RESUMEN
Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (â¼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of â¼1400 ng/ml to achieve therapeutic efficacy.
Asunto(s)
Amantadina/farmacología , Amantadina/farmacocinética , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower ßamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Síndrome de Down/tratamiento farmacológico , Proteínas Hedgehog/metabolismo , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Pirazoles/farmacología , Quinolinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Síndrome de Down/patología , Síndrome de Down/fisiopatología , Inhibidores Enzimáticos/farmacología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/fisiología , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/patología , Sinapsis/fisiologíaRESUMEN
Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated ß-amyloid precursor protein (ßAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-ß peptides (Aß) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aß that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the ß-secretase-derived ßAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aß is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aß deposits are detected ~12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the ßAPP(swe) and Tau(P301L) mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest ßAPP catabolite and main contributor to the intracellular ßAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/fisiología , Precursor de Proteína beta-Amiloide/fisiología , Hipocampo/patología , Interneuronas/patología , Fragmentos de Péptidos/fisiología , Envejecimiento/fisiología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/química , Animales , Western Blotting , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Hipocampo/enzimología , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/química , Presenilina-1/genética , Presenilina-1/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Pirazoles/farmacología , Sulfonamidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ratones , Pirazoles/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Sport participation is an important part of the development, both physically and mentally, of children and adolescents in the United States. Illness and injury associated with sport and physical activities may occur in the school setting. Although most sport-related illness and injury in students are considered minor emergencies, life-threatening illnesses or injuries may occur. It is important for the school nurse to recognize potential life-threatening emergencies associated with sport and physical activity, to initiate stabilization of the student with life-threatening symptoms, and to triage these students to an appropriate level of care (back to the classroom, home with their guardian with follow up at their primary healthcare provider's office, or directly to the closest emergency department [ED] via Emergency Medical Services [EMS]). This article specifically describes the initial assessment and management of shoulder and hip injuries in pediatric athletes.
Asunto(s)
Traumatismos en Atletas , Lesiones de la Cadera , Servicios de Enfermería Escolar , Adolescente , Niño , Humanos , Estados Unidos , Urgencias Médicas , Hombro , Atletas , Ejercicio Físico , Atención a la Salud , Traumatismos en Atletas/diagnósticoRESUMEN
Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aß(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Caprolactama/análogos & derivados , Inhibidores Enzimáticos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Caprolactama/síntesis química , Caprolactama/química , Caprolactama/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Infusiones Parenterales , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Fragmentos de Péptidos/metabolismoRESUMEN
The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
Asunto(s)
Encéfalo/metabolismo , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Administración Oral , Diseño de Fármacos , Enlace de Hidrógeno , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-ActividadRESUMEN
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos con 3 Anillos/química , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Pirazoles/farmacología , Sulfonamidas/farmacología , Animales , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Piperidinas/química , Piperidinas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Humanos , Ratones , Modelos Moleculares , Piperidinas/uso terapéutico , Relación Estructura-Actividad , Sulfonamidas/uso terapéuticoRESUMEN
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Piperidinas/química , Sulfonamidas/química , Animales , Descubrimiento de Drogas , Estabilidad de Medicamentos , Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/síntesis química , Etilaminas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Alquilación , Enfermedad de Alzheimer , Animales , Encéfalo/metabolismo , Línea Celular , Perros , Diseño de Fármacos , Cobayas , Humanos , Indicadores y Reactivos , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Relación Estructura-ActividadRESUMEN
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Pirazoles/química , Quinolinas/química , Sulfonamidas/química , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Diseño de Fármacos , Ratones , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Illness and injury associated with sport and physical activities may occur in the school setting. Although most sport-related illness and injury in students are considered minor emergencies, life- and limb-threatening illnesses or injuries may occur, such as sudden cardiac arrest, heat stroke, status asthmaticus, catastrophic brain or cervical spine injuries, hypoglycemia, blunt chest/abdominal injuries, or extremity fractures requiring surgery. It is important for the school nurse to recognize potential life- and limb-threatening emergencies associated with sport and physical activity, to initiate stabilization of the student with life- and limb-threatening symptoms, and to triage these students to an appropriate level of care (back to the classroom, home with their guardian with follow up at their primary healthcare provider's office, or directly to the closest emergency department via emergency medical services). This article describes the initial assessment and management of three common emergencies associated with sport and physical activities.
Asunto(s)
Urgencias Médicas/enfermería , Pautas de la Práctica en Enfermería , Deportes , Adolescente , Traumatismos del Tobillo/enfermería , Traumatismos en Atletas/enfermería , Golpe de Calor/enfermería , Humanos , Luxaciones Articulares/enfermería , Masculino , Esguinces y Distensiones/enfermería , Lesiones de CodoRESUMEN
STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine motivations for compliance with bracing among female patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Bracing prevents the need for surgery for the majority of girls with AIS with curves of 20° to 40° and 2 or more years of growth remaining. The main obstacle to success is compliance. The factors that either promote or impede compliance previously have not been fully clarified. METHODS: Participants were females 10 to 16 years of age who were prescribed a brace to be worn 16 hours per day for AIS. Each completed a "Scoliosis Compliance Questionnaire" composed of the SRS-22r and five original sections focused on patients' attitudes to scoliosis, situations in which they found wearing the brace to be most and least difficult, factors that motivate brace wear, and interventions that could potentially improve compliance. RESULTS: Thirty-nine subjects completed the study, mean age 13 years (range 11-15 years), at a mean of 15.4 months (range 4-39 months) of brace wear at the time of recruitment. More than 90% of patients stated that their main motivations for compliance were the desire to avoid surgery and to prevent curve progression. Compliance was most challenging during the summer and while at school. Many patients reported pain and skin irritation in the brace. The majority reported they would likely improve their hours of wear if they were able to communicate with a peer in the same situation. SRS-22r scores were similar to those of healthy adolescents. CONCLUSIONS: The most important influences promoting brace wear are the patient's desire to avoid surgery and to prevent curve progression. Peer support potentially may improve compliance. LEVEL OF EVIDENCE: Level III.
RESUMEN
CASE: We present the case of a six-year-old boy who was referred to the pediatric orthopaedics division of our academic medical center by his primary care physician for a concern regarding possible fractured clavicles. He was diagnosed with cleidocranial dysplasia, a genetic condition characterized by skeletal and dental anomalies, primarily delayed ossification of midline osseous structures. On radiographs, cleidocranial dysplasia has been linked to both coxa vara and a characteristic "chef's hat" appearance of the femoral head. CONCLUSION: Cleidocranial dysplasia has multiple potential orthopaedic complications, and an awareness of this condition, its presentations, and its diagnosis is useful for all physicians.