ABSTRACT
In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.
ABSTRACT
Considerando todas las investigaciones realizadas hasta la fecha sobre las causas que contribuyen al deterioro de la membrana peritoneal y su fisiopatología, se puede concluir que es de gran interés investigar si la administración de heparinaintraperitoneal puede aportar un beneficio sobre el mantenimiento de la función peritoneal en los enfermos tratados con diálisis peritoneal (DP). Las acciones descritas a favor de esta idea son:1) La inflamación crónica del peritoneo es una causa de alteración de la función peritoneal y la heparina tiene acciónantiinflamatoria.2) La fibrosis peritoneal debida a diálisis peritoneal o a traumatismo puede ser evitada o mejorada con heparina ip.3) La heparina (HNF y HBPM, incluida bemiparina) indúcela síntesis de tPA por las células mesoteliales, lo que supone una acción fibrinolítica.4) La heparina, más la HBPM que la HNF, inhibe la angiogénesis.5) La heparina intraperitone al favorece la eliminación delos AGE en la DP.6) Modelos animales y estudios clínicos de corta extensión han demostrado una mejora de la función peritoneal con heparina.7) Por el momento, no se han encontrado problemas de seguridad en su administración intraperitoneal. Es por tanto una hipótesis verosímil que el uso de heparinaintraperitoneal puede modificar favorablemente la función peritoneal de pacientes en diálisis peritoneal (AU)
Multiple investigations performed on peritoneal pathophysiology during peritoneal dialysis (PD) suggest that intraperitonealheparin might modify most of the causes of membrane deterioration. The actions described favouring this idea are:1) Peritoneal Chronic inflammation alters peritoneal function and heprain has anti-inflammatory properties.2) Peritoneal fibrosis related to peritoneal dialysis or traumaticinjury may be avoided or limited with heparin.3) Heparine induces tPA síntesis by mesothelial cells, which represents a potentiation of fibrinolytic action.4) Heparine, sècifically low-molecular weight heparin, inhibitsangiogenesis.5) Intraperitoneal heparin favors the removal of advanced glycosilation end products in PD.6) Animal models and clinical studies with small series of patients have demonstrated an improvement of peritoneal function with intraperitoneal heparine use.7) Until now, no adverse effects of the intraperitoneal heparinuse have been found. In consequence, it is a plausible hipothesis to consider that intraperitonealheparin may favourably modify peritoneal function inpatients under peritoneal dialysis (AU)
Subject(s)
Peritoneal Dialysis/methods , Dialysis Solutions/pharmacology , Renal Insufficiency, Chronic/drug therapy , Clinical Trials as Topic , Heparin/therapeutic use , Basement Membrane/injuries , Peritoneal Fibrosis/physiopathology , Neovascularization, Physiologic/physiology , Proteoglycans/pharmacokineticsABSTRACT
Multiple investigations performed on peritoneal pathophysiology during peritoneal dialysis (PD) suggest that intraperitoneal heparin might modify most of the causes of membrane deterioration. The actions described favouring this idea are: 1) Peritoneal Chronic inflammation alters peritoneal function and hepraine has anti-inflammatory properties. 2) Peritoneal fibrosis related to peritoneal dialysis or traumatic injury may be avoided or limited with heparin. 3) Heparine induces tPA synthesis by mesothelial cells, which represents a potentiation of fibrinolytic action. 4) Heparine, specifically low-molecular weight heparin, inhibits angiogenesis. 5) Intraperitoneal heparin favors the removal of advanced glycosilation end products in PD. 6) Animal models and clinical studies with small series of patients have demonstrated an improvement of peritoneal function with intraperitoneal heparine use. 7) Until now, no adverse effects of the intraperitoneal heparin use have been found. In consequence, it is a plausible hypothesis to consider that intraperitoneal heparin may favourably modify peritoneal function in patients under peritoneal dialysis.
Subject(s)
Glucans/administration & dosage , Glucose/administration & dosage , Hemodialysis Solutions , Heparin, Low-Molecular-Weight/administration & dosage , Metabolic Diseases/drug therapy , Peritoneal Dialysis , Peritoneum/metabolism , Randomized Controlled Trials as Topic , Humans , IcodextrinABSTRACT
Residual renal function (RRF) is of paramount importance in patients with end-stage renal disease, with benefits that go beyond contributing to achievement of adequacy targets. Several studies have found that RRF rather than overall adequacy (as estimated from total small solute removal rates) is an essential marker of patient and, to a lesser extent, technique survival during chronic peritoneal dialysis (PD) therapy. In addition, RRF is associated with a reduction in blood pressure and left ventricular hypertrophy, increased sodium removal and improved fluid status, lower serum beta(2)-microglobulin, phosphate and uric acid levels, higher serum hemoglobin and bicarbonate levels, better nutritional status, a more favorable lipid profile, decreased circulating inflammatory markers, and lower risk for peritonitis in PD. As compared with conventional hemodialysis, PD is associated with a slower decrease in RRF. This highlights the usefulness of strategies oriented to preserve both RRF and the long-term viability of the peritoneal membrane. Several factors contributing to the loss of RRF have been identified and should be avoided. Renoprotective drugs and new glucose-sparing, more biocompatible PD regimes may prove useful tools to preserve RRF and peritoneal membrane function in the near future.
Subject(s)
Kidney Failure, Chronic/therapy , Kidney/physiopathology , Peritoneal Dialysis/methods , Cardiovascular Diseases/etiology , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/physiopathology , Nutritional Status , Peritoneal Dialysis/adverse effects , Peritonitis/etiology , Renal DialysisABSTRACT
An autosomal recessive deficiency of blood coagulation factor XI (FXI) has been described in Holstein cattle. Current testing methods are unsuitable for accurately identifying carriers (heterozygotes) of the disease. To identify the molecular basis of this deficiency, a polymerase chain reaction (PCR)-based strategy was implemented to clone and sequence the bovine FXI gene (F11) from animals of different genotypes. Approximately 14 kb of genomic DNA sequence and 1.8 kb of cDNA sequence, corresponding to exon 3 through the 3'-UTR, of the bovine gene were obtained. Comparison of sequences derived from homozygous normal and deficient individuals revealed that FXI deficiency in Holsteins is associated with the insertion of a 76 bp segment [AT(A)(28)TAAAG(A)(26)GGAAATAATAATTCA] within exon 12. This insertion introduces a stop codon that results in a mature FXI protein lacking the functional protease domain encoded by exons 13, 14 and 15. Based on these data, a DNA-based diagnostic test has been developed for accurate genotyping. Using this method, the frequency of the mutated allele has been determined to be 1.2% in a contemporary population of the USA Holstein sires.
Subject(s)
Cattle Diseases/genetics , Factor XI Deficiency/veterinary , Mutation/genetics , Animals , Base Sequence , Cattle , Cloning, Molecular , DNA Primers , Factor XI/genetics , Factor XI Deficiency/genetics , Gene Frequency , Genotype , Molecular Sequence Data , Polymerase Chain Reaction/methods , Sequence Alignment , Sequence Analysis, DNASubject(s)
Kidney Tubules/drug effects , Acetaminophen/adverse effects , Apoptosis/drug effects , Caspase 8 , Caspases/physiology , Cyclosporine/adverse effects , Cysteine Proteinase Inhibitors/pharmacology , Cysteine Proteinase Inhibitors/therapeutic use , Cytokines/adverse effects , Endoplasmic Reticulum/drug effects , Epithelium/drug effects , Humans , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Mitochondria/drug effects , Models, Biological , Proto-Oncogene Proteins c-bcl-2/physiology , bcl-X Protein , fas Receptor/physiologySubject(s)
Amyloidosis/diagnosis , HIV Seropositivity/complications , Adult , Amyloidosis/etiology , Humans , MaleABSTRACT
En la enfermedad de Fabry el déficit de la enzimalisosomal α-galactosidasa A causa el acúmulo lisosomalde glicoesfingolípidos, como la globotriaosilceramida(Gb3), y clínica neurológica, renal, cardíaca,cutánea, ocular y de otros sistemas. La afectaciónrenal condicionaba el pronóstico vital hastala generalización de la diálisis. La disponibilidad deun tratamiento de sustitución enzimático ha hechorenacer el interés por esta enfermedad. Publicacionesrecientes actualizan los aspectos genéticos, clínicosy diagnósticos1-7. Además, la financiación decompañías farmacéuticas ha permitido el desarrollode campañas para identificar, con fines terapéuticos,el mayor número posible de familias, y de iniciativascomo la creación de la Fundación Española parael diagnóstico y estudio de la enfermedad de Fabry(www.fedef.org). Por otra parte, las compañías farmacéuticas han distribuido información, en ocasionesconfusa, sobre las características de las enzimasdisponibles en el mercado y sobre decisiones judicialesreferentes a la publicidad de estos productos
Subject(s)
Fabry Disease/diagnosis , Fabry Disease/epidemiology , Fabry Disease/therapy , Enzymes/therapeutic use , alpha-Galactosidase/therapeutic use , Renal Dialysis/trends , Kidney/pathologySubject(s)
Kidney Glomerulus/cytology , Nephrotic Syndrome/pathology , Proteinuria/pathology , Animals , Apoptosis , Basement Membrane/pathology , Cell Differentiation , Endothelium/pathology , Forecasting , Genetic Predisposition to Disease , Glomerulonephritis/pathology , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney Glomerulus/pathology , Kidney Glomerulus/physiopathology , Nephrosis, Lipoid/pathology , Nephrotic Syndrome/etiology , Permeability , Proteinuria/etiologySubject(s)
Acetaminophen/adverse effects , Acute Kidney Injury/chemically induced , Kidney Tubules/drug effects , Acetylcysteine/therapeutic use , Acute Kidney Injury/drug therapy , Acute Kidney Injury/pathology , Apoptosis/drug effects , Cells, Cultured/drug effects , Humans , Kidney Tubules/pathologyABSTRACT
No disponible
Subject(s)
Animals , Humans , Apoptosis , Permeability , Nephrotic Syndrome , Nephrosis, Lipoid , Proteinuria , Genetic Predisposition to Disease , Basement Membrane , Cell Differentiation , Kidney Glomerulus , Endothelium , Glomerulonephritis , Forecasting , Glomerulosclerosis, Focal SegmentalABSTRACT
No disponible
Subject(s)
Humans , Apoptosis , Cells, Cultured , Acetylcysteine , Acetaminophen , Acute Kidney Injury , Kidney TubulesABSTRACT
La calcifilaxia es un proceso poco frecuente pero grave, descrito mayoritariamente en pacientes con insuficiencia renal, y que se caracteriza por la calcificación de arteriolas dérmicas, que puede llevar a la ulceración con necrosis e isquemia de la piel. Los mecanismos implicados en su patogenia han evolucionado. Aunque existe controversia, el producto calcio-fósforo elevado es el determinante individual más relevante, aunque no de manera universal. Dada la (..) (AU)
Calciphylaxis is an uncommon but serious disease process that affects mainly patients with advanced renal failure. Calciphylaxis is characterized by dermal arteriolar calcification that leads to skin ulceration, necrosis, ischemia and secondary infection. The pathogenesis is poorly understood, although the calcium phosphorus product has been proposed as a major cause. Given the high morbidity and mortality rate, emphasis should be placed on prevention and early diagnosis of vascular calcification, as well as in prophylaxis of secondary infection. We (..) (AU)
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Calciphylaxis/diagnosis , Renal Insufficiency, Chronic/complications , Dialysis/adverse effects , Arteriolosclerosis/diagnosis , Calcium/blood , Phosphorus/blood , Hyperparathyroidism, Secondary/prevention & control , Obesity/complicationsSubject(s)
Colitis, Ischemic/diagnosis , Renal Dialysis/adverse effects , Adult , Anti-Inflammatory Agents/adverse effects , Arteriosclerosis/complications , Arthritis, Infectious/complications , Arthritis, Infectious/surgery , Calcinosis/complications , Clostridium Infections/complications , Clostridium Infections/surgery , Colitis, Ischemic/etiology , Colitis, Ischemic/therapy , Colonic Diseases/etiology , Female , Graft Rejection , Hepatitis C, Chronic/complications , Humans , Hyperparathyroidism, Secondary/complications , Hyperparathyroidism, Secondary/surgery , Kidney Failure, Chronic/complications , Kidney Transplantation , Leukopenia/complications , Parathyroidectomy , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Ulcer/etiologyABSTRACT
Recientemente se ha recomendado el test de equilibrio peritoneal (TEP) con intercambio hipertónico (3,86 por ciento/4,25 por ciento glucosa) para evaluar la capacidad de ultrafiltración peritoneal y, mediante el análisis de la concentración de sodio del dializado, estudiar ciertas causas de fallo de ultrafiltración, como la disfunción de acuaporinas. Sin embargo, no existe suficiente información sobre la mejor forma de expresar variaciones de la concentración de sodio del dializado, sobre los valores de la normalidad de este parámetro y sobre los posibles efectos adversos de la aplicación del TEP con intercambio hipertónico en la población general de pacientes en diálisis peritoneal.Realizamos un TEP con intercambio hipertónico en 22 pacientes. Siete pacientes presentaron un defecto de ultrafiltración (ultrafiltración < 0,4 L). Los pacientes con defecto de ultrafiltración tenían un transporte peritoneal de solutos pequeños y una concentración de sodio en el dializado más elevados y habían estado más tiempo en diálisis peritoneal. La concentración de sodio en el dializado a los 60 y 240 minutos se correlacionó directamente con el transporte peritoneal de solutos, calculado como D/PCr240 (r = 0,74, p = 0,0008 y r = 0,84, p < 0,0001) e inversamente con la ultrafiltración (r = 0,64, p = 0,0016 y r = 0,72, p = 0,0002). La ausencia de caída de la concentración de sodio en el dializado, sugerente de defecto de acuaporinas, es infrecuente. La concentración de sodio en el dializado a los 60 minutos discrimina mejor a los pacientes con fallo de ultrafiltración que parámetros como el D/PNa o la caída absoluta de los valores de sodio con respecto al tiempo cero. Como efectos adversos observamos hipotensión sintomática en 2 pacientes con ultrafiltración conservada.En conclusión, aunque el TEP hipertónico permite confirmar el diagnóstico de fallo de ultrafiltración, la medida del sodio en el dializado solo aporta información adicional en los raros casos en que existe un defecto severo en la función de acuaporinas. El empleo rutinario del TEP hipertónico puede provocar efectos adversos en pacientes sin defecto de ultrafiltración. (AU)