Mantenimiento de niveles plasmáticos de levetiracetam en infusión paliativa subcutánea, continua y prolongada mediante infusores elastoméricos / Maintenance of plasma levels of levetiracetam in subcutaneous, continuous and prolonged palliative infusion by elastomeric infusors

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[Maintenance of plasma levels of levetiracetam in subcutaneous, continuous and prolonged palliative infusion by elastomeric infusors]. / Mantenimiento de niveles plasmáticos de levetiracetam en infusión paliativa subcutánea, continua y prolongada mediante infusores elastoméricos.

TITLE: Mantenimiento de niveles plasmáticos de levetiracetam en infusión paliativa subcutánea, continua y prolongada mediante infusores elastoméricos.

Eficacia y seguridad en la infusión subcutánea de oxicodona mediante infusor elastomérico de larga duración / Efficacy and safety of oxycodone subcutaneous infusion using a long-term elastomeric infusion device

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Estrogen receptors alpha and beta in non-target organs forhormone action: review of the literature

Estrogens are known to influence genetic expression by interfering in cell growth and differentiation throughdifferent mechanisms, both in organs associated with reproduction and in other areas. Recently, the numberof studies investigating these receptors in different tissues by means of the immunohistochemical methodhas been increasing. Another method that has also been used recently is investigation of the expression ofRNA-m at the specific receptors by means of PCR. The effects of estrogen have been analyzed in relationto a significant number of tissue types that are not associated with reproduction, for example bones and thecardiovascular, gastrointestinal, immunological and central nervous systems. Hence, the aim of the presentstudy was to review the literature on estrogen receptors in non-target organs for the action of this hormone,i.e. in organs that are not associated with reproduction.

Cuidados Paliativos en un caso de la enfermedad del «hombre de piedra» / No disponible

La fibrodisplasia osificante progresiva es una enfermedad muy poco frecuente del tejido conectivo caracterizada por formación heterotópica de hueso en el interior de tejidos blandos. Carece de tratamiento específico y se comporta como un proceso crónico, progresivo y altamente invalidante por producir anquilosis de las principales articulaciones del esqueleto axial y de los miembros, y en los estadios finales suele dar lugar a graves complicaciones cardiopulmonares por las deformidades que origina en la caja torácica. Presentamos el caso de una mujer afectada por esta enfermedad que fue tratada por nuestro equipo de soporte durante el ingreso hospitalario como ejemplo de una enfermedad rara subsidiaria de ser atendida, en estadios avanzados, mediante cuidados paliativos (AU)

Progressive ossifying fibrodysplasia is an uncommon connective tissue disease characterized by synthesis of heterotopic bone into the soft tissues. It has no specific treatment and develops as a chronic, progressive and very disabling condition that has many limitations because of anchylosis in limb and spine joints. Serious cardio-pulmonary complications occur in advanced stages secondary to deformities in the thoracic cavity. We report a case of a woman affected by this disease who was treated by our support care team during hospitalization as an example of a rare disease cared for in advanced stages according to a palliative care program (AU)

Otosclerose: resultados de estapedotomias / Otosclerosis: stapedotomy results

Introduçäo: Otospongiose ou otosclerose é uma moléstia heredo-degenerativa da cápsula labiríntica relativamente comum e que ocorre principalmente em mulheres entre 20 e 30 anos de idade. Nas últimas décadas a estapedotomia tem sido uma técnica preferida por muitos cirurgiöes para o tratamento da otosclerose. Assim, esse trabalho analisa os resultados de 59 estapedotomias realizadas no Hospital Paulista de Otorrinolaringologia nos últimos 7 anos. Forma de estudo: Clínico randomizado. Materiais e Métodos: Estudo retrospectivo de 59 pacientes com otosclerose, submetidos a estapedotomia por um mesmo cirurgiäo, e com seguimento clínico e audiométrico. Resultados: Melhora auditiva comprovada pelo fechamento do gap na audiometria em 53 pacientes (90 por cento). Complicaçöes ocorridas säo relacionadas por ordem decrescente de freqüência: deslocamento da prótese (7 por cento), alteraçöes no paladar (7 por cento), paralisia facial (3 por cento), vertigem (3 por cento), extrusäo total da prótese (1,5 por cento), tinnitus persistente (1,5 por cento), perfuraçäo da membrana timpânica (1,5 por cento). Conclusäo: A estapedotomia vem se mostrando uma boa opçäo terapêutica, já que, em geral, apresenta baixa morbidade e altas taxas de sucesso, proporcionando melhor qualidade de vida para os portadores de otosclerose

Regulation of endothelial nitric oxide synthase expression in the vascular wall and in mononuclear cells from hypercholesterolemic rabbits.

BACKGROUND: We recently obtained evidence demonstrating that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-untranslated 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 eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction. METHODS AND RESULTS: Endothelium-dependent relaxation to acetylcholine and the calcium ionophore A23187 was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with cerivastatin (0.1 mg. kg body wt(-1). d(-1)) 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. Cerivastatin treatment upregulated eNOS expression and reduced the interaction of the cytosolic protein with the 3'-untranslated region of eNOS mRNA. Mononuclear cells from hypercholesterolemic rabbits also showed a marked reduction of eNOS expression and eNOS mRNA stability and an increase in binding activity of the cytosolic protein, which were also prevented by cerivastatin treatment. CONCLUSIONS: These results demonstrate the presence of a 60-kDa protein that binds to eNOS mRNA and reductions in eNOS expression in both vascular wall and mononuclear cells that are prevented by cerivastatin.

Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor-alpha release by cultured smooth muscle cells.

BACKGROUND: Inflammatory related cardiovascular disease, i.e. cardiac allograft rejection, myocarditis, septic shock, are accompanied by cytokine production, which stimulates the expression of inducible nitric oxide (iNOS). MATERIALS AND METHODS: The aim of the present study was to examine whether anti-inflammatory doses of acetylsalicylic acid (aspirin) could regulate iNOS protein expression in bovine vascular smooth muscle cells (BVSMCs) in culture. RESULTS: Interleukin 1 beta (IL-1 beta, 0.03 U mL-1) induced nitric oxide release by BVSMCs. Aspirin inhibited nitric oxide release from IL-1 beta-stimulated BVSMCs in a dose-dependent manner. In addition, aspirin significantly inhibited iNOS protein expression in BVSMCs and reduced the translocation of the nuclear factor-kappa B (NF-kappa B). Furthermore, aspirin and the blockade of NO generation by BVSMCs reduced the production of tumour necrosis factor alpha (TNF-alpha) by these cells. CONCLUSION: High doses of aspirin inhibited iNOS protein expression in BVSMCs and decreased NF-kappa B mobilization. The inhibition of iNOS expression by aspirin was further associated with a reduced ability of BVSMCs to produce TNF-alpha. This study could provide new mechanisms of action for aspirin in the treatment of the inflammation-related cardiovascular diseases.

Expression of inducible nitric oxide synthase after endothelial denudation of the rat carotid artery: role of platelets.

There is functional evidence suggesting that endothelial denudation stimulates inducible nitric oxide synthase (iNOS) activity in the vascular wall. In vitro studies have shown that iNOS expression in smooth muscle cells is reduced by endothelial cells. In the present study we have analyzed the time course of iNOS protein expression in the arterial wall after in vivo deendothelialization. Endothelial denudation was performed in the left carotid artery of Wistar rats, and the right carotid artery was used as control. Whereas iNOS protein was weakly expressed 6, 24, and 48 hours after endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after vascular damage. Because platelet adhesion and aggregation occur early after endothelial damage, we studied the role of activated platelets in the negative modulation of iNOS protein expression during the first 2 days after endothelial denudation. Early after in vivo endothelial injury, platelet-depleted rats showed a marked iNOS protein expression in the vascular wall. Similar results were obtained by blocking the platelet glycoprotein (GP) IIb/IIIa. Although iNOS protein is present in the arterial wall several days after endothelial denudation, early after arterial wall injury iNOS protein is weakly expressed. Platelets play a crucial role in preventing iNOS protein expression early after endothelial damage, an effect that can be avoided with GP IIb/IIIa blockers. Although iNOS protein was weakly expressed in vivo in the rat carotid artery wall 6, 24, and 48 hours after balloon endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after arterial damage. iNOS expression could be increased early after endothelial injury by removing circulating platelets and by an antibody against the GP IIb/IIIa. In conclusion, platelets prevent iNOS protein expression early after endothelial balloon damage, an effect that can be avoided with GP IIb/IIIa blocking agents.

Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats.

Two NO synthase (NOS) isoforms have been described in vessels, an endothelial constitutive NOS (eNOS) and an inducible NOS (iNOS). The purpose of the present study was to examine the endothelium-dependent and endothelium-independent hypotensive response in aging rats, analyzing the ability of their vessels to produce NO. The studies were performed in 2 groups of euvolemic, conscious, male Wistar rats: aging rats (n=20, 18 months old) and young rats (n=20, 5 months old). The hypotensive responses to acetylcholine, bradykinin, and sodium nitroprusside were determined. Furthermore, the expression of the NOS isoforms by Western blot and the eNOS and iNOS activities, defined as Ca2+-dependent and Ca2+-independent conversion of [14C]L-arginine into [14C]L-citrulline, respectively, were also determined. In the aging rats, we found an impaired hypotensive response to acetylcholine and bradykinin (2 NO- and endothelium-dependent hypotensive agents) that was accompanied by a preserved hypotensive response to sodium nitroprusside. Aging rats also demonstrated an enhanced sensitivity response to the pressor effect of the L-arginine antagonist L-Nomega-nitro-L-arginine and a reduced vasoconstrictor response to angiotensin II. The inhibition of NO synthesis normalized the pressor effect of angiotensin II in the aging animals. Nitrite plus nitrate plasma levels were increased in aging rats. Furthermore, cGMP content was also higher in the aging vessels. In the aging aortas, the expression of both eNOS and iNOS isoforms was enhanced. However, in aging rats, the activity of the eNOS isoform was markedly reduced, a finding that was accompanied by the presence of iNOS activity. The vessel wall of aging rats showed an enhanced expression of eNOS and iNOS isoforms. However, eNOS activity was reduced in the aging animals. These findings could explain the impaired endothelium-dependent hypotensive response associated with aging.

Role of nitric oxide in autocrine control of growth and apoptosis of endothelial cells.

Nitric oxide (NO) is a growth inhibitor for diverse cellular types. In the present study, we have found that the inhibition of NO production in bovine endothelial cells by an L-arginine competitive antagonist induces DNA replication and promotes the transition from prereplicative to replicative phases of the endothelial cell cycle and an increase in c-myc and c-fos oncogene-encoded protein expression. The inhibition of NO generation had, however, a markedly different outcome depending on the state of confluence of the cells, i.e., proliferation was found in subconfluent cells, whereas apoptosis occurred in confluent cells. Moreover, Western blot analysis revealed differences in the constitutive NO synthase expression in proliferating compared with growth-arrested cells. In conclusion, these results disclose an alternative mechanism of endothelial cell apoptosis at the confluent state, which is related to NO inhibition. Moreover, the fact that the apoptotic phenomenon occurred in the presence of growth factors indicates the existence of apoptotic mechanisms that do not require growth factor deprivation.

Role of endothelium-related mechanisms in the pathophysiology of renal ischemia/reperfusion in normal rabbits.

The present study addressed the effect of interventions aimed to increase NO in the setting of acute renal ischemia/reperfusion (I/R) in uninephrectomized rabbits. In the 60-minute post-I/R period, L-arginine+superoxide (O2.-) dismutase (SOD) synergistically improved the renal functional (69.4% versus 10.4% of the pre-I/R glomerular filtration rate with or without L-arginine+SOD, respectively; p < .01) and histological parameters (82.9% decrease of medullary congestion in L-arginine+SOD, P < .01 versus vehicle) and blocked the I/R-dependent neutrophil accumulation (89.3% reduction). In spite of these results over the short term, a second set of experiments disclosed that the protection by L-arginine+SOD was no longer present at 24 and 48 hours (plasma creatinine in vehicle-treated versus L-arginine+SOD-treated animals [mg/100 mL]: 24 hours after I/R, 9.4 +/- 1.9 versus 8.07 +/- 0.65; 48 hours after I/R, 11.6 +/- 3.6 versus 9.7 +/- 0.9; P = NS in all the cases). Additional experiments were conducted using a milder 30-minute ischemic model, which showed no significant functional or histological protection by using L-arginine+SOD. In conclusion, our experiments disclosed the following: (1) the critical importance of the interaction between NO and O2.- in the acute protective effect of L-arginine (this effect not only improved renal function and histology but also reduced neutrophil accumulation) and (2) the discordance existing between the immediate protection afforded by L-arginine+SOD and the lack of protection observed at 24 and 48 hours. This finding suggests that a punctual intervention on the NO system at the time of I/R is not sufficient to reduce renal damage over the long term.

Endothelial cells inhibit NO generation by vascular smooth muscle cells. Role of transforming growth factor-beta.

Endothelial cell (EC)-released agents are active regulators of vascular smooth muscle cell (VSMC) functions. The first aim of the present work was to analyze the effect of ECs on interleukin-1 beta (IL-1 beta)-induced NO production by SMCs. Bovine aortic ECs (BAECs) and BVSMCs in culture were used for the study. IL-1 beta (0.03 U/L) stimulated nitrite production by BVSMCs. This increase was smaller in the presence of BAECs. This effect was accompanied by reduced expression of inducible NO synthase (iNOS) in BVSMCs coincubated with BAECs, as analyzed by Western blot analysis. The reduction in iNOS protein expression was partially reversed by a polyclonal antibody against transforming growth factor-beta (TGF-beta). Furthermore, we examined the cytotoxic effect of the NO released from BVSMCs on both BAECs and the BVSMCs themselves. Incubation of BAECs with IL-1 beta-prestimulated BVSMCs induced EC toxicity, which was partially inhibited by an inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester, or an inhibitor of iNOS expression, dexamethasone. No cytotoxic effect of IL-1 beta on BVSMCs themselves was detected. ECs modulate iNOS expression in SMCs by mechanisms that include a TGF-beta-dependent pathway. The NO released from SMCs exerts cytotoxic effects on the adjacent endothelium without altering the viability of the SMCs.

Role of endothelin in the pathophysiology of renal ischemia-reperfusion in normal rabbits.

The present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/ reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/ reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.

Aspirin-stimulated nitric oxide production by neutrophils after acute myocardial ischemia in rabbits.

BACKGROUND: In recent studies, it has been hypothesized that the protective anti-ischemic effects of aspirin outweigh the effects of inhibition of platelet thromboxane A2 synthesis. Recently, we have found that the antiaggregating effects of aspirin significantly affect nitric oxide (NO) generation by neutrophils. METHODS AND RESULTS: The present study used circulating neutrophils from myocardial ischemic rabbits to assess the effect of aspirin on the circulating neutrophil-derived NO production and, subsequently, on the modulation of platelet activation. Neutrophils were obtained after 60 minutes of coronary artery occlusion followed by 60 minutes of reperfusion. Sham-operated animals were used as controls. The results demonstrated that aspirin stimulated the production of NO by neutrophils obtained from both sham-operated rabbits and rabbits with myocardial ischemia. However, neutrophils isolated from animals with myocardial ischemia showed an enhanced ability to generate NO in the presence of aspirin. As a functional in vitro marker, we observed that neutrophils had a NO-dependent, platelet-antiactivating effect in the presence of aspirin. In the absence of aspirin, ischemic neutrophils did not modify platelet activation, even though they produced increased amounts of NO. An inhibitory role of superoxide anion on the neutrophil-related antiplatelet effect was suggested because superoxide dismutase induced significant platelet inhibition by myocardial ischemic neutrophils in the absence of aspirin. CONCLUSIONS: Our results show that myocardial ischemia/reperfusion stimulates production of NO by circulating neutrophils, an effect that was enhanced in the presence of aspirin. These results suggest a novel interpretation of the protective effect of aspirin on myocardial ischemia damage.

Effects of aspirin on platelet-neutrophil interactions. Role of nitric oxide and endothelin-1.

BACKGROUND: In recent studies, the hypothesis has been raised that the mechanisms by which aspirin acts as a protective anti-ischemic agent exceed the inhibition of platelet thromboxane A2 synthesis. Recently, new data have been obtained disclosing a platelet-antiaggregating effect by neutrophils, which occurs through a nitric oxide (NO)/cGMP-dependent pathway. METHODS AND RESULTS: The present study, using platelets and neutrophils from normal subjects, was undertaken to assess the putative effect of aspirin on the neutrophil-mediated, platelet-inactivating effect. Aspirin facilitated the inhibitory effect of neutrophils on platelet activation by thrombin, ADP, or epinephrine. This effect was equally evident in vitro and in blood samples of normal individuals taking aspirin. A significant stimulation of NO-mediated mechanisms in the presence of aspirin was disclosed by different methods, as follows: (1) the increased metabolism of arginine to citrulline, (2) the increase of cGMP in the platelet/neutrophil system, and (3) the inhibitory action of the L-arginine (L-Arg)-competitive analogue L-NMMA, which was reversed by L-Arg. The effect of aspirin appeared to be related to cyclooxygenase inhibition, since it was reproduced by using indomethacin. The vasoconstricting peptide endothelin-1 (ET-1) reversed the effect of aspirin through the endogenous production of platelet-activating factor (PAF) by neutrophils, as judged by the marked inhibitory effect of the PAF antagonist BN-52021. CONCLUSIONS: Our results show that a significant part of the effect of aspirin on platelet activation involves a neutrophil-mediated, NO/cGMP-dependent mechanism. The presence of ET-1 counterbalances these effects of neutrophils on platelet activation, therefore acting as an indirect proactivating agent. These results add new elements for interpreting the effects of aspirin on the interactions between blood cells, with special reference to high endothelin states (for example, ischemia/reperfusion processes).

Effects of nitric oxide on red blood cells: changes in erythrocyte resistance to hypotonic hemolysis and potassium efflux by experimental maneuvers that decrease nitric oxide.

To determine the role of nitric oxide (NO)-dependent mechanisms on erythrocyte properties, we exposed red cells to L-arginine competitive analogues, 8Br-cyclic guanosine monophosphate (8Br-cGMP) and neutrophil-eliminating filters. These treatments significantly decreased hypotonic hemolysis, increased potassium efflux and caused a spiculate change in erythrocyte morphology. These effects were related to a decrease of NO caused by the three types of treatments.

Mechanisms of renal effects of different agents stimulating production of cGMP.

The effect of agents stimulating the production of guanosine 3',5'-cyclic monophosphate (cGMP) by different mechanisms was compared in conscious unrestrained Wistar rats by administration of infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and atrial natriuretic peptide (ANP). ACh (10 micrograms.kg-1.min-1, n = 8), SNP (200 micrograms.kg-1.min-1, n = 8), and ANP (0.5 micrograms.kg-1.min-1, n = 7) induced natriuresis (urinary Na gradient: 399, 499, and 504 microeq/h, respectively; P less than 0.001 with respect to baseline) and diuresis (urine volume gradient: 0.87, 0.82, and 0.92 ml/h, respectively; P less than 0.001). Urinary cGMP increased (P less than 0.001) with the three agents (delta pmol cGMP/min: ACh 22.3, SNP 42.5, and ANP 48.4); in addition, a parallel increase in renal cGMP content was observed with the three agents (ACh 1.6, SNP 2.8, and ANP 3.5 times with respect to controls; P less than 0.05). Mean arterial pressure did not change with the aforementioned dose of ANP but decreased by 10 and 40% with ACh and SNP, respectively. Glomerular filtration rate increased by a similar magnitude with the three compounds. The competitive inhibitor of L-arginine, N omega-nitro-L-arginine (L-NNA), significantly decreased the diuretic, natriuretic, and hypotensive effects of ACh without affecting the actions of SNP and ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects and mesangial cell contraction induced by endothelin are mediated by PAF.

The recently discovered vasoactive peptide endothelin and platelet activating factor (PAF) share similar renal effects. The purpose of the present series of experiments has been to analyze the functional relations between the effect of endothelin on renal function and glomerular and mesangial cell contraction and the production and actions of PAF in kidney. Endothelin 1 nmol/kg body wt induced a transient decrease of glomerular filtration rate (from 1.99 +/- 0.17 to 0.56 +/- 0.18 ml/min) and renal blood flow (from 10.8 +/- 1.3 to 2.7 +/- 0.3 ml/min). Endothelin also induced a marked reduction of planar cell surface area of cultured mesangial cells (30 +/- 5%) and of cross sectional area of isolated glomeruli (from 1.51 +/- 0.02 to 1.31 +/- 0.02 m2 x 10(-8]. BN-52021 or WEB-2170, two potent specific inhibitors of PAF receptor binding, blocked the effects of endothelin on renal function and on the contraction of isolated glomeruli and mesangial cells. In addition, endothelin induced a significant increase in the production of PAF by isolated glomeruli (Basal, 81 +/- 10 pg/mg protein; endothelin, 10(-7) M, 140 +/- 18 pg/mg protein). Endothelin also stimulated the incorporation of [3H]acetate into PAF, both in glomeruli (264.27 +/- 27.7%) and mesangial cells (251 +/- 41%). These effects were blocked by EGTA and by verapamil. Our results suggest that PAF may be a mediator of the effects of endothelin on renal function and glomerular and mesangial cell contraction.