Tratamientos modificadores de la enfermedad en pacientes con esclerosis múltiple en España / Disease-modifying treatments for patients with multiple sclerosis in Spain

La esclerosis múltiple es una enfermedad desmielinizante crónica del sistema nervioso central y discapacitante a largo plazo. Existen diferentes tratamientos modificadores de la enfermedad. Estos pacientes, a pesar de ser generalmente jóvenes, tienen una elevada comorbilidad y riesgo de polimedicación por su compleja sintomatología y discapacidad. Objetivo principal determinar el tipo de tratamiento modificador de la enfermedad en los pacientes atendidos en servicios de farmacia de hospitales españoles. Objetivos secundarios Conocer los tratamientos concomitantes, determinar la prevalencia de la polifarmacia, identificar la prevalencia de interacciones y analizar la complejidad farmacoterapéutica. Método estudio observacional, transversal y multicéntrico. Se incluyeron todos los pacientes con diagnóstico de esclerosis múltiple y tratamiento modificador de la enfermedad activo a los que se atendió en las consultas de pacientes externos o en los hospitales de día durante la segunda semana de febrero 2021. Se recogieron: el tratamiento modificador, las comorbilidades y los tratamientos concomitantes para determinar el patrón de multimorbilidad, polifarmacia, complejidad farmacoterapéutica (Medication Regimen Complexity Index) e interacciones medicamentosas. Resultados se incluyeron 1.407 pacientes de 57 centros de 15 Comunidades Autónomas. La forma de presentación de la enfermedad más frecuente fue la forma remitente recurrente (89,3%). El tratamiento modificador de la enfermedad más prescrito fue dimetilfumarato (19,1%), seguido de teriflunomida (14,0%). De los tratamientos modificadores parenterales, los 2 más prescritos fueron el acetato de glatiramero y el natalizumab con un 11,1 y 10,8% respectivamente. El 24,7% de los pacientes tenían una comorbilidad y el 39,8% al menos 2 comorbilidades. El 13,3% pertenecía al menos a uno de los patrones definidos de multimorbilidad y el 16,5% pertenecían a 2 o más patrones. ... (AU)

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability.Objective primaryTo determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments.Secondary objectivesTo determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyse pharmacotherapeutic complexity.MethodObservational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions.Results1,407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had one comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). ... (AU)

[Translated Article] Disease-modifying treatments for patients with multiple sclerosis in Spain.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. OBJECTIVE PRIMARY: To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. SECONDARY OBJECTIVES: to determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyze pharmacotherapeutic complexity. METHOD: Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. RESULTS: 1407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had 1 comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3-15.0). CONCLUSIONS: We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterized concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Disease-modifying treatments for patients with multiple sclerosis in Spain. / Tratamientos modificadores de la enfermedad en pacientes con esclerosis múltiple en España.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. OBJECTIVE PRIMARY: To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. SECONDARY OBJECTIVES: To determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyse pharmacotherapeutic complexity. METHOD: Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. RESULTS: 1,407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had one comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3 -- 15.0). CONCLUSIONS: We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterised concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Sclerotherapy and Topical Nasal Propranolol: An Effective and Safe Therapy for HHT-Epistaxis.

OBJECTIVES: Epistaxis is the most frequent clinical manifestation of hereditary hemorrhagic telangiectasia (HHT). Several topical, systemic, and surgical treatments have been tried, but none have been completely effective. The aim of the present study is to evaluate whether a combined treatment sclerotherapy and topical therapy with propranolol 0.5% nasal formulation would reduce the epistaxis due to HHT and improve patient's quality of life. METHODS: An observational cross-sectional study was carried out. The primary outcome measure was frequency and severity of epistaxis as measured by the epistaxis severity score (ESS) at baseline (4 weeks before therapy) and at least 4 weeks after the treatment was implemented. Quality of life was analyzed using EuroQol-5D (EQ-5D) scale and visual analogue (VAS) scale before and after treatment. RESULTS: A total of 38 consecutive patients subjected to the combined treatment were evaluated (mean age: 57.2 years, standard deviation [SD] = 13.9; 60.5% women). The mean time of treatment was 37.1 weeks (SD = 14.9). Combined therapy significantly reduces frequency and severity of epistaxis, with an ESS improvement of 5 points from 6.9 ± 2.6 to 1.9 ± 1.3 (P < 0.05); however, the EQ-5D scale increased from 0.66 ± 0.27 to 0.93 ± 0.12 (P < 0.05). The difference in VAS means showed an increase from 44.6 ± 28.3 to 82.5 ± 12.5 (P < 0.05). The increases in quality of life are in line with the drop in ESS. CONCLUSION: The study demonstrated that combined therapy (sclerotherapy and topical nasal propranolol) significantly reduced the epistaxis due to HHT and increased patients' quality of life. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:2216-2223, 2019.

Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2.

Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-beta(1) subunit expression in a concentration-dependent manner. The maximal reduction in sGC-beta(1) subunit expression was achieved with 1 ppm lead. Vitamin C (30 micromol/L) partially restored sGC-beta( 1) subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-beta(1) subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 micromol/L) and with rofecoxib (1 micromol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-beta(1) subunit induced by lead in the rat vascular wall.

Endothelin-1 induced proinflammatory markers in the myocardium and leukocytes of guinea-pigs: role of glycoprotein IIB/IIIA receptors.

AIM: To assess whether endothelin-1 (ET-1) induces the in vivo expression of inflammatory-related proteins, namely cyclooxygenase-2 (COX-2) and tissue factor, in the myocardium and circulating leukocytes of guinea-pigs. The involvement of platelets was also analyzed. METHODS: ET-1 (0.013 microg/min) was infused to male guinea-pigs for 45 min in the presence and absence of tirofiban, a nonpeptidic blocker of the glycoprotein IIb/IIIa receptor (GPIIb/IIIa). Tissue factor and COX-2 expression were determined by Western blot. RESULTS: No changes in mean arterial pressure and heart rate were detected. ET-1-infused guinea-pigs showed a marked increase in the number of platelets expressing activated GPIIb/IIIa receptors (0.8+/-0.03% vs. 6.5+/-0.2%; P<0.05). Tirofiban (10 microg/Kg bw/min) blunted ex vivo platelet aggregation in response to ADP, although only partially reduced COX-2 and tissue factor expression in both the myocardium and leukocytes of ET-1-infused guinea-pigs. The myocardium of platelet-depleted guinea-pigs also showed a reduced COX-2 expression after ET-1 infusion (57+/-3% reduction; P<0.05). In vitro studies demonstrated that platelets (10(7) and 10(9) platelets/well) enhanced ET-1 (10(-7) mol/l)-induced COX-2 expression in heart slices. CONCLUSION: ET-1 stimulated in vivo the expression of the pro-inflammatory proteins COX-2 and tissue factor in the myocardium and in leukocytes by a mechanism GPIIb/IIIa platelet receptors.

[Effect of HMG-CoA reductase inhibition on endothelial dysfunction-inducing protein in hypercholesterolemic rabbits]. / Efecto de la inhibición de la HMG-CoA reductasa sobre la proteína inductora de disfuncion endotelial en conejos hipercolesterolémicos.

INTRODUCTION AND OBJECTIVES: In our laboratory, we recently obtained evidence that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-unstranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and the level of eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction. METHODS AND RESULTS: Endothelium-dependent relaxation in response to acetylcholine was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with simvastatin (25 mg/kg body weight/day) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-KDa cytosolic protein and reduced stability of eNOS mRNA. Simvastatin treatment upregulated eNOS expression and reduced the interaction of cytosolic protein with the 3'-untranslated region of eNOS mRNA. CONCLUSIONS: These results demonstrate the presence of a 60-KDa protein that binds to eNOS mRNA and reduces eNOS expression in the vascular wall.

Efecto de la inhibición de la HMG-CoA reductasa sobre la proteína inductora de disfunción endotelial en conejos hipercolesterolémicos / Effect of HMG-CoA reductase inhibition on endothelial dysfunction-inducing protein in hypercholesterolemic rRabbits

Introducción y objetivos. Recientemente se ha demostrado en nuestro laboratorio que las células endoteliales en cultivo expresan proteínas citosólicas que forman complejos con el ARNm de la óxido nítrico sintasa endotelial (NOSe) en la región 3' que no codifica para proteína (3'-UTR). Esta unión fue asociada con la desestabilización del ARNm de dicha enzima. El objetivo de este estudio fue determinar la presencia de estas proteínas citosólicas y el nivel de expresión de la proteína NOSe en la pared vascular de conejos hipercolesterolémicos como un modelo in vivo de disfunción endotelial. Métodos y resultados. La relajación dependiente del endotelio a acetilcolina estuvo reducida en segmentos aórticos de conejos hipercolesterolémicos comparados con los conejos control. El tratamiento de los conejos hipercolesterolémicos con simvastatina (25 mg/kg peso/día) restauró la relajación dependiente del endotelio.La expresión de NOSe se encontró reducida en la pared vascular de los conejos hipercolesterolémicos, lo cual se acompañó de un aumento en la capacidad de unión de la proteína citosólica de 60 kDa y de una reducción en la estabilidad del ARNm de la NOSe. El tratamiento con simvastatina aumentó la expresión de NOSe y redujo la interacción de la proteína citosólica a la región 3'-UTR del ARNm de la NOSe. Conclusiones. Estos resultados demuestran una relación entre la presencia de la proteína de 60 kDa y la abundancia de NOSe en la pared vascular y la funcionalidad endotelial (AU)

Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: regulation by estrogen.

OBJECTIVES: (a) To identify the subtype of estrogen receptor (ER) expressed in neutrophils from premenopausal women and in neutrophils from men under different estrogen conditions and (b) to analyze the association between the modifications in the expression of ER subtypes and neuronal nitric oxide synthase (nNOS) expression induced by estrogen. METHODS: Neutrophils were isolated from pre-menopausal women during different stages of the menstrual cycle and from ten men for in vitro estrogen incubations. RESULTS: Neutrophils from premenopausal women expressed both ERalpha and ERbeta subtypes which were increased in the ovulatory phase of the menstrual cycle. Neutrophils derived from men also expressed ERalpha and ERbeta but only ERalpha expression was enhanced by in vitro incubation with 17beta-estradiol (10(-8) mol/l). In vitro incubation of neutrophils from women with 17beta-estradiol enhanced expression of both ER-alpha and ER-beta subtypes. nNOS protein was overexpressed in neutrophils from premenopausal women during the ovulatory phase. 17beta-Estradiol (10(-8) mol/l) also increased nNOS protein expression in neutrophils derived from men. Mithramycin A (10(-6) mol/l) and curcumin (10(-6) mol/l), prevented the upregulation of nNOS and ERalpha in neutrophils derived from men, suggesting the involvement of AP-1 and Sp-1 transcription factors. CONCLUSIONS: Although the in vivo levels of circulating estrogen concentrations seem to be associated with overexpression of both ERalpha and ERbeta in neutrophils from premenopausal women, which was further confirmed by the in vitro experiments with neutrophils from women, in vitro incubation of neutrophils from men with 17beta-estradiol only increased ERalpha protein expression which was associated with enhanced expression of nNOS protein.

Aspirin prevents Escherichia coli lipopolysaccharide- and Staphylococcus aureus-induced downregulation of endothelial nitric oxide synthase expression in guinea pig pericardial tissue.

The aim was to analyze whether pericardial tissue expresses endothelial NO synthase (eNOS) protein and to determine the presence of cytosolic proteins that bind to eNOS mRNA. The effect of aspirin on the above-mentioned parameters was also analyzed. eNOS protein was expressed in pericardial tissue from male guinea pigs. Escherichia coli lipopolysaccharide (LPS, 10 microgram/mL) and Staphylococcus aureus endotoxin (SA, 10 microgram/mL) reduced eNOS protein expression and shortened the half-life of the eNOS messenger. Under basal conditions, cytosolic extracts from pericardial samples bound to the 3'-untranslated region (3'-UTR) of eNOS mRNA, which was enhanced by LPS and SA. Proteinase K fully prevented the binding of cytosolic pericardial extracts to 3'-UTR of eNOS mRNA, suggesting the involvement of proteins that were further characterized as 60- and 51-kDa proteins. Aspirin (1 to 10 mmol/L) restored eNOS expression in either LPS- and SA-stimulated pericardial samples and reduced the binding activity of the pericardial cytosolic proteins to 3'-UTR of eNOS mRNA. Indomethacin also reduced the downregulation of eNOS by LPS and diminished the binding activity of the cytosolic proteins, although higher doses of indomethacin than of aspirin were needed to improve these parameters. In conclusion, eNOS protein is expressed in guinea pig pericardial tissue. LPS and SA stimulate the binding activity of pericardial cytosolic proteins to 3'-UTR of eNOS mRNA and reduce eNOS protein expression. High doses of aspirin and indomethacin protect eNOS protein expression and reduce the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting an inverse association between the presence of these cytosolic proteins and eNOS expression.

Reduction of the soluble cyclic GMP vasorelaxing system in the vascular wall of stroke-prone spontaneously hypertensive rats: effect of the alpha1 -receptor blocker doxazosin.

OBJECTIVE: The aim of the present study was to analyse the nitric oxide (NO)/cyclic GMP (cGMP) relaxing system in spontaneously hypertensive rats of the stroke-prone substrain (SHRSP). DESIGN: The study was performed in 20-week-old SHRSP rats. A group of normotensive Wistar-Kyoto (WKY) rats was used as control. RESULTS: The endothelium-dependent relaxation to acetylcholine was reduced in SHRSP rats (n = 15). No modifications in the expression of the endothelial nitric oxide synthase were found in the vascular wall of WKY rats (n = 15) and SHRSP rats. SHRSP rats demonstrated an impaired relaxing response to the NO-donor sodium nitroprusside that was accompanied by a reduction in the level of the main second messenger of NO, cyclic GMP. The expression of the soluble guanylate cyclase (sGC) beta1-subunit was markedly reduced in the vascular wall of SHRSP rats. In the experimental model of SHRSP, an increased concentration of catecholamines has been reported. Therefore, we evaluated the effect of an alpha1-receptor blocker, doxazosin, on the NO/cGMP system. Doxazosin [10 mg/kg body weight (bw) per day for 15 days, n = 15] reduced mean arterial pressure (MAP) in SHRSP rats. Treatment with doxazosin preserved the endothelium-independent relaxation response to sodium nitroprusside in aortic segments from SHRSP rats which was associated with an increased expression of the sGC beta1-subunit. A dose of doxazosin (1 mg/kg bw per day, n = 15) that did not modify MAP partially prevented sGC protein expression in the vascular wall. CONCLUSIONS: Independently of the endothelial NO-generating system, impaired vasorelaxation could also result from vascular smooth muscle cell layer dysfunction. Doxazosin treatment improved the endothelial-independent relaxation and preserved the cGMP generating system in the vascular wall of SHRSP rats.

Alteration of the soluble guanylate cyclase system in the vascular wall of lead-induced hypertension in rats.

Low-level lead exposure is a known cause of hypertension that has been associated with increased reactive oxygen species activity and endothelial-dependent vasorelaxation impairment. The effect of lead exposure on the vascular nitric oxide (NO)/cyclic guanocine monophosphate (cGMP) system was analyzed. Wistar rats were exposed to 5 ppm lead acetate in the drinking water during 30 d. Mean arterial BP increased significantly in the lead-treated rats. Relaxation to both acetylcholine and sodium nitroprusside (SNP) was reduced in lead-treated rats; however, the vascular wall of lead-administered rats showed an increased expression of endothelial NO synthase. The expression of both subunits (alpha(1) and beta(1)) of soluble guanylate cyclase (sGC) and the cGMP accumulated in the vascular wall were decreased in lead-treated rats. Cotreatment of lead with vitamin C (3 mmol/L) prevented the increase on mean arterial BP, improved the relaxation to both acetylcholine and sodium nitroprusside, and restored the normal expression of endothelial NO synthase and sGC proteins in the vascular wall. In conclusion, lead exposure altered both the endothelium-dependent and -independent relaxing response and induced a reduced expression of sGC in the vascular wall. These effects were abrogated with the antioxidant vitamin C, which suggests the involvement of reactive oxygen species in the regulation of the NO/cGMP relaxing system in the vascular wall of lead-treated rats.

Doxazosina y guanilato ciclasa soluble en un modelo de ratas hipertensas / Doxazosin and Soluble Guanylate Cyclase in a Rat Model of Hypertension

Introducción. Aunque existen diferentes estudios sobre la capacidad del endotelio de generar óxido nítrico en la disfunción endotelial asociada a la hipertensión, el sistema de la guanilato ciclasa soluble (GCs) ha sido menos estudiado. Objetivo. Analizar en ratas espontáneamente hipertensas que desarrollan accidentes cerebrovasculares (SHRSP) el nivel de expresión de la GCs en la pared vascular. También se estudió el efecto del tratamiento con doxazosina, antagonista 1-adrenérgico, sobre la expresión de la GCs en la pared vascular de estos animales. Métodos. Se utilizaron ratas SHRSP (edad, 20 semanas; n = 24). Un grupo de estas ratas fue tratado con doxazosina (10 mg/kg peso/día; n = 12) durante 2 semanas, y se comparó con ratas Wistar-Kyoto (WKY) normotensas (n = 12).Resultados. Segmentos aórticos aislados de ratas SHRSP presentaron una disminución de la respuesta vasodilatadora al nitroprusiato sódico. La respuesta al nitroprusiato sódico mejoró en las ratas SHRSP tratadas con doxazosina respecto de las SHRSP sin tratamiento. La expresión de la 1-GCs determinada por Western blot e inmunohistoquímica estaba disminuida en las ratas SHRSP respecto a las WKY. La administración de doxazosina aumentó la expresión de GCs, particularmente en la capa media cuando se comparara con ratas SHRSP no tratadas. Conclusiones. En las ratas SHRSP existe una disminución de la expresión de 1-GCs en la pared vascular y una reducción en la respuesta a nitroprusiato sódico que mejora tras la administración de doxazosina cuando se compara con SHRSP no tratadas. Estos resultados sugieren la importancia que también puede tener el sistema de la GCs en el tratamiento global de la disfunción endotelial (AU)

Expression of endothelial nitric oxide synthase in human peritoneal tissue: regulation by Escherichia coli lipopolysaccharide.

Changes in the expression of endothelial nitric oxide synthase (eNOS) in the peritoneum could be involved in the peritoneal dysfunction associated with peritoneal inflammation. Demonstrated recently in bovine endothelial cells was the existence of cytosolic proteins that bind to the 3'-untranslated region (3'-UTR) of eNOS mRNA and could be implicated in eNOS mRNA stabilization. The present work demonstrates that eNOS protein is expressed in human endothelial and mesothelial peritoneal cells. Escherichia coli lipopolysaccharide shortened the half-life of eNOS message, reducing eNOS protein expression in peritoneal mesothelial and endothelial cells. Moreover, under basal conditions, human peritoneal samples expressed cytosolic proteins that bind to the 3'-UTR of eNOS mRNA. The cytosolic proteins that directly bind to 3'-UTR were identified as a 60-kD protein. After incubation of human peritoneal samples with lipopolysaccharide, the binding activity of the cytosolic 60-kD protein increased in a time-dependent manner. Studies are now necessary to determine the involvement of this 60-kD protein in the regulation of eNOS expression in peritoneal cells and particularly its involvement in the peritoneal dysfunction associated with inflammatory reactions.

Efecto del losartán sobre la activación de plaquetas humanas por tromboxano A2 / Effect of losartan on human platelets activation by thromboxane A2

Introducción y objetivo. Estudios previos han demostrado que el losartán, antagonista de los receptores de tipo AT-1 de la angiotensina II (Ang II) podría bloquear al receptor del tromboxano A2 (TXA2) en la pared vascular.El objetivo del trabajo fue estudiar el efecto del losartán sobre la activación de plaquetas humanas. Materiales y métodos. Las plaquetas fueron obtenidas de 15 voluntarios sanos con edades comprendidas entre los 26 y 40 años. La activación plaquetaria fue medida por cambios en la transmisión de luz del plasma rico en plaquetas estimuladas por un análogo sintético del TXA2, el U46619 (5 × 10-6 mol/l).Resultados. El U46619 estimuló la agregación de las plaquetas, siendo significativamente inhibida por el losartán de manera dosis dependiente. Sólo dosis altas del EXP 3174, el metabolito hepático principal del losartán, consiguieron inhibir la activación plaquetaria inducida por el U46619. Captopril, inhibidor de la enzima convertidora de angiotensina, no fue efectivo en modificar la agregación plaquetaria inducida por el análogo del TXA2. A pesar de que las plaquetas expresan receptores de tipo AT-1 de la Ang II, la Ang II exógena no modificó la agregación plaquetaria inducida por U46619. La unión del U46619 a las plaquetas fue competitivamente inhibida por el losartán en forma dependiente de la dosis. Sin embargo, sólo dosis altas de EXP 3174 redujeron la unión del U46619. Captopril no modificó la unión del U46619 a las plaquetas. Conclusiones. Losartán disminuyó la agregación plaquetaria por un mecanismo dependiente de TXA2. El EXP 3174 demostró una menor potencia que losartán en reducir la activación plaquetaria por TXA2. El captopril y la Ang II exógena no tuvieron efecto sobre la activación de plaquetas humanas. Estos resultados sugieren que el losartán redujo la activación plaquetaria inducida por el TXA2 por un mecanismo independiente del bloqueo de los receptores de tipo AT-1 (AU)

Efecto del triflusal sobre la agregación y secreción de las plaquetas humanas: papel del óxido nítrico / Effect of Triflusal on Human Platelet Aggregation and Secretion: Role of Nitric Oxide

Introducción y objetivos. Recientes estudios in vitro realizados en nuestro laboratorio demostraron que el triflusal reduce la agregación plaquetaria mediante la estimulación de la producción de óxido nítrico (NO) por los neutrófilos. El objetivo de este trabajo fue evaluar si el tratamiento in vivo con triflusal también aumenta la capacidad de los neutrófilos de generar NO analizando el papel del NO liberado por los neutrófilos sobre la agregación y secreción plaquetaria. Métodos. El estudio se realizó en 12 voluntarios sanos de 32 ñ 6 años a los que se administró triflusal (600 mg/día) durante 5 días, extrayéndoles plaquetas y neutrófilos antes y después del tratamiento y midiéndoles su capacidad de producir NO, el porcentaje de agregación de sus plaquetas frente a ADP y la capacidad de liberar factor transformante del crecimiento (TGF- ). Resultados. Tras el tratamiento con triflusal se obtuvieron los siguientes resultados: a) aumento de la producción de NO en los neutrófilos; b) potenciación de la inhibición de la agregación plaquetaria en presencia de neutrófilos, efecto que se revertía al incubar los neutrófilos con un antagonista de L-arginina, L-NAME, y c) la presencia de neutrófilos redujo la liberación del TGF- por las plaquetas determinado como medida de secreción plaquetaria, por un mecanismo independiente del NO. Conclusiones. Nuestro estudio demuestra que el tratamiento con triflusal (600 mg/día/5 días) estimula la producción de NO por los neutrófilos. Tras el tratamiento con triflusal los neutrófilos inhiben la agregación y la secreción de las plaquetas. El efecto antiagregante plaquetario demostrado por los neutrófilos fue dependiente del NO, pero no así la inhibición de la desgranulación plaquetaria (AU)

Enfermedad de Alport y hematuria recidivante: estudio comparativo y revisión de la literatura / Alport disease and recurrent hematuria: comparative study and review of the literature

Se estudian 10 casos de nefropatías con patología de la membrana basal (M.B.), recibidas en la Fundación Jiménez Díaz. Seis corresponden a Enfermedad de Alport (EA), uno a Nefropatía Familiar Benigna (H.F.B.) y tres a Hematuria Recidivante (H.R.) no urológica. Se realiza una valoración clínico-evolutiva, y los hallazgos histológicos y ultraestructurales en ocho de ellos mediante Indices Morfológicos de actividad y cronicidad (valor númerico). Resultados: Encontramos engrosamiento predominante de la membrana basal en EA, excepto en uno de los casos que tuvo laminación extensa y poco compromiso de la función renal. La HFB mostró adelgazamiento extenso y uniforme (media de 213 nm., y espesor mínimo de 120 nm.). Las HR presentaron engrosamiento e irregularidades de la MB, ninguno presentó laminación y uno adelgazamiento y ruptura. Conclusiones: La relación encontrada con la función renal permite concluir que el Indice morfológico puede ser útil para la valoración de los pacientes con Nefropatías hereditarias, sobre todo, aquellas de naturaleza progresiva