly whiskers, stunted growth, and expansion of the hypertrophic zone of growth plate cartilage. Humanization of this monoclonal antibody to a human IgG4 antibody (LY3016859) enables clinical development. Importantly, administration of the humanized antibody to cynomolgus monkeys is absent of the skin toxicity observed with current EGFR inhibitors used clinically and no other pathologies were noted, indicating that neutralization of Tgfa could provide a relatively safe profile as it advances in clinical development.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Anticuerpos Monoclonales Humanizados/metabolismo , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Neutralizantes/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Epirregulina , Humanos , Inmunoglobulina G/inmunología , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Miofibroblastos/citología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Unión Proteica , Factor de Crecimiento Transformador alfa/genéticaRESUMEN
AIMS: To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor ß (TGF-ß) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. METHODS: The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-ß RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. RESULTS: No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l⻹ h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. CONCLUSIONS: A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development.
Asunto(s)
Pirazoles/farmacocinética , Quinolinas/farmacocinética , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores , Estudios de Cohortes , Descubrimiento de Drogas , Femenino , Glioblastoma/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Pirazoles/farmacología , Quinolinas/farmacologíaRESUMEN
Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of proapoptotic genes and decreased expression of antiapoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY). We tested the hypothesis that prior exposure to WY would increase susceptibility to apoptosis inducers such as Jo2, an antibody which activates the Fas (Apo-1/CD95) death pathway. When compared to their untreated counterparts, wild-type mice pretreated with WY exhibited increased caspase-3 activation and hepatocyte apoptosis following challenge with Jo2. Livers from WY-treated peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice were resistant to the effects of Jo2. In the absence of Jo2 and detectable apoptosis, wild-type mice treated with WY exhibited increases in the activated form of caspase-9. As caspase-9 is a component of the apoptosome, we examined the expression of upstream effectors of apoptosome activity including members of the Bcl-2 family. The levels of the antiapoptotic Mcl-1 transcript and protein were significantly decreased by PPs. PPARalpha-null mice were also resistant to another treatment (concanavalin A) that induces hepatocyte apoptosis. These results (1) indicate that PPARalpha activation increases sensitivity of the liver to apoptosis and (2) identify a mechanism by which PPARalpha could serve as a pharmacological target in diseases where apoptosis is a contributing feature.
Asunto(s)
Apoptosis/efectos de los fármacos , Hígado/efectos de los fármacos , PPAR alfa/agonistas , Proliferadores de Peroxisomas/farmacología , Pirimidinas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino , Caspasa 3 , Caspasa 9 , Caspasas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/biosíntesis , PPAR alfa/deficiencia , PPAR alfa/genética , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Ácido Tricloroacético/farmacologíaRESUMEN
Transforming growth factor-beta (TGF-ß) signaling regulates a wide range of biological processes. TGF-ß plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-ß signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-ß receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Esquema de Medicación , Cardiopatías/inducido químicamente , Estructura Molecular , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/patología , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/química , Pirazoles/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/química , Quinolinas/farmacocinética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Defects in growth hormone secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress, and decreases in factors that contribute to cardiovascular disease and cancer. Peroxisome proliferators (PP) alter a subset of these changes in wild-type mice through activation of the nuclear receptor family member PP-activated receptor alpha (PPARalpha). We tested the hypothesis that an overlap in the transcriptional programs between untreated dwarf mice and PP-treated wild-type mice underlies these similarities. Using transcript profiling, we observed a statistically significant overlap in the expression of genes differentially regulated in control Snell dwarf mice (Pit-1dw) compared with phenotypically normal heterozygote (+/dw) control mice and those altered by the PP 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid (WY-14,643) in +/dw mice. The genes included those involved in beta- and omega-oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14) and those involved in stress responses (the chaperonin, T-complex protein1epsilon) and cardiovascular disease (fibrinogen). The levels of some of these gene products were also altered in other dwarf mouse models, including Ames, Little, and growth hormone receptor-null mice. The constitutive increases in PPARalpha-regulated genes may be partly caused by increased expression of PPARalpha mRNA and protein as observed in the livers of control Snell dwarf mice. These results indicate that some of the beneficial effects associated with the dwarf phenotype may be caused by constitutive activation of PPARalpha and regulated genes.
Asunto(s)
Enanismo/genética , Regulación de la Expresión Génica/fisiología , PPAR alfa/fisiología , Animales , Secuencia de Bases , Cartilla de ADN , Ratones , Ratones Noqueados , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , PPAR alfa/deficiencia , PPAR alfa/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Determining the key events in the induction of liver cancer in mice by trichloroethylene (TRI) is important in the determination of how risks from this chemical should be treated at low doses. At least two metabolites can contribute to liver cancer in mice, dichloroacetate (DCA) and trichloroacetate (TCA). TCA is produced from metabolism of TRI at systemic concentrations that can clearly contribute to this response. As a peroxisome proliferator and a species-specific carcinogen, TCA may not be important in the induction of liver cancer in humans at the low doses of TRI encountered in the environment. Because DCA is metabolized much more rapidly than TCA, it has not been possible to directly determine whether it is produced at carcinogenic levels. Unlike TCA, DCA is active as a carcinogen in both mice and rats. Its low-dose effects are not associated with peroxisome proliferation. The present study examines whether biomarkers for DCA and TCA can be used to determine if the liver tumor response to TRI seen in mice is completely attributable to TCA or if other metabolites, such as DCA, are involved. Previous work had shown that DCA produces tumors in mice that display a diffuse immunoreactivity to a c-Jun antibody (Santa Cruz Biotechnology, SC-45), whereas TCA-induced tumors do not stain with this antibody. In the present study, we compared the c-Jun phenotype of tumors induced by DCA or TCA alone to those induced when they are given together in various combinations and to those induced by TRI given in an aqueous vehicle. When given in various combinations, DCA and TCA produced a few tumors that were c-Jun+, many that were c-Jun-, but a number with a mixed phenotype that increased with the relative dose of DCA. Sixteen TRI-induced tumors were c-Jun+, 13 were c-Jun-, and 9 had a mixed phenotype. Mutations of the H-ras protooncogene were also examined in DCA-, TCA-, and TRI-induced tumors. The mutation frequency detected in tumors induced by TCA was significantly different from that observed in TRI-induced tumors (0.44 vs 0.21, p < 0.05), whereas that observed in DCA-induced tumors (0.33) was intermediate between values obtained with TCA and TRI, but not significantly different from TRI. No significant differences were found in the mutation spectra of tumors produced by the three compounds. The presence of mutations in H-ras codon 61 appeared to be a late event, but ras-dependent signaling pathways were activated in all tumors. These data are not consistent with the hypothesis that all liver tumors induced by TRI were produced by TCA.