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INTRODUCTION: Juvenile polyposis syndrome it is an uncommon autosomal dominant inherited condition. Hamartomatous polyps can affect the entire gastrointestinal tract but usually predominates in the colon. We introduce a case of juvenile polyposis syndrome presented with massive gastric polyposis that requires a total gastrectomy. CASE PRESENTATION: A 22-year-old man presented symptoms of chronic upper gastrointestinal bleeding. Gastroscopy showed massive gastric polyposis. Initially endoscopic polypectomy was performed, but due to the progressive symptoms, a total gastrectomy was then performed. Histology confirmed massive gastric juvenile polyposis. CONCLUSION: Massive gastric polyposis it is an uncommon manifestation of juvenile polyposis syndrome.
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BACKGROUND AND STUDY AIMS: In patients with gastroesophageal reflux disease (GERD), temporary electrical stimulation of the lower esophageal sphincter (LES) increases LES pressure without interference with LES relaxation. The aim of the current study was to investigate the safety and efficacy of long term LES electrical stimulation therapy (LES-EST), using a permanently implanted stimulator for the treatment of GERD. PATIENTS AND METHODS: Patients with GERD who were at least partially responsive to proton pump inhibitors (PPIs) and who had hiatal hernia of ≤ 3 cm and esophagitis of Los Angeles Grade A, B, or C were included in the study. Stimulation electrodes were placed in the LES and a pulse generator (EndoStim LES Stimulation System; EndoStim BV, The Hague, The Netherlands) was implanted laparoscopically. LES stimulation was delivered at 20 Hz, 215 µs, 3 - 8 mA in multiple 30-minute sessions. Patients were evaluated at follow-up using the GERD Health-Related Quality of Life (HRQL) questionnaire, daily symptom and medication diaries, the SF-12 Health Survey, esophageal pH testing, and high resolution manometry. RESULTS: A total of 24 patients (mean age 53 ± 12 years; 14 men) were implanted and 23 completed the 12-month evaluation. No serious implantation or stimulation-related adverse affects or sensations were reported. Median composite GERD-HRQL score at 12 months was 2.0 (interquartile range [IQR] 0 - 3.0), which was significantly better than baseline scores both on PPI therapy (median 9.0, IQR 6.0 - 10.0; P = 0.002) and off PPIs (median 23.5, IQR 21 - 25.75; P < 0.001). The median percentage of the 24-hour period with esophageal pH < 4.0 at baseline was 10.1 % (IQR 7.7 - 15.5), which was reduced to 3.3 % (1.8 - 6.9) at 12 months (P < 0.001), with 69 % of patients showing either normalization or > 50 % improvement in their distal esophageal pH. At 12 months, 96 % of patients (22/23) were completely off PPI medication. CONCLUSION: During the long term follow-up of 12 months, LES - EST was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in esophageal acid exposure with elimination of daily PPI usage, and no stimulation-related adverse effects.
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Terapia por Estimulación Eléctrica , Esfínter Esofágico Inferior/fisiopatología , Reflujo Gastroesofágico/terapia , Adulto , Terapia por Estimulación Eléctrica/efectos adversos , Electrodos Implantados , Monitorización del pH Esofágico , Femenino , Estudios de Seguimiento , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Masculino , Manometría , Persona de Mediana Edad , Presión , Inhibidores de la Bomba de Protones/uso terapéutico , Calidad de Vida , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Glutamate-mediated excitotoxicity has been purported to underlie many neurodegenerative disorders. A subtype of glutamate receptors, namely N-methyl-d-aspartate (NMDA) receptors, has been recognized as potential targets for neuroprotection. To increase our understanding of the mechanisms that underlie this neuroprotection, we employed a mouse model of glutamate receptor-induced excitotoxic injury. Primary cortical neurons derived from postnatal day-0 CD-1 mice were cultured in the presence or absence of neuroprotective molecules and exposed to NMDA. Following a recovery period, whole genome expression was measured by microarray analysis. We used a combination of database and text mining, as well as systems modeling to identify signatures within the differentially expressed genes. While molecules differed in their mechanisms of action, we found significant overlap in the expression of a core group of genes and pathways. Many of these molecules have clear links to neuronal protection and survival, including ion channels, transporters, as well as signaling pathways including the mitogen-activated protein kinase (MAPK), the Toll-like receptor (TLR), and the hypoxic inducible factor (HIF). Within the TLR pathway, we also discovered a significant enrichment of interferon regulatory factor 7 (IRF7)-regulated genes. Knockdown of Irf7 by RNA interference resulted in reduced survival following NMDA treatment. Given the prominent role that IRF7 plays in the transduction of type-I interferons (IFNs), we also tested whether type-I IFNs alone functioned as neuroprotective agents and found that type-I IFNs were sufficient to promote neuronal survival. Our data suggest that the TLR/IRF7/IFN axis plays a significant role in recovery from glutamate-induced excitotoxicity.
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Ácido Glutámico/fisiología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Calcio/metabolismo , Adhesión Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Minería de Datos , Biblioteca de Genes , Estudio de Asociación del Genoma Completo , Ácido Glutámico/metabolismo , Factor 1 Inducible por Hipoxia/biosíntesis , Ratones , Proteínas Quinasas Activadas por Mitógenos/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Receptores Toll-Like/biosíntesis , TranscriptomaRESUMEN
Oral ulcers are a frequent problem in transplant medicine. It is important to consider infectious etiologies, exacerbated by the immunosuppressive treatment, but other etiologies are also possible, like adverse drug reactions. Mycophenolate mofetil (MMF) is an immunosuppressive medication that has been used in combination with calcineurin inhibitors and steroids. Reports of renal transplant patients with oral ulcers related to MMF have appeared lately and herein we have described 2 cases in liver transplant patients. Their oral ulcers resolved quickly after suspension of the medication. Our 2 cases in liver transplant patients represented a unique setting for this type of complication.
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Inmunosupresores/efectos adversos , Trasplante de Hígado/inmunología , Ácido Micofenólico/análogos & derivados , Úlceras Bucales/inducido químicamente , Adulto , Antibacterianos/uso terapéutico , Ciclosporina/uso terapéutico , Femenino , Humanos , Resistencia a la Meticilina , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Resultado del TratamientoRESUMEN
BACKGROUND: Drug induced liver disease (DILD) is common and of difficult diagnosis. AIM: To report the clinical, laboratory and pathological findings in 33 patients with DILD. PATIENTS AND METHODS: We revised 1,164 liver biopsies and 57 were selected as suspicious of DILD. In these, the scale proposed by Maria et al was applied to assess the possibility of hepatotoxicity reactions and 33 were selected. RESULTS: The 33 cases had a mean age of 48 +/- 18 years and 14 were male. Forty eight medications were involved, with an average of 1.4 drugs per patient. The main drugs were antimicrobials, antineoplastics-immunosuppressives and non-steroidal antiinflammatory drugs. The clinical presentations in order of frequency were cholestasis, hepatitis, asymptomatic, fulminant hepatitis and cirrhosis. The laboratory alterations observed in cases with hepatitis were 20 fold transaminase and bilirubin elevation. In cholestasis, moderate elevations of alkaline phosphatases and gamma glytamyl transferase were observed. Pathology showed hepatocellular damage, cholestasis and mixed damage, but also submassive necrosis and cirrhosis in one case. CONCLUSIONS: The present study confirms that DILD is frequently unpredictable and that it can cause a wide variety of clinical and pathological presentations, that can even evolve to chronicity.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Hepatopatías/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas , Hepatopatías/diagnósticoRESUMEN
A novel, 10-step, solid-phase method, based on a secondary amide linker, was developed to construct a diverse library of indole-based SFLLR peptide mimetics as thrombin receptor (protease-activated receptor 1, PAR-1) antagonists. The key steps include stepwise reductive alkylation, urea formation, and Mannich reaction. Screening of the library led to a quick development of the SAR and the significant improvement of PAR-1 activity.
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Indazoles/síntesis química , Receptores de Trombina/antagonistas & inhibidores , Urea/síntesis química , Amidas/química , Fibrinolíticos/síntesis química , Fibrinolíticos/química , Fibrinolíticos/farmacología , Indazoles/química , Indazoles/farmacología , Indoles/química , Imitación Molecular , Urea/análogos & derivados , Urea/química , Urea/farmacologíaAsunto(s)
Fibrinolíticos/síntesis química , Indazoles/síntesis química , Indoles/síntesis química , Receptores de Trombina/antagonistas & inhibidores , Urea/síntesis química , Angioplastia de Balón , Animales , Constricción Patológica , Fibrinolíticos/química , Fibrinolíticos/farmacología , Cobayas , Indazoles/química , Indazoles/farmacología , Indoles/química , Indoles/farmacología , Imitación Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Ratas , Receptor PAR-1 , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/química , Urea/farmacologíaRESUMEN
BACKGROUND: Hypertriglyceridemia over 1,000 mg/dl can provoke acute pancreatitis and its persistence can worsen the clinical outcome. On the contrary, a rapid decrease in triglyceride level is beneficial. Plasmapheresis has been performed in some patients to remove chylomicrons from the circulation, while heparin and/or insulin have been administered in some other cases to rapidly reduce blood triglycerides. Heparin and insulin stimulate lipoprotein-lipase activity and accelerate chylomicron degradation. AIM: To report five patients with acute pancreatitis treated with heparin and insulin. PATIENTS AND METHODS: Five patients (4 females and 1 male) seen in the last two years, who suffered acute pancreatitis induced by hypertriglyceridemia are reported. Initial blood triglyceride levels were above 1,000 mg/dl (range 1,590-8,690 mg/dl). Besides the usual treatment of acute pancreatitis, heparin and/or insulin were administered intravenously in continuous infusion. Heparin dose was guided by usual parameters of blood coagulation, and insulin dose, by serial determinations of blood glucose. Pancreatic necrosis was demonstrated in 4 patients. RESULTS: Serum triglyceride levels decreased to < 500 mg/dl within 3 days in all cases. No complication of treatment was observed and all patients survived. Early and late complications of pancreatitis occurred in one patient. CONCLUSION: Administration of heparin and/or insulin is an efficient alternative to reduce triglyceride levels in patients with acute pancreatitis and hypertriglyceridemia.
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Anticoagulantes/uso terapéutico , Heparina/uso terapéutico , Hipertrigliceridemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Adulto , Quilomicrones/efectos de los fármacos , Femenino , Humanos , Hipertrigliceridemia/complicaciones , Lipoproteína Lipasa/efectos de los fármacos , Masculino , Persona de Mediana Edad , Pancreatitis/etiología , Triglicéridos/sangreRESUMEN
The protease-activated thrombin receptor-1 (PAR-1) can be activated by both the tethered ligand exposed by thrombin cleavage and a synthetic peptide having the tethered ligand sequence (thrombin receptor agonist peptide or TRAP). We conducted a mutational analysis of extracellular residues of the receptor potentially involved in interaction with both the tethered ligand and the soluble peptide agonist. Agonist-stimulated calcium efflux in X. laevis oocytes or inositol phosphate accumulation in COS-7 cells was used to assess receptor activation. We have also examined the binding of a radiolabeled TRAP for the wild-type and mutant PAR-1 receptors. Our results indicated that most of the mutations strongly affected TRAP-induced responses without significantly altering thrombin-induced responses or TRAP binding. Several point mutations and deletion of extracellular domains (DeltaEC3, DeltaNH3) drastically altered the ability of mutant receptors to respond to TRAP, but not to thrombin, and did not affect the affinity for the radiolabeled TRAP by these mutant receptors. Only mutations that disrupted the putative disulfide bond or substitution of multiple acidic residues in the second extracellular loop by alanine had a significant effect on both ligand binding and thrombin activation. These results suggest that although both agonists can activate PAR-1, there are profound differences in the ability of thrombin and TRAP to activate PAR-1. In addition, we have found PAR-1 mutants with the ability to dissociate receptor-specific binding from functional activity.
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Proteínas/metabolismo , Receptores de Trombina/agonistas , Receptores de Trombina/metabolismo , Trombina/metabolismo , Secuencia de Aminoácidos , Animales , Plaquetas/efectos de los fármacos , Células COS , Ensayo de Inmunoadsorción Enzimática , Humanos , Hidrólisis , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Oocitos , Fosfatidilinositoles/metabolismo , Conformación Proteica , Proteínas/farmacología , Ensayo de Unión Radioligante , Receptor PAR-1 , Receptores de Trombina/genética , Transfección , Xenopus laevisRESUMEN
Expression of the wild-type alpha subunit of Gq stimulates phospholipase C and induces hypertrophy in cardiomyocytes. Addition of Gq-coupled receptor agonists additionally activates phospholipase C, as does expression of a constitutively active mutant form of Galphaq. Under these conditions, hypertrophy is rapidly succeeded by apoptotic cellular and molecular changes, including myofilament disorganization, loss of mitochondrial membrane potential, alterations in Bcl-2 family protein levels, DNA fragmentation, increased caspase activity ( approximately 4-fold), cytochrome c redistribution, and nuclear chromatin condensation in approximately 12% of the cells. We used various interventions to define the molecular relationships between these events and identify potential sites at which these features of apoptosis could be rescued. Treatment with caspase inhibitors prevented DNA fragmentation and promoted myocyte survival; however, cytochrome c release and loss of mitochondrial membrane potential still occurred. In contrast, treatment with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore, not only prevented DNA fragmentation and reduced nuclear chromatin condensation but also preserved mitochondrial membrane potential and limited cytochrome c redistribution to only approximately 2% of cells. These data demonstrate the central role of mitochondrial membrane potential in initiation of caspase activation and downstream apoptotic events and suggest that preservation of mitochondrial integrity is crucial for prolonging the life and function of cardiomyocytes exposed to pathological levels of stress.
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Proteínas de Unión al GTP Heterotriméricas/fisiología , Mitocondrias/fisiología , Miocardio/citología , Adenoviridae/genética , Animales , Antibacterianos/farmacología , Apoptosis , Ácido Bongcréquico/farmacología , Caspasas/metabolismo , Células Cultivadas , Grupo Citocromo c/metabolismo , Activación Enzimática , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Permeabilidad/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Fosfolipasas de Tipo C/metabolismoRESUMEN
Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease alpha-thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. We have discovered a series of potent peptide-mimetic antagonists of PAR-1, exemplified by RWJ-56110. Spatial relationships between important functional groups of the PAR-1 agonist peptide epitope SFLLRN were employed to design and synthesize candidate ligands with appropriate groups attached to a rigid molecular scaffold. Prototype RWJ-53052 was identified and optimized via solid-phase parallel synthesis of chemical libraries. RWJ-56110 emerged as a potent, selective PAR-1 antagonist, devoid of PAR-1 agonist and thrombin inhibitory activity. It binds to PAR-1, interferes with PAR-1 calcium mobilization and cellular function (platelet aggregation; cell proliferation), and has no effect on PAR-2, PAR-3, or PAR-4. By flow cytometry, RWJ-56110 was confirmed as a direct inhibitor of PAR-1 activation and internalization, without affecting N-terminal cleavage. At high concentrations of alpha-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, albeit not in human platelets; whereas, at high concentrations of SFLLRN-NH(2), RWJ-56110 blocked activation responses in both cell types. Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis. Selective PAR-1 antagonists, such as RWJ-56110, should serve as useful tools to study PARs and may have therapeutic potential for treating thrombosis and restenosis.
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Imitación Molecular , Péptidos/síntesis química , Receptores de Trombina/antagonistas & inhibidores , Secuencia de Bases , Línea Celular , Cartilla de ADN , Humanos , Péptidos/metabolismo , Péptidos/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Ensayo de Unión Radioligante , Receptor PAR-1 , Receptores de Trombina/metabolismoRESUMEN
The thrombin receptor PAR-1 is activated by alpha-thrombin to stimulate cells, including platelets, through the tethered-ligand sequence SFLLRN. We have discovered a novel series of heterocycle-peptide hybrids comprised of a tripeptide segment, such as Cha-Arg-Phe, and an N-terminal heterocyclic group, many of which behave as full PAR-1 agonists. Certain compounds with an aminotriazole group, such as 4 and 16, are nearly as potent as SFLLRN-NH2 in inducing platelet aggregation. Also, some arylethenoyl "N-capped" compounds, such as 52 and 57, exhibit mixed PAR-1 agonist-antagonist activity.
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Compuestos Heterocíclicos/química , Oligopéptidos/farmacología , Receptores de Trombina/agonistas , Triazoles/química , Línea Celular , Humanos , Oligopéptidos/síntesis química , Oligopéptidos/química , Receptor PAR-1 , Receptores de Trombina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The thrombin receptor (PAR-1) is an unusual transmembrane G-protein coupled receptor in that it is activated by serine protease cleavage of its extracellular N-terminus to expose an agonist peptide ligand, which is tethered to the receptor itself. Synthetic peptides containing the agonist motif, such as SFLLRN for human PAR-1, are capable of causing full receptor activation. We have probed the possible bioactive conformations of thrombin receptor-activating peptides (TRAPs) by systematic introduction of certain conformational perturbations, involving alpha-methyl, ester psi(COO), and reduced-amide psi(CH2N) scans, into the minimum-essential agonist sequence (SFLLR) to probe the importance of the backbone conformation and amide NH hydrogen bonding. We performed extensive conformational searches of representative pentapeptides to derive families of putative bioactive structures. In addition, we employed 1H NMR and circular dichroism (CD) to characterize the conformational disposition of certain pentapeptide analogues experimentally. Activation of platelet aggregation by our pentapeptide analogues afforded a structure-function correlation for PAR-1 agonist activity. This correlation was assisted by PAR-1 receptor binding data, which gauged the affinity of peptide ligands for the thrombin receptor independent of a functional cellular response derived from receptor activation (i.e. a pure molecular recognition event). Series of alanine-, proline-, and N-methyl-scan peptides were also evaluated for comparison. Along with the known structural features for PAR-1 agonist peptides, our work adds to the understanding of peptide topography relative to platelet functional activity and PAR-1 binding. The absolute requirement of a positively charged N-terminus for strong agonist activity was contradicted by the N-terminal hydroxyl peptide psi(HO)S-FLLR-NH2. The amide nitrogen between residues 1 and 2 was found to be a determinant of receptor recognition and the carbonyl groups along the backbone may be involved in hydrogen bonding with the receptor. Position 3 (P3) of TRAP-5 is known to tolerate a wide variety of side chains, but we also found that the amide nitrogen at this position can be substituted by an oxygen, as in SF-psi(COO)-LLR-NH2, without diminishing activity. However, this peptide bond is sensitive to conformational changes in that SFPLR-NH2 was active, whereas SF-NMeL-LR-NH2 was not. Additionally, we found that position 3 does not tolerate rigid spacers, such as 3-aminocyclohexane-1-carboxylic acid and 2-aminocycloalkane-1-carboxylic acid, as analogues 1A, 1B, 2A, 2B, 3, 4, 5A and 5B lack agonist activity. On the basis of our results, we suggest that an extended structure of the agonist peptide is principally responsible for receptor recognition (i.e. binding) and that hydrophobic contact may occur between the side chains of the second (Phe) and fourth (Leu) residues (i.e. P2-P4 interaction).
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Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Receptores de Trombina/metabolismo , Dicroismo Circular , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Fragmentos de Péptidos/síntesis química , Inhibidores de Agregación Plaquetaria/química , Conformación Proteica , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Previous studies have shown small bowel motor activity abnormalities in patients with liver cirrhosis of different etiologies, but motility has not been studied in patients with primary biliary cirrhosis. Our aim was to investigate proximal small bowel motility in these patients. METHODS: Twenty-five female patients presenting clinical, biochemical, serological, and histological findings compatible with primary biliary cirrhosis, 10 female patients with nonalcoholic liver cirrhosis, and 10 normal female controls were studied. Motility of the upper small bowel was measured in the fasted state by means of perfused manometric catheters, connected to external transducers and positioned in the small bowel under fluoroscopy. RESULTS: The average amplitude of contractions was significantly decreased in patients with primary biliary cirrhosis compared with other liver cirrhosis (20.2+/-1.0 vs 32+/-2.9 mm Hg). Also, a significantly increased frequency of cluster of contractions and an increased duration of phase II of the migrating motor complex as seen in liver cirrhosis was observed when compared with normals. CONCLUSION: We conclude that primary biliary cirrhosis patients present motor abnormalities of the small intestine similar to those of patients with liver cirrhosis of other etiologies. In addition, a decrease in the amplitude of small bowel contractions was also found in these patients, suggesting a myogenic involvement.
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Motilidad Gastrointestinal/fisiología , Intestino Delgado/fisiopatología , Cirrosis Hepática Biliar/fisiopatología , Adulto , Anciano , Ayuno/fisiología , Femenino , Humanos , Cirrosis Hepática/fisiopatología , Persona de Mediana Edad , Complejo Mioeléctrico Migratorio/fisiología , Valores de Referencia , Factores de TiempoRESUMEN
BACKGROUND: Local infiltration with corticoids is a simple therapy for rheumatic disorders devoid of systemic adverse reactions. AIM: To compare the efficacy of two betametasone preparations from two different pharmaceutical laboratories in the treatment of patients with osteoarthritis or epicondylitis. PATIENTS AND METHODS: Fourty patients with knee osteoarthritis and 12 patients with epicondylitis were studied. Using a double blind protocol, one of the two betametasone preparations was used for local infiltration of the lesions. The change in a global score of clinical variables including pain and disability was assessed after 30 days of the infiltration. RESULTS: In patients with osteoarthritis, the global score decreased significantly with both preparations, but no differences were observed between preparations (7.3 +/- 1.8 to 3.9 +/- 2.3 with preparation A and 7.8 +/- 1.9 to 3.6 +/- 2.3 with preparation B). In patients with epicondylitis, pain was also significantly reduced but no differences between preparations was observed (7 +/- 2.1 to 1.4 +/- 2.5 for preparation A and 4.6 +/- 2.8 to 1.2 +/- 1.6 for preparation B). CONCLUSIONS: Local infiltration with both betametasone preparations was equally effective in the treatment of patients with knee osteoarthritis or epicondilytis.
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Betametasona/administración & dosificación , Glucocorticoides/administración & dosificación , Húmero/lesiones , Traumatismos de la Rodilla/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Inyecciones Intraarticulares , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Factores de TiempoRESUMEN
The thrombin receptor (PAR-1) is activated by alpha-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. A series of azole-based carboxamides, designed after SFLLR, were synthesized and evaluated in vitro. The compounds inhibited platelet aggregation induced by SFLLRN-NH2 or alpha-thrombin, and blocked the binding of [3H]-S-(p-F-Phe)-Har-L-Har-KY-NH2 to a CHRF membrane preparation of PAR-1. Oxazole 30 bound to PAR-1 with an IC50 of 1.6 microM, and gave IC50 values of 25 microM and 6.6 microM against alpha-thrombin- and SFLLRN-NH2-induced platelet aggregation, respectively.
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Compuestos Heterocíclicos/farmacología , Imitación Molecular , Fragmentos de Péptidos/química , Receptores de Trombina/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Receptor PAR-1 , Relación Estructura-ActividadRESUMEN
5-Hydroxytryptamine (5-HT) receptors contain seven putative transmembrane domains and couple via different guanine nucleotide binding proteins to specific effector enzymes. Studies with other receptors identify the second and third intracellular loops or the C-terminus of the receptor as important for selective effector coupling. However, it is not known which regions of the 5-HT receptor determine effector coupling specificity. To address this question, we constructed a chimeric 5-HT receptor in which the third intracellular (i3) loop is derived from the 5-HT2A receptor, which is coupled to activation of phospholipase C, and the rest of the sequence is derived from the 5-HT1B receptor, which is coupled to inhibition of adenylyl cyclase. The chimeric receptor exhibited ligand binding properties similar to those of the 5-HT1B receptor and distinct from those of the 5-HT2A receptor. This suggests that the i3 loop is not critical for the unique pharmacology of the 5-HT1B receptor. In contrast, the chimeric receptor exhibited signaling properties similar to those of the 5-HT2A receptor and distinct from those of the 5-HT1B receptor. This indicates that the i3 loop determines the effector coupling specificity of the 5-HT2A receptor.