Angiotensin-(1-7), a protective peptide against vascular aging.

Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound aging alterations make arteries more prone to vascular disease, including hypertension, atherosclerosis and other arterial complications that impact the organism beyond the cardiovascular system and accelerate frailty. For these reasons, preventing or delaying the hallmarks of vascular aging is nowadays a major health goal, especially in our aged societies. In this context, angiotensin(Ang)-(1-7), a major player of the protective branch of the renin-angiotensin system, has gained relevance over recent years as growing knowledge on its anti-aging properties is being unveiled. Here, we briefly review the main actions of Ang-(1-7) against vascular aging. These include protection against vascular cell senescence, anti-inflammatory and antioxidant effects together with the induction of cytoprotective systems. Ang-(1-7) further ameliorates endothelial dysfunction, a hallmark of vascular aging and disease, attenuates fibrosis and calcification and promotes protective angiogenesis and repair. Although further research is needed to better understand the anti-aging properties of Ang-(1-7) on the vasculature, this heptapeptide arises as a promising pharmacological tool for preventing vascular aging and frailty.

Resultados de aplicar durante 13 años el protocolo de cribado universal de la hipoacusia en recién nacidos y estudio de los casos que no superan el cribado / Results of applying for 13 years the universal newborn hearing screening protocol and study of cases that do not pass the screening

Introducción: La detección precoz de la hipoacusia permite realizar un tratamiento temprano de los pacientes mejorando significativamente su pronóstico. Con este objetivo se implantó en la Comunidad Valencia el programa de cribado universal de la hipoacusia neonatal. Material y métodos: Se realizó un estudio de los resultados de dicho cribado desde su implantación en enero de 2002 hasta diciembre de 2014, es decir, durante 13 años consecutivos. Posteriormente se revisaron todos los casos que no superaron el cribado. Resultados: La cobertura del cribado alcanzó en pocos años a prácticamente el 100% de la población, con un total de recién nacidos cribados de 14.339. La tasa global de derivación a confirmación fue del 1%, y hubo un 0,7% de pérdidas. Se diagnosticaron 32 casos de hipoacusia neurosensorial (2,23/1.000 recién nacidos). Se estudiaron los casos que no superaron el cribado auditivo, y se halló una asociación entre diferentes variables, como los antecedentes familiares y la edad gestacional, con la presencia de hipoacusia neurosensorial bilateral. Conclusiones: El programa de cribado de la hipoacusia neonatal requiere unos años para su total universalización y cumplir de forma fiable las recomendaciones de la Comisión para la Detección Precoz de la Hipoacusia. Tras estudiar los casos que no superaron el cribado, se propone la edad gestacional como factor de riesgo para el desarrollo de hipoacusia. Asimismo, se considera que los neonatos con malformaciones craneofaciales se beneficiarían de ser remitidos directamente a una prueba de confirmación, así como de la realización de pruebas de imagen, por la alta probabilidad de presentar una patología malformativa asociada en el oído medio. Por otro lado, este ensayo permite recomendar la realización de un estudio cardiológico a los recién nacidos con diagnóstico de hipoacusia neurosensorial bilateral

Introduction: Early detection of hearing loss allows early treatment of these patients by significantly improving their prognosis. With this aim, the universal screening program for neonatal hearing loss was implemented in the Comunidad Valenciana. Material and methods: The results of this screening are studied, from its implementation in January 2002 to December 2014 (13 consecutive years). Subsequently, all the cases that did not pass the screening were reviewed. Results: The coverage of the screening reaches in a few years to practically 100% of the population, with 14339 of newborns being screened. The overall rate of referral to confirmation was 1% and there was 0.7% of losses. Thirty-two cases of neurosensory hearing loss were diagnosed (2.23/1000 newborns). We studied those cases that did not pass the auditory screening, finding an association between different variables such as family history of deafness and gestational age with the presence of bilateral sensorineural hearing loss. Conclusions: The neonatal hearing loss screening program requires a few years to be fully universalized and can reliably fulfill the recommendations of Comisión para la Detección Precoz de la Hipoacusia. After studying those cases that did not exceed the screening, gestational age is proposed as a risk factor for the development of hearing loss. Neonates with craniofacial malformations would also benefit from being referred directly to confirmatory test, as well as from the imaging test, due to the high probability of associated malformative pathology in the middle ear. On the other hand, this study allows the recommendation of a cardiological study to the newborns with diagnosis of bilateral sensorineural hearing loss

[Cardiovascular risk study in patients with renin-angiotensin system blockade by means of the proteone of circulating extracellular vesicles]. / Estudio del riesgo cardiovascular en pacientes con bloqueo del sistema renina-angiotensina a través del proteoma de las vesículas extracelulares circulantes.

INTRODUCTION: Extracellular vesicles (EVs) are released to the bloodstream by certain cell types due to transport, activation and cell death processes. Blood count of EVs from platelet and endothelial origin has been proved to be a cardiovascular risk biomarker. Thus, EVs proteome might reflect the underlying cellular processes in hypertensive patients with albuminuria. MATERIAL AND METHODS: Protein content of circulating EVs was analyzed by liquid chromatography coupled to mass spectrometry. EVs were isolated by an ultracentrifugation protocol optimized in order to avoid contamination by blood plasma proteins. Purity of the isolated fraction was verified by electronic and confocal microscopy, and by flow cytometry. RESULTS: We hereby show a method to isolate circulating EVs from hypertensive patients with/without albuminuria with high yield and purity. Besides, we provide a reference proteome of the EVs of these patients, composed of 2,463 proteins, and prove that the proteins carried by these vesicles are associated with crucial processes involved in the inherent cardiovascular risk. CONCLUSION: The proteome of circulating EVs is an interesting source of indicators in the evaluation of cardiovascular risk in hypertensive patients with renin-angiotensin system blockage.

Proteomic Biomarkers of Atherosclerosis.

SUMMARY: Biomarkers provide a powerful approach to understanding the spectrum of cardiovascular diseases. They have application in screening, diagnostic, prognostication, prediction of recurrences and monitoring of therapy. The "omics" tool are becoming very useful in the development of new biomarkers in cardiovascular diseases. Among them, proteomics is especially fitted to look for new proteins in health and disease and is playing a significant role in the development of new diagnostic tools in cardiovascular diagnosis and prognosis. This review provides an overview of progress in applying proteomics to atherosclerosis. First, we describe novel proteins identified analysing atherosclerotic plaques directly. Careful analysis of proteins within the atherosclerotic vascular tissue can provide a repertoire of proteins involved in vascular remodelling and atherogenesis. Second, we discuss recent data concerning proteins secreted by atherosclerotic plaques. The definition of the atheroma plaque secretome resides in that proteins secreted by arteries can be very good candidates of novel biomarkers. Finally we describe proteins that have been differentially expressed (versus controls) by individual cells which constitute atheroma plaques (endothelial cells, vascular smooth muscle cells, macrophages and foam cells) as well as by circulating cells (monocytes, platelets) or novel biomarkers present in plasma.

Gender differences in the effect of aspirin on retinal ischemia, prostanoid synthesis and nitric oxide production in experimental type 1-like diabetes.

BACKGROUND: The protective effect of acetylsalicylic acid (aspirin) against cardiovascular events is known to be weaker in women than in men. The present study was designed to test whether this effect of aspirin differed between sexes in an experimental model of diabetes with retinal ischemia. METHODS: We compared nondiabetic rats and rats after 1, 2 and 3 months of diabetes that were given 2 mg/kg/day p.o. of aspirin from the first day of diabetes. The variables recorded were platelet aggregation, production of thromboxane B(2) (TxB(2)), 6-keto-prostaglandin F(1alpha) and aortic nitric oxide, and the percentage of the retinal surface occupied by horseradish peroxidase (HRP)-permeable vessels. RESULTS: In female rats made diabetic, TxB(2) synthesis was more markedly reduced, and the percentage of HRP-permeable retinal vessels was less markedly reduced, than in their male counterparts. The response to aspirin treatment was weaker in female than in male diabetic rats in terms of inhibition of TxB(2) synthesis, increased nitric oxide production, and prevention of the increase in the percentage of retinal surface covered by HRP-permeable vessels. CONCLUSION: Aspirin was less effective in preventing retinal ischemia in experimental diabetes in female than in male rats.

Antioxidant and antiplatelet effects of the alpha-tocopherol-aspirin combination in type 1-like diabetic rats.

We analyze the effect of the combination of acetylsalicylic acid (2 mg/kg/day p.o.) and alpha-tocopherol (25 mg/kg/day p.o.) in a type-1-like experimental model of diabetes mellitus on platelet factors, endothelial antithrombotic factors and tissue oxidative stress. In diabetic rats, the combination of drugs had a greater inhibitory effect on platelet aggregation than in untreated control animals with diabetes (88.87%). The combination of drugs had little effect on the inhibition of thromboxane production (-90.81%) in comparison to acetylsalicylic acid alone (-84.66%), potentiated prostacyclin production (+162%) in comparison to alpha-tocopherol alone (+30.55%), and potentiated nitric oxide production (+241%) in comparison to either drug alone (acetylsalicylic acid +125%, alpha-tocopherol +142%). The combination of the two drugs improved the thromboxane/prostacyclin balance (0.145+/-0.009) in comparison to untreated diabetic animals (4.221+/-0.264) and in untreated healthy animals (0.651+/-0.045). It did not potentiate the antioxidant effect of either drug alone, but did increase tissue concentrations of reduced glutathione, especially in vascular tissue (+90.09% in comparison to untreated animals). In conclusion, in the experimental model of diabetes tested here, the combination of acetylsalicylic acid and alpha-tocopherol led to beneficial changes that can help protect tissues from thrombotic and ischemic phenomena.

Effects of hypoxia reoxygenation in brain slices from rats with type 1-like diabetes mellitus.

BACKGROUND: The aim of this study was to determine whether the brain tissue of type 1 diabetic animals is more susceptible to damage by hypoxia reoxygenation than healthy animals. METHODS: This study used rats with diabetes of 1, 2 and 3 months (N = 15 rats/group). Brain slices were subjected to hypoxia and reoxygenation for 180 min in vitro. We measured oxidative stress (lipid peroxidation, glutathione concentration and enzyme activities related to glutathione), concentration of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) pathway (nitrite + nitrate, activities of constitutive (cNOS) and inducible (iNOS) nitric oxide synthase). As a parameter of cell death we measured the efflux of lactate dehydrogenase (LDH). RESULTS: After reoxygenation LDH activity increased in comparison to nondiabetic animals by 40, 40.6 and 68.9% in animals with diabetes of 1, 2 and 3 months duration, respectively. These changes were accompanied by greater increases in lipid peroxides (25.4, 93.7 and 92.8%). PGE(2) accumulated in significantly larger amounts in diabetic animals (62.5, 85.5 and 114%), and nitrite + nitrate accumulation was significantly greater in rats with diabetes of 2 (40.2%) and 3 months duration (24.0%). iNOS activity increased significantly in all the groups of diabetic animals, with the largest increases in rats with diabetes of 2 (18.6%) and 3 months duration (21.1%). CONCLUSIONS: The biochemical pathways involved in oxidative stress and neuronal death are more sensitive to hypoxia reoxygenation in type 1-like diabetic, as compared to normal, rats.

Effects of aspirin plus alpha-tocopherol on brain slices damage after hypoxia-reoxygenation in rats with type 1-like diabetes mellitus.

Diabetes mellitus is a risk factor for cerebrovascular ischemic disease. Aspirin (acetylsalicylic acid) is the most widely used drug for the secondary prevention of thrombotic phenomena. It has been also recently demonstrated that alpha-tocopherol influenced in vitro the antiplatelet effect of aspirin. The aim of the present study is to evaluate the effects aspirin plus alpha-tocopherol on cerebral oxidative stress, prostaglandin production and the nitric oxide pathway in a model of hypoxia-reoxygenation in rat brain slices. Our results show an imbalance in brain oxidative status (reflected mainly as the increase in lipid peroxides) as a result of diabetes itself rather than a failure of the glutathione-based antioxidant system. Moreover, our results also show a higher concentration of prostaglandins in the brain of diabetic animals and a higher nitric oxide concentration, mainly through a high iNOS activity. After 180 min of post-hypoxia reoxygenation, LDH activity was 40.6% higher in animals with diabetes, in comparison to non-diabetic animals. The increase of the LDH efflux observed in non-treated rats was reduced by 31.2% with aspirin, by 34.7% with alpha-tocopherol and by 69.8% with the association aspirin-alpha-tocopherol. The accumulation of prostaglandin E2 observed in diabetic non-treated rats was reduced statistically after the treatment with aspirin (34.2% inhibition), alpha-tocopherol (19.3% inhibition) or the association aspirin-alpha-tocopherol (54.4% inhibition). Nitric oxide production after 180 min reoxygenation was significantly reduced in aspirin (36.4%), alpha-tocopherol (22.7%) and aspirin-alpha-tocopherol (77.8%) treated rats with respect to diabetic non-treated animals; this was related mainly with a reduction in iNOS activity. The association between aspirin and alpha tocopherol could protects against brain ischemic-reperfusion damage with a better profile than aspirin alone.

Influence of vitamin E on the antiplatelet effect of acetylsalicylic acid in human blood.

We analysed the in vitro interaction between acetylsalicylic acid and vitamin E on the principal antiplatelet sites of action of acetylsalicylic acid, i.e., platelet aggregation, prostanoid production in platelets and leukocytes, and nitric oxide synthesis. Aggregation was measured in whole blood and in platelet-rich plasma (PRP) with ADP, collagen or arachidonic acid as platelet inducers, and we measured the production of thromboxane B2, prostacyclin and nitric oxide. Vitamin E potentiated the antiplatelet effect of acetylsalicylic acid in both whole blood and PRP. In PRP induced with collagen the IC50 for acetylsalicylic acid alone was 339+/-11.26, and that of acetylsalicylic acid+vitamin E was 0.89+/-0.09 (P<0.05). Vitamin E did not enhance inhibition of platelet thromboxane production by acetylsalicylic acid. Vitamin E spared or even increased prostacyclin levels, and acetylsalicylic acid+vitamin E diminished the inhibition of prostacyclin synthesis by acetylsalicylic acid (IC50 acetylsalicylic acid alone=1.81+/-0.15 microM; IC50 acetylsalicylic acid+vitamin E= 12.92+/-1.10 microM, P<0.05). Vitamin E increased the effect of acetylsalicylic acid on neutrophil nitric oxide production 42-fold (P<0.05). We conclude that vitamin E potentiates the antiplatelet effect of acetylsalicylic acid in vitro, and thus merits further research in ex vivo studies.

Protective effect of triflusal and its main metabolite HTB in an in vitro model of anoxia-reoxygenation in rat brain slices: comparison with acetylsalicylic and salicylic acids.

Triflusal is a fluorinated derivative of acetylsalicylic acid (ASA) with demonstrated antithrombotic activity. Recently, evidence for a neuroprotective effect has been obtained. The aim of this study was to compare the neuroprotective effects of the main metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid, HTB) and the ASA metabolite salicylic acid (SA) in an in vitro model of anoxia-reoxygenation in rat brain slices. Rat brain slices (n=10 per group) were subjected to a period of anoxia followed by 180 min reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and LDH efflux, a biochemical marker of cell death. Various concentrations (10, 100 and 1,000 microM) of triflusal, HTB, ASA or SA were tested. Triflusal at 10, 100 and 1,000 microM decreased LDH efflux in rat brain slices after anoxia/reoxygenation by 24%, 35% and 49% respectively. This effect was proportionately greater than that of ASA (0%, 13% and 32%). The results with HTB were similar to those with triflusal, whereas SA showed a greater protective effect than ASA (13%, 33% and 35%). The antioxidant effects of HTB and SA on the biochemical mechanisms of cell damage studied here were also greater than the effects of triflusal and ASA, a finding attributable mainly to the decrease in lipid peroxidation and to the ability of HTB to also increase glutathione levels. The triflusal metabolite reduced inducible NO synthase activity by 18%, 21% and 30%, whereas SA inhibited this activity by 9%, 17% and 23%. Triflusal and HTB led to greater increases in NO synthase than ASA or AS. In conclusion, the metabolite HTB plays an important role in the neuroprotective effect of triflusal, at least in the experimental model of anoxia-reoxygenation tested here.

Relación del efecto analgésico de fentanilo agudo con la regulación a la alta de los receptores 5-HT1A cerebrales en la rata / Relationship between the analgesic effect of acute fentanyl and upregulation of brain 5-HT1A receptors in the rat

Los agonistas 5-HT1A presentan efecto analgésico. El efecto analgésico de los agonistas µ puede ser bloqueado por antagonistas selectivos 5-HT1A. Para determinar el mecanismo de producción del sinergismo observado entre los receptores µ y serotoninérgico 5-HT1A en relación con su efecto antinociceptivo, determinamos el efecto analgésico de fentanilo tras estímulo nociceptivo de tipo térmico y mecánico en la rata relacionándolo con la afinidad y la densidad máxima de los receptores 5-HT1A de trece áreas cerebrales mediante técnicas de autorradiografía. Fentanilo presentó un efecto analgésico dosis y tiempo dependiente ante los dos estímulos nociceptivos. Paralelamente a la aparición del efecto analgésico, fentanilo originó una regulación a la alta de los receptores 5-HT1A al incrementar de forma dosis-dependiente su densidad sin modificar su afinidad. La dosis mayor de fentanilo (12,8 µg.kg-1) originó un incremento de la densidad de los receptores 5-HT1A estadísticamente significativo y que se correlacionó de forma positiva con su efecto analgésico en las áreas terminales corticales fronto-parietal externa (+64 por ciento), interna (+69 por ciento) y piriforme (+113 por ciento), las regiones del hipocampo CA1 (+111 por ciento) y DGm (+60 por ciento), los núcleos amigdalinos PMCo (+101 por ciento) y AHiAL (+91 por ciento) y el hipotálamo (+127 por ciento). El efecto analgésico de fentanilo en tratamiento agudo se explicaría, al menos, por dos mecanismos. Su capacidad de estimular la neurotransmisión opiácea actuando directamente sobre los receptores opiáceos µ. Y porque, al incrementar los niveles de 5-HT a nivel central y al regular a la alta los receptores 5-HT1A de zonas cerebrales terminales, se facilitaría la estimulación de estos receptores. Dado que los receptores 5-HT1A postsinápticos actúan como heteroreceptores de efecto inhibidor sobre neuronas no serotoninérgicas originando una hiperpolarización neuronal, fentanilo, al facilitar el estímulo de estos receptores originaría una inhibición de la actividad neuronal en todas estas áreas terminales impidiendo la transmisión del estímulo nociceptivo. Esto explicaría la disminución del efecto analgésico de los agonistas opiáceos µ que originan los antagonistas selectivos 5-HT1A y el mayor efecto analgésico observado al coadministrar agonistas µ y fármacos capaces de incrementar los niveles de 5-HT como los ISRS. Se necesitan estudios posteriores que determinen con exactitud el mecanismo por el que el estímulo de los receptores µ origina la regulación a la alta de los receptores 5-HT1A postsinápticos y el papel de cada una de las áreas cerebrales en la percepción del estímulo nociceptivo (AU)

Effects of triflusal on oxidative stress, prostaglandin production and nitric oxide pathway in a model of anoxia-reoxygenation in rat brain slices.

Acetylsalicylic acid (ASA) is the most widely used drug in the prevention of ischemic vascular accidents, mainly because of its antithrombotic effect. Recently, evidence of a neuroprotective effect has appeared. The aim of this study was to evaluate the neuroprotective effect of triflusal, a fluorinated derivative of ASA, in a model of anoxia-reoxygenation in rat brain slices. Rats (n=10 per group) were treated for 7 days with 1, 10 or 50 mg/kg/day p.o. of triflusal or ASA or solvent (control group), then brain slices were obtained and subjected to a period of anoxia followed by 180 min of reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and cell death (lactate dehydrogenase (LDH) efflux). Triflusal decreased cell death in rat brain slices subjected to reoxygenation after anoxia by 21%, 42% and 47% with 1, 10 and 50 mg/kg/day, respectively. This effect was proportionately greater than the effect of ASA (0%, 25% and 24%). The antioxidant effects of triflusal on the biochemical mechanisms of cell damage studied here were also greater than the effects of ASA: lipid peroxidation was reduced by 29%, 35% and 36% with triflusal, and 0%, 19% and 29% with ASA. Inducible NO synthase activity was reduced by 25%, 27% and 30% with triflusal, and 0%, 25% and 24% with ASA. Triflusal can be considered an alternative to ASA as a neuroprotective agent, at least in the experimental model of anoxia-reoxygenation used in the present study.

Antioxidant effects of a single dose of acetylsalicylic acid and salicylic acid in rat brain slices subjected to oxygen-glucose deprivation in relation with its antiplatelet effect.

The aim of the present study was to analyze the relative participation of the antiplatelet and the antioxidant effects of acetylsalicylic acid (ASA) and salicylic acid (SA) after a single dose (1 or 10 mg/kg i.p.) in an in vitro model of anoxia in slices of rat brain. After 20 min of drug administration, blood and brain were obtained (n=6 rats per group). We measured: lipid peroxidation, glutathione levels and lactate dehydrogenase efflux (LDH), ASA and SA concentrations and platelet aggregation in whole blood. An increase in lipid peroxidation (80%) and in LDH efflux (520%) and a decrease in glutathione levels (35%) were observed after 120 min anoxia in saline-treated rats. SA reduced this oxidative stress and LDH efflux, but it did not modify platelet aggregation. ASA strongly inhibited platelet aggregation but exerted a poor antioxidant effect. ASA was not detectable in brain tissue. We conclude that repeated doses of ASA are necessary to obtain a tissular antioxidant effect, probably when liver generates enough SA.

Antioxidant effect of acetylsalicylic and salicylic acid in rat brain slices subjected to hypoxia.

Acetylsalicylic acid (ASA) reduces the incidence of ischemic stroke mainly through its antithrombotic action; however, it also has a direct neuroprotective effect. The present study was designed to evaluate the effect of ASA on oxidative stress and the activity of nitric oxide synthase (NOS) in an in vitro model of hypoxia in rat brain slices. Rat brain slices were perfused with nitrogen (hypoxia) for a maximum of 120 min, after which we measured lipid peroxidation, glutathione levels, glutathione-related enzyme activities, and constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) activities. In brain tissue subjected to hypoxia, ASA reduced oxidative stress and iNOS activity (all increased by hypoxia), but only when used at higher concentrations. The effects of salicylic acid (SA) were similar but more intense than were those of ASA. After oral administration, the effect of SA was much greater than that of ASA, and the decrease in cell death with SA was seen much more clearly. In view of the greater effect of SA compared to ASA on changes in oxidative stress parameters in a model of hypoxia, and higher brain concentrations of SA when it is administered alone than when ASA is given (undetectable levels), we conclude that SA plays an important role in the cytoprotective effect in brain tissue after ASA administration.

Female rats show an increased sensibility to the forced swim test depressive-like stimulus in the hippocampus and frontal cortex 5-HT1A receptors.

Affective disorders are more common in women. The forced swim test acts like a depressive stimulus. Hippocampus and frontal cortex 5-HT1A receptors of female and male Wistar rats subjected to the forced swim test were compared with a sham group. The forced swim test diminishes (P<0.05) the hippocampus 3H-8OH-DPAT bound in the female rats (184+/-16 fmol/mg protein) with respect to the male rats (309+/-41 fmol/mg protein) and to the female sham rats (255+/-20 fmol/mg protein). The forced swim test increases the frontal cortex 5-HT1A receptors in the female rats with respect to the female sham group (40.4+/-5 versus 24.7+/-4 fmol/mg protein, P<0.05). An increased sensibility of the 5-HT1A receptors to depressive-stimulus may be one mechanism underlying the higher prevalence of depression in female.

Effects of camonagrel, a selective inhibitor of platelet thromboxane synthase, on the platelet-subendothelium interaction.

The aim of this study was to compare the effects of a new thromboxane synthase inhibitor, camonagrel, on platelet aggregation and platelet-subendothelium interaction under flow conditions, in comparison with a standard thromboxane synthase inhibitor (dazoxiben) and a cyclooxygenase inhibitor (acetylsalicylic acid). With respect to platelet aggregation in whole blood, the 50% inhibitory concentrations (IC(50)) of camonagrel were between 318 and 797 micromol/l after induction with collagen and adenosine 5'-diphosphate, respectively. For inhibition of thromboxane B(2) synthesis, the IC(50) values were 868 +/- 68 micromol/l; prostaglandin E(2) was inhibited only by acetylsalicylic acid (IC(50) for camonagrel >2,000 micromol/l), and the leukocyte 6-keto-PGF(1alpha) level was increased by camonagrel. The greatest reduction in percentage subendothelial surface occupied by platelets (mainly in the thrombi) after blood perfusion was seen after incubation with camonagrel in the range of concentrations that inhibited collagen-induced platelet aggregation. In conclusion, camonagrel reduced platelet-subendothelium interaction under flow conditions, showing this effect in a range of concentrations lower than in inhibition of platelet aggregation.

Differences in the effects of extended-release aspirin and plain-formulated aspirin on prostanoids and nitric oxide in healthy volunteers.

This study was designed to evaluate the effects of extended-release aspirin on platelet aggregation and the production of prostanoids and nitric oxide. The participants in this double blind, randomized and crossover study were 20 healthy volunteers. Interventions were 150 mg of plain-formulated aspirin (PFASA) and 150 mg of extended-release aspirin (ERASA). Blood samples were collected before and 10, 20, 60, 120, 240, 480 and 1440 min after the first dose; 3, 7 and 14 days after daily administration and 24 h after the last dose. The main measures were platelet aggregometry, thromboxane B2, 6-keto-prostaglandin (PG) F1alpha and nitric oxide in each control. Platelet aggregation was inhibited by 50% with ERASA, and by 77% with PFASA. No differences were found in chronic treatment. Thromboxane B2 was inhibited more by the latter (51-67%), but 90% inhibition was observed in both groups after 3 days. The levels of 6-keto-PGF1alpha was reduced by 20% with ERASA and by 58% with PFASA. Nitric oxide production increased in both groups, but after 24 h, and 7-14 days, elevated concentrations of nitric oxide were found only in the ERASA. The antiplatelet effects of ERASA provide pharmacological advantages (greater prostacyclin synthesis and prolonged increase in nitric oxide production) over those provided by the plain formulation.

[Generic drugs: good or bad? Physician's knowledge of generic drugs and prescribing habits]. / Genéricos: ¿buenos o malos? Conocimientos y actitudes de los médicos ante los medicamentos genéricos.

In this article we analyze the responses of 1220 Spanish physicians who participated in a survery about generic drugs. A previously validated questionnaire was sent to physicians through the Spanish Medical Councils of the different provinces. Four items were analyzed: what doctors know about generic drugs (knowledge); physicians' prescribing habits concerning these drugs (attitude and professional competence); how prescription of generic drugs effects pharmaceutical costs amd, finally, what doctors believe a generic drug should be. The influence of physician-related variables (age, type of contract, specialty, workload, etc.) on prescribing of generic drugs was also analyzed. In view of the results, we believe that to rationalize expenditure through and appropriate policy on generic drugs Spanish health authorities should offer more and better training and information (clear and independent) about what generic drugs are.

Genéricos: ¿buenos o malos? Conocimientos y actitudesde los médicos ante los medicamentos genéricos / Generic drugs: good or bad? Physician's knowledge of generic drugs and prescribing habits

En este artículo se analizan y exploran las respuestas de 1.220 médicos españoles que respondieron a una encuesta sobre medicamentos genéricos enviada a través de los colegios oficiales de médicos provinciales. A partir de los datos de la encuesta, que fue previamente validada, se obtuvieron 4 factores analizados: qué saben los médicos sobre los medicamentos genéricos (conocimiento); cómo se comportan ante la prescripción de estos medicamentos (actitudes y competencia profesional); cómo influirá las prescripción de estos medicamentos en el control del gasto farmacéutico y, finalmente, qué piensan los médicos sobre lo que debe ser un medicamento genérico. También se ha analizado qué factores o variables del médico (edad, tipo de contrato, especialidad, presión asistencial, etc.) influyen en esta opiniones y en qué sentido. En vista de los resultados obtenidos, creemos que la primera medida que habría que adoptar por parte de las autoridades sanitarias de nuestro país, si se quiere racionalizar el gasto mediante una buena política de medicamentos genéricos, será la de ofrecer más y mejor formación e información (clara e independiente) de lo que son las especialidades farmacéuticas genéricas (AU)

In this article we analyze the responses of 1220 Spanish physicians who participated in a survery about generic drugs. A previously validated questionnaire was sent to physicians through the Spanish Medical Councils of the different provinces. Four items were analyzed: what doctors know about generic drugs (knowledge); physicians' prescribing habits concerning these drugs (attitude and professional competence); how prescription of generic drugs effects pharmaceutical costs amd, finally, what doctors believe a generic drug should be. The influence of physician-related variables (age, type of contract, specialty, workload, etc.) on prescribing of generic drugs was also analyzed. In view of the results, we believe that to rationalize expenditure through and appropriate policy on generic drugs Spanish health authorities should offer more and better training and information (clear and independent) about what generic drugs are (AU)

The effect of propofol on the interaction of platelets with leukocytes and erythrocytes in surgical patients.

UNLABELLED: We tested the antiplatelet effect described for propofol in vitro in surgical patients. Platelet aggregation induced by adenosine diphosphate, collagen, and arachidonic acid was tested in samples of whole blood, platelet-rich plasma (PRP), PRP with red blood cells, and PRP with leukocytes. Also measured were platelet production of thromboxane (Tx)B(2) and leukocyte production of 6-keto-prostaglandin F(1 alpha) (a stable metabolite of prostacyclin) and plasma levels of nitrites + nitrates (indicator of nitric oxide production). Anesthesia was induced with a bolus IV injection of sodium thiopental 4 mg/kg (n = 10), with a bolus dose of 2.5 mg/kg of propofol (n = 20), or with propofol total IV anesthesia (n = 20). Sodium thiopental did not modify any of the analytical values. In patients who received a bolus injection of propofol, platelet aggregation was significantly reduced in whole blood and in PRP + leukocytes. Platelet production of TxB(2) was reduced by 35%; the inhibition of 6-keto-prostaglandin F(1 alpha) was not statistically significant. Plasma levels of nitrites + nitrates increased by 37%; this change correlated significantly with the decrease in systolic and diastolic blood pressure (both P < 0.05). Similar changes, albeit of larger magnitude, were seen in patients who were given total IV anesthesia with propofol. In conclusion, propofol inhibited platelet aggregation in surgical patients mainly as a result of the inhibition of Tx synthesis and the increase in nitric oxide production. These effects are thought to be related to the hypotensive effect of this anesthetic. IMPLICATIONS: In vitro experiments have shown that propofol inhibits platelet aggregation and increases nitric oxide production. This study shows that doses habitually used to induce or maintain anesthesia also have these effects. These findings have potential applications for patients at increased risk for bleeding and may partly explain the hypotensive effect of propofol.