RESUMEN
This review discusses the accumulated evidence that pro-opiomelanocortin (POMC) gene products as well as other pituitary neuropeptides derived from related genes (Proenkephalin, PENK; Prodynorphin, PDYN, and Pronociceptin, PNOC) can exert direct effects on B lymphocytes to modulate their functions. We also review the available data on receptor systems that might be involved in the transmission of such hormonal signals to B cells.
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Linfocitos B/metabolismo , Neuropéptidos/metabolismo , Animales , Encefalinas/metabolismo , Humanos , Proopiomelanocortina/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismoRESUMEN
We sought evidence for direct effects of repository corticotropin (RCI; an FDA-approved treatment for selected cases of SLE) on isolated human B lymphocytes activated by engagement of TLR9 and B cell receptors. ODN 2395/αIgM treatment was found to result in induction of 162 distinct mRNAs and suppression of 80 mRNAs at 24â¯h. RCI treatment resulted in suppression of 14 of the ODN 2395/αIgM -induced mRNAs (mean suppression to 23.6⯱â¯3.1% of stimulated value). The RCI-suppressed mRNAs included two critical regulators of class switch recombination, AICDA and BATF. RCI treatment also resulted in induction of 5 of the ODN 2395/αIgM -suppressed mRNAs (mean induction by RCIâ¯=â¯7.65⯱â¯2.34-fold). The RCI-induced mRNAs included SLAMF3, a cell surface receptor capable of inhibiting autoantibody responses. These studies reveal that RCI treatment of human B cells reverses key elements of the early mRNA response to TLR9 and B cell receptor engagement.
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Hormona Adrenocorticotrópica/farmacología , Linfocitos B/efectos de los fármacos , Receptores de Antígenos de Linfocitos B/inmunología , Receptor Toll-Like 9/inmunología , Adulto , Linfocitos B/inmunología , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
Since the start of the Ebola virus disease (Ebola) outbreak in West Africa, Sierra Leone has reported 8,706 confirmed Ebola cases and 3,956 deaths. During September 15-16, 2015, heavy rains flooded the capital, Freetown, resulting in eight deaths, home and property destruction, and thousands of persons in need of assistance. By September 27, approximately 13,000 flood-affected persons registered for flood relief services from the government. On September 17, two stadiums in Freetown were opened to provide shelter and assistance to flood-affected residents; a total of approximately 3,000 persons stayed overnight in both stadiums (Sierra Leone Ministry of Health and Sanitation, personal communication, September 2015). On the same day the stadiums were opened to flood-affected persons, the Ministry of Health and Sanitation (MoHS) and Western Area Ebola Response Center (WAERC) staff members from CDC, the World Health Organization (WHO), and the African Union evaluated the layout, logistics, and services at both stadiums and identified an immediate need to establish Ebola response activities. The patient in the last Ebola case in the Western Area, which includes Freetown, had died 37 days earlier, on August 11; however, transmission elsewhere in Sierra Leone was ongoing, and movement of persons throughout the country was common.
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Desastres , Brotes de Enfermedades/prevención & control , Inundaciones , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Características de la Residencia , Saneamiento/normas , Sierra Leona/epidemiologíaRESUMEN
OBJECTIVE: To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP-13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation. METHODS: The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS-4 and ADAMTS-5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis. RESULTS: The potent and selective MMP-13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose-dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results. CONCLUSION: This highly selective MMP-13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP-13 inhibitor. These data support the potential therapeutic value of selective MMP-13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.
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Cartílago Articular/fisiopatología , Metaloproteinasa 13 de la Matriz/fisiología , Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis de la Rodilla/fisiopatología , Pirimidinas/farmacología , Tetrazoles/farmacología , Animales , Artritis Experimental , Biomarcadores/orina , Cartílago Articular/patología , Colágeno Tipo II/orina , Perros , Femenino , Osteoartritis de la Rodilla/patología , Líquido Sinovial/químicaRESUMEN
Repository corticotropin injection (RCI), a complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides, has been found to suppress key aspects of gene expression and cellular function in human B lymphocytes in vitro. The present studies reveal that neither individual POMC peptides (α-MSH, ACTH1-39, ACTH1-24, ß-endorphin) nor other related pituitary neuropeptides are sufficient to elicit these effects, even though specific receptors capable of transmitting signals from these peptides are expressed by human B cells. RCI's direct effects on human B cells may require complementary signals from multiple components of the preparation.
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Linfocitos B/efectos de los fármacos , Neuropéptidos/farmacología , Hormonas Hipofisarias/farmacología , Adulto , Anciano , Animales , Células Cultivadas , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Porcinos , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the decrease of cartilage destruction by a novel orally active and specific matrix metalloproteinase 13 (MMP-13) inhibitor in three different animal models of rheumatoid arthritis (RA). MATERIALS AND METHODS: The SCID mouse co-implantation model of RA, the collagen-induced arthritis (CIA) model in mice and the antigen-induced arthritis model (AIA) in rabbits were used. RESULTS: In the SCID mouse co-implantation model, the MMP-13 inhibitor reduced cartilage destruction by 75%. In the CIA model of RA, the MMP-13 inhibitor resulted in a significant and dose-dependent decrease in clinical symptoms as well as of cartilage erosion by 38% (30 mg/kg), 28% (10 mg/kg) and 21% (3 mg/kg). No significant effects were seen in the AIA model. No toxic effects were seen in all three animal models. CONCLUSION: Although several MMPs in concert with other proteinases have a role in the process of cartilage destruction, there is a need for highly selective MMP inhibitors to reduce severe side effects that occur with non-specific inhibitors. Significant inhibition of MMP-13 reduced cartilage erosions in two of three tested animal models of RA. These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.
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Antirreumáticos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz , Administración Oral , Animales , Antirreumáticos/administración & dosificación , Artritis Experimental/enzimología , Artritis Experimental/patología , Artritis Reumatoide/enzimología , Artritis Reumatoide/patología , Cartílago Articular/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Masculino , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones SCID , Conejos , Membrana Sinovial/enzimologíaRESUMEN
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
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Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Ácidos Picolínicos/química , Inhibidores de Proteasas/química , Tetrazoles/química , Administración Oral , Animales , Sitios de Unión , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Metaloproteinasa 13 de la Matriz/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Tetrazoles/síntesis química , Tetrazoles/farmacología , Zinc/químicaRESUMEN
Osteoarthritis (OA) is a degenerative joint disease that has no FDA-approved treatment. The current standard of care does not address the regeneration of the damaged cartilage. Human growth hormone (hGH) is part of the insulin-like growth factor (IGF)-1 axis. There has been preclinical data that suggest its potential regenerative property in the joint. However, unformulated recombinant hGH (rhGH) is short-lived in the joint, and does not provide a desirable pharmacokinetic (PK) profile to support a clinical treatment paradigm. Polyethylene glycol (PEG)ylation is a potential method to extend the half-life of rhGH in the joint. The purpose of this study was to delineate the PK/PD profile of PEG-rhGH in the knee joint in a rat preclinical model of OA. After intra-articular (IA) injection of 100 microg into a rat knee joint that underwent medial meniscectomy, PEG-rhGH exhibits 2-fold longer half-lives in joint than native hGH. However, PEG-rhGH has a much longer systemic exposure. IA injections of PEG-rhGH also resulted in higher levels of IGF-1 in the joint and serum when compared with native rhGH. In order to develop PEG-rhGH as an IA therapeutic treatment for OA, careful dose selection is necessary to avoid systemic effects while retaining its anabolic efficacy in the joint.
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Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/farmacocinética , Osteoartritis/metabolismo , Polietilenglicoles/farmacocinética , Proteínas Recombinantes/farmacocinética , Animales , Modelos Animales de Enfermedad , Semivida , Masculino , Osteoartritis/tratamiento farmacológico , Polietilenglicoles/química , Ratas , Ratas Sprague-DawleyRESUMEN
The contribution of inducible nitric oxide synthase (iNOS) to oxidative/nitrative stress is well-documented in inflammation, but difficult to quantify. Using a novel, recently developed assay for 3-nitrotyrosine (3-NT), we characterized iNOS activity and its inhibition in preclinical models of inflammation. In particular, we utilized the 3-NT assay to assess the role of iNOS in the disease pathology as well as for proof of pharmacology of iNOS inhibitors in an acute endotoxin challenge model, in models of rheumatoid arthritis (RA) such as rat adjuvant- and collagen-induced arthritis (AIA and CIA) and a model of osteoarthritis (OA) such as rat sodium monoiodoacetate-induced arthritis (MIA). Quantification of nitrotyrosine was performed using immuno-affinity 2-D LC-MS/MS assay. This assay is a very specific and reproducible and is amenable to a number of biological fluids. Plasma levels of 3-NT were significantly elevated in an acute model of inflammation (rat LPS) and in models of rheumatoid arthritis (adjuvant- and collagen-induced arthritis), and osteoarthritis (monoiodoacetate-induced arthritis). Plasma 3-NT correlated with the severity of the inflammatory response; thus, a 20-fold increase was observed in the rat LPS model, a 10-fold increase in AIA, and only a 2.5-fold elevation in CIA. Pharmacological intervention with iNOS inhibitors decreased 3-NT levels and associated pathology. 3-NT determination allowed for better elucidation of the role of iNOS in RA and OA disease pathology and provided proof of pharmacology for NOS inhibitors in animal models of RA and OA.
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Óxido Nítrico Sintasa de Tipo II/fisiología , Tirosina/análogos & derivados , Animales , Artritis Experimental , Artritis Reumatoide , Biomarcadores/sangre , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Inflamación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Osteoartritis , Ratas , Índice de Severidad de la Enfermedad , Tirosina/sangreRESUMEN
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
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Metaloproteinasa 13 de la Matriz/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Osteoartritis/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tetrazoles/síntesis química , Tetrazoles/farmacología , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Colagenasas/efectos de los fármacos , Perros , Diseño de Fármacos , Humanos , Riñón/metabolismo , Macaca fascicularis , Masculino , Inhibidores de la Metaloproteinasa de la Matriz/toxicidad , Modelos Moleculares , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
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Antiinflamatorios/síntesis química , Antineoplásicos/síntesis química , Fármacos Cardiovasculares/síntesis química , Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Piperidinas/síntesis química , Piranos/síntesis química , Sulfonas/síntesis química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Bovinos , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Macaca fascicularis , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/farmacología , Piranos/química , Piranos/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Although hand hygiene is the most important measure in the prevention of nosocomial infection, adherence to recommendations among health care workers (HCW) is low. Evaluation of compliance with hand hygiene was carried out in a Spanish teaching hospital. METHODS: In 2005, adherence to hand hygiene was evaluated hospital wide through direct observation, collecting data on hand hygiene carried out whenever indicated (opportunity for hand hygiene). Compliance was defined as handwashing/disinfection in an opportunity for hand hygiene according to hospital protocols. The results were analyzed using mixed effects models, with the HCW observed as the random effect. RESULTS: A total of 1254 opportunities for hand hygiene were observed in 247 HCWs. Mean compliance was 20%. Although few differences were observed among types of HCW, compliance varied according to hospital area (69% in the intensive care unit [ICU]) and timing with respect to patient contact (compliance after contact was twice that before contact). Multivariate analyses revealed a protective odds ratio (OR) for nonadherence in ICUs (OR, 0.04; 95% confidence interval (95% CI): 0.01-0.10) and after patient contact (OR, 0.25; 95% CI: 0.17-0.38). CONCLUSION: Low adherence observed suggests that new interventions should focus in modification of HCWs' habits and attitudes, working at several levels: individual and institutional.