Aspirin 15cH has Different Effects on Morphology and Function of Lipopolysaccharide-Challenged RAW 264.7 Macrophages In Vitro Compared to a Pharmacological Dose of Aspirin.

INTRODUCTION: Aspirin is one of the most commonly used drugs worldwide. It is known to present antipyretic, anti-inflammatory and anti-thrombotic actions, making it extremely useful in a wide range of clinical contexts. Interestingly, homeopathically prepared Aspirin 15cH has been found to have a pro-thrombotic effect in rats, raising the hypothesis that Aspirin 15cH could also modulate the activity of inflammatory cells in different pathological processes. OBJECTIVE: Our objective was to assess what effect Aspirin 15cH has on RAW 264.7 macrophages in vitro. METHODS: The effects of Aspirin 15cH on biochemical and morphological activities of lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were evaluated. These effects were compared with unchallenged macrophages (negative control), untreated LPS-stimulated macrophages, macrophages treated with succussed water (vehicle control), or aspirin 200 µg/mL (pharmacological inhibitor of LPS activity). Cell morphology (adhered cell area and cytoskeleton arrangements), cell viability, toll-like receptor-4 (TLR-4) expression, and the production of nitric oxide, cytokines and intracellular reactive oxygen species were assessed. RESULTS: Aspirin 15cH reduced the number of cells expressing TLR-4 on the surface (p = 0.03) and induced a "columnar" morphology of macrophage pseudopods, indicating changes in cytoskeleton arrangement. When cells were treated with both Aspirin 15cH and LPS, cell morphology became heterogeneous, suggesting that sub-populations of cells had differing sensitivities to LPS or Aspirin 15cH. Exposure of the cells to LPS alone, succussed water or aspirin 200 µg/mL produced effects consistent with the literature. CONCLUSION: Aspirin 15cH, aspirin 200 µg/mL, LPS and succussed water appear to act as independent stimuli able to induce different patterns of macrophage response. Aspirin 15cH induced changes suggestive of M2 polarization of the macrophages (i.e., toward a wound healing or tissue repair, rather than inflammatory, phenotype). These preliminary findings need to be confirmed in further specific studies.

Macrophage activity regulation by high dilution of aspirin and its possible mechanism

Under LPS-stimulus, platelets can activate macrophagesby a cell-to-cell contact or through cytokine degranulation. Rebound effects of anti-thrombotic agents, such as prostanoids and COX inhibitors can lead to thrombosis, infarct, and stroke. Aspirin has been prescribed for decades due to its powerful antiplatelet action, but it is also related to paradoxical effects such as withdrawal syndrome peaks, resistance, and thrombogenesis. Ultra-diluted aspirin can also produce the same effect in one hour, regardless of Cox-2, by still unknown pathways. Antithrombotic effects of aspirin are also reversed by its high dilutions.Aims: This study aims to characterize the effects of aspirin 15cH on macrophages challenged with LPS, a Cox-2 activator.Methodology: RAW 264.7 macrophages were sown in 24 wells plates using R10medium, boosted with 1µg/ml LPS,and treated with aspirin 15 cH and controls. The activity was evaluated after 24 hours. Supernatants were evaluated for cytokines, nitric oxide, and dielectric oscillations, through solvatochromic dyes (Cartwright's method).Results and discussion: macrophage spreading was increased by aspirin 15 cH, anLPS-like effect. Paradoxically, a significant reduction of this effect was noted when both, LPS and aspirin 15 cH, were added. Succussed water reversed the effect of LPS, leading to TNF (p<0.05) production close to baseline levels. Also, the single treatment with succussed water inhibited IL-10 production (p<0.05), but aspirin 200 µg/mL (positive control) highly increased it (p<0.0001), showing the validity of the model. Nitric oxide production was strengthened by LPS presence (p<0.0001), as expected, but partially downregulated after treatment with aspirin 200 µg/mL, water and succussed water. A pilot study with solvatochromic dyes showed no significant difference among treatments.Conclusion: The main data suggest that aspirin 15 cH increases macrophage activity but presents a paradoxal effect when mixed with LPS. On the other hand, succussed water itself has modulatory effects on macrophages.

The use of homeopathic dilutions in Agricultural research is a growing field of research [Editorial]

The use of homeopathic dilutions in Agricultural research is a growing field of research. In a paper published in 2015 in Homeopathy Journal, Jägeret al. identified 167 experimental studies, and these numbers have been growing in recent years [1]. In this number, Mirzajani et al. from the University of Zanjan, Iran, show that ultra-high dilutionsof Calendula officinalisandArnica montanainduce physiological, metabolic, and hormonal changes in ornamental plants and may help against irrigation and temperature stress.COVID pandemic is still a public health problem in 2021. Our second paper is an observational retrospective case series study of 183 consecutive patients treated by two groups of homeopathic doctors between February and June of 2020 in Belgium. One of four homeopathic medicines (Bryonia alba, Phosphorus, Arsenicum album, and Gelsemium sempervirens) was used in 66% of the cases. A shorter length in symptoms duration was observed along with a possible lesser hospitalization rate.An uncontrolled, open-label, and non-randomized HPT performed with a Coronavirus nosode 30CH is presented as our third paper. The study was done on 10 subjects, and no serious adverse events were observed. This study was part of a Phase 1 exploration of this nosode, obtained from a clinical sample and was conducted in Mumbai, India.In an interesting clinical paper, Gilla et al. review anxiety disorders, analyze possible future derivations of the COVID 19 pandemic and discuss possible repertorization symptoms and homeopathic treatments for increasing world public health problems.In an elegant experimental design, Banerjee et al. show that 30c potencies of the weedicide Paraquat increase chlorophyll content and growth in rice crops. This exciting paper shows that homeopathic dilutions and high doses of this weedicide produce opposite effects. Moreover, Paraquat 30c dilutions may be used to increase the growth in rice crops, a conclusion with an uttermost consequence in a plant that contributes to the nutrition of half of the world's population.The paper of Bricarello et al. tries to fill the theoretical gap between repertorization and the simillimum remedy in humans and its possible application of this methodology in vegetables, suggesting a possible way.The short communication of Sonntag shows a possible activity of Bacillus firmus D6 modulating the immune system.The editorial team wishes you to enjoy the reading of our selected publications.

Effects of Ultra-Low-Dose Aspirin in Thrombosis and Haemorrhage.

BACKGROUND: Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models. METHODS: This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis. RESULTS: Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis. CONCLUSIONS: Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.

Aspirina en dosis ultrabajas y hormesis / Aspirin in ultra-low doses and hormesis

La relación entre hormesis y Homeopatía resulta hoy en día controvertida. Por un lado, sus primeros fundamentos fueron enunciados con el objeto de explicar los efectos de la Homeopatía. Por otro lado, la mayoría de los trabajos realizados que muestran efectos horméticos fueron realizados a concentraciones mucho mayores que las utilizadas en Homeopatía. El presente trabajo muestra varios puntos de contacto entre la Homeopatía y el concepto de hormesis, y muestra la relación que existe entre los trabajos realizados sobre los efectos de la aspirina 15CH y los distintos tipos de hormesis.

La homeopatía, una ciencia dinámica / Homeopathy, a dynamic science

El doctor Francisco Xavier Eizayaga (1921-2001) dedicó más de 50 años de su vida al ejercicio y la enseñanza de la Homeopatía en varios países de Latinoamérica y Europa. El texto que presentamos es un resumen de la conferencia que el prestigiado médico homeópata ofreció el 8 de junio de 1979 en las instalaciones de la Escuela Nacional de Medicina y Homeopatía, perteneciente al Instituto Politécnico Nacional. En él se aborda el progreso de la medicina y se enfatiza que, aunque el léxico de esta materia se ha multiplicado, lo que verdaderamente debe importar al médico son los hechos, que siempre son mejores que los elementos teóricos. El doctor Eizayaga habla de tópicos tan variados como la posología, el uso de las diferentes potencias, la importancia de contar con escuelas de gran calidad para atajar la aparición de “iluminados o curanderos”, así como de la Ley de semejanza o similitud, y el concepto de fuerza vital. (AU)

Dr. Francisco Xavier Eizayaga (1921-2001) has spent more than 50 years of his life practicing and teaching homeopathy in several countries in Latin America and Europe. The present text is an abstract of the conference that the prestigious homeopath offered in June 8, 1979 at the Escuela Nacional de Medicina y Homeopatía (National School of Medicine and Homeopathy) which belongs to Instituto Politécnico Nacional (National Polytechnic Institute) in México. In it, the progress in medicine is addressed and the author emphasized that although the lexicon in this matter has multiplied, what really should matter to the practitioner are the facts, which are always better than theoretical elements. Dr. Eizayaga talks about various topics as the dosage, the use of different potencies, the importance of high-quality schools to stop the emergence of “healers or enlightened masters”, the Law of Similars and the concept of vital force. (AU)

Aspirin discontinuation syndromes: clinical implications of basic research studies.

Abrupt discontinuation of many drugs used in medicine causes withdrawal syndromes, some of which can be fatal. Discontinuation of a number of cardiovascular drugs can increase the risk of cardiovascular events. Whereas aspirin administration is known to decrease the risk of vascular ischemic problems, aspirin withdrawal may temporarily increase the risk of thrombotic events. Indeed, aspirin withdrawal has been associated with an increased risk of thrombosis both in clinical and fundamental research studies. Such complications occur within the first month after interrupting aspirin therapy and their mechanism remains unexplained. We have previously demonstrated that aspirin, when injected as a single high dose (100 mg/kg), induces a prothrombotic state in the rat, similar to that described above, 8 and 10 days after administration. This effect in the rat may be reproduced 1 hour after a single injection of ultra-low-dose aspirin. Caution is therefore required regarding the possibility of drug discontinuation effects within the framework of drug safety evaluation.

Campo de acción y limitaciones de la homeopatía / Scope and limitations of homeopathy

A través de las seguientes páginas, el connotado médico homeópata argentino Francisco Xavier Eizayaga (Santa Fe, Argentina, 23 de enero de 1923 - Buenos Aires, Argentina, 25 de junio de 2001) efectúa un recorrido a través de las ideas de autores como Armando Grosso, Tomás Pablo Paschero, Proceso Sánchez Ortega, James Tyler Kent y Samuel hahnemann, para reunir sus opiniones en cuanto al campo de acción de la Homeopatía. Forman parte de a discusión factores como el grado de evolución de la enfermedad, las características psicológicas del paciente, los miasmas, el fondo constitucional, las lesiones patológicas locales, la sintomatología general y el medicamento simillimum entre otros.

Over the following pages, the noted Argentine homeopath Francisco Xavier Eiza¬yaga (Santa Fe, Argentina, January 23, 1923 - Buenos Aires, Argentina, June 25, 2001) takes a look through the ideas of writers Iike Armando Grosso, Tomás Pablo Paschero, Proceso Sanchez Ortega, James Tyler Kent and Samuel Hahnemann, to gather their views on the scope of homeopathy. The degree of evolution of the disease, the patient's psychological characteristics, the miasma, the constitutional background, local pathological lesions, the general symptoms and the medication simillimum are part of the discussion factors as among others.

Campo de acción y limitaciones de la homeopatía / Scope and limitations of homeopathy

A través de las seguientes páginas, el connotado médico homeópata argentino Francisco Xavier Eizayaga (Santa Fe, Argentina, 23 de enero de 1923 - Buenos Aires, Argentina, 25 de junio de 2001) efectúa un recorrido a través de las ideas de autores como Armando Grosso, Tomás Pablo Paschero, Proceso Sánchez Ortega, James Tyler Kent y Samuel hahnemann, para reunir sus opiniones en cuanto al campo de acción de la Homeopatía. Forman parte de a discusión factores como el grado de evolución de la enfermedad, las características psicológicas del paciente, los miasmas, el fondo constitucional, las lesiones patológicas locales, la sintomatología general y el medicamento simillimum entre otros.

Over the following pages, the noted Argentine homeopath Francisco Xavier Eiza¬yaga (Santa Fe, Argentina, January 23, 1923 - Buenos Aires, Argentina, June 25, 2001) takes a look through the ideas of writers Iike Armando Grosso, Tomás Pablo Paschero, Proceso Sanchez Ortega, James Tyler Kent and Samuel Hahnemann, to gather their views on the scope of homeopathy. The degree of evolution of the disease, the patient's psychological characteristics, the miasma, the constitutional background, local pathological lesions, the general symptoms and the medication simillimum are part of the discussion factors as among others.

Hepatic encephalopathy: An approach to its multiple pathophysiological features.

Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.

Paradoxical effect of aspirin.

Low-dose aspirin is an important therapeutic option in the secondary prevention of myocardial infarction (MI) and ischemic stroke, basedon its unique cost-effectiveness and widespread availability. In addition, based on the results of a number of large studies, aspirin is also widely used in the primary prevention of MI. This paper provides an update of the available data to offer greater clarity regarding the risks of aspirin with respect to hemorrhagic stroke. In the secondary prevention of cardiovascular, cerebrovascular, and ischemic events, the evidence supports that the benefits of aspirin treatment significantly outweigh the risk of a major hemorrhage. When considering whether aspirin is appropriate, the absolute therapeutic cardiovascular benefits of aspirin must be balanced with the possible risks associated with its use, being hemorrhagic stroke. Regarding these clinical facts, normal, COX 1 -/-, and COX 2 -/- mice were treated with a wide range of doses of aspirin and studied by induced hemorrhagic time. The results outlined three major conclusions: high doses of aspirin induce hemorrhage, while low doses of aspirin do not. In the absence of COX 1, ultra low doses of aspirin produce an antihemorrhagic effect not observed with intermediate doses. The absence of COX 2 induced a hemorrhagic effect that needs further research, probably originated in compensatory phenomena.

Thrombotic events associated to aspirin therapy.

Acetyl salicylic acid (ASA) is widely used in clinical practice. Previous studies done in rats showed unexpected thrombotic potencies of this drug used at ultra-low doses. This review is the first report in which the effects of a wide range of ASA concentration on a microvessel model of laser-induced thrombus formation and Induced Hemorrhagic Time in animals were largely studied.

Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals.

UNLABELLED: Aspirin administration decreases the risk of vascular ischemic problems. However, aspirin withdrawal may temporarily increase this risk. Previous studies reported that high dilutions of aspirin might cause a pro-thrombotic effect. This paper studies the effect of the lower end of the aspirin dose-response curve, its possible mechanism and clinical implications. PROTOCOL: Wistar rats were distributed into 100 groups of 10 rats each. Aspirin was injected at 100 mg/kg, 1 mg/kg and at several different aspirin dilutions along with cyclooxygenase (COX) 1 (SC-560), COX 2 (NS-398) or both selective inhibitors simultaneously using a laser-induced thrombosis model. RESULTS: The higher doses of aspirin decreased thrombosis. An opposite trend was observed with the lowest doses. SC-560 produced an anti-thrombotic effect antagonized by the highest aspirin dilutions. NS-398 created a pro-thrombotic effect that was antagonized by aspirin at higher doses. Simultaneous inhibition of COX 1 and 2 produced changes similar to COX 1 inhibition. CONCLUSION: COX 2 inhibition induced a pro-thrombotic effect that was antagonized by aspirin at 1 mg/kg or 100 mg/kg. The administration of the lowest aspirin doses induced a pro-thrombotic effect stronger than the antithrombotic effect of COX 1 selective inhibition. The mechanism of this last pro-thrombotic effect is induced by residual aspirin and is independent of COX 1 inhibition. This study may explain the cause of the paradoxical thrombo-embolic complications observed after aspirin discontinuation, an effect of residual aspirin rather than a rebound effect, and highlights the importance of low doses of substances as a barely studied source of side-effects.

Aspirin therapy: an attempt to explain the events of prothrombotic complications after treatment discontinuation.

Aspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment non-compliance, surgery or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in one single dose of 100 mg/kg bw has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only one hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. High-dose ASA counterbalances the lack of COX 2 with an antithrombotic effect. No effect of residual ASA was observed in COX 2 -/- mice, thus confirming the existence of a COX 2 inhibition pathway. COX 2 inhibition produced by residual ASA is the probable cause of ischaemic accidents and drug-eluting stents thrombosis a few days after ASA withdrawal.

Prothrombotic and hemorrhagic effects of aspirin.

Aspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment noncompliance, surgery, or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in 1 single dose of 100 mg/kg body weight has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only 1 hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. In conclusion, the prothrombotic effects described in recent observational studies are likely produced by a direct effect of aspirin, whose putative mechanism involving COX 2 inhibition remains poorly understood.

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension.

AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS: Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed. RESULTS: The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION: These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Reverse effect of aspirin: is the prothrombotic effect after aspirin discontinuation mediated by cyclooxygenase 2 inhibition?

BACKGROUND: While aspirin is the drug most often used to prevent cardiovascular complications, its discontinuation induces an increased risk of acute coronary syndrome and ischemic stroke in some patients. OBJECTIVES: We hypothesized that infinitesimal concentrations of aspirin could persist in plasma after its discontinuation, thereby inducing a prothrombotic effect that could be due to a modification in the mechanism of action of aspirin via the cyclooxygenase 1 (COX-1) and COX-2 pathways. METHODS AND RESULTS: We studied the effects of ultra-low-dose aspirin (ULDA) as well as those of sc-560 and ns-398, specific COX-1 and COX-2 inhibitors, on induced hemorrhagic time and in a model of laser-induced thrombosis in rats. In the laser-induced thrombosis model, ULDA treatment increased the number of emboli and the duration of embolization, thereby confirming its prothrombotic effect described in previous publications. This effect was also observed in rats pretreated with sc-560 but not in those pretreated with ns-398. CONCLUSIONS: We demonstrated that ULDA induced a prothrombotic effect in the rats studied. This strongly suggests that a very small amount of aspirin could remain in the patient's blood after aspirin therapy, leading to cardiovascular complications. This effect may be mediated by the COX-2 pathway.

Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered.

AIM: To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation,at 14 and 40 d after ligation when portal pressure is spontaneously normalized. METHODS: Adult male Wistar rats were divided into four groups: Group I: Sham14d , sham operated; Group II: PH14d , portal vein stenosis; (both groups were used 14 d after surgery); Group III: Sham40d, Sham operated and Group IV: PH40d Portal vein stenosis (Groups II and IV used 40 d after surgery). Plasma ammonia,plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected,were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS: Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION: The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility.Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.

Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension.

In our previous study, we demonstrated the effect of ultralow-dose aspirin (ULDA) on platelet activity and bleeding in rats with portal hypertension (PHT) produced by portal vein ligation (PVL). This paper reports modifications in this effect caused by blocking NO production by nitro arginine methyl ester (NAME) and cyclooxygenase (COX) activity with indomethacin. PVL rats and sham-operated controls were treated with placebo, indomethacin or NAME and 30 min thereafter with placebo or ULDA treatment. Platelet activity was studied by a model of in vivo laser-induced thrombus production in the mesenteric circulation, induced hemorrhage time (IHT) and platelet aggregation ex vivo induced by adenosine diphosphate in an aggregometer. The PVL group receiving placebo showed a decreased platelet activity with prolonged IHT, an effect that was reversed by ULDA. Indomethacin induced a decreased platelet activity in the control rats and a prolonged IHT. In PHT with ULDA, in vivo platelet activity was enhanced but the normalization of IHT observed in rats without indomethacin was blunted. The addition of NAME normalized the diminished in vivo platelet aggregation and increased the IHT observed in PVL animals. These changes decreased the effect of ULDA in both sham-operated and PVL animals. The effect of indomethacin was more clearly modified by ULDA than the effect of NAME, thus suggesting that modifications in the COX pathway might alter the effect of ULDA. The simultaneous administration of indomethacin and ULDA could inhibit its beneficial effect on bleeding in rats with PHT.

Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin.

Aspirin (ASA) is widely accepted as antithrombotic drug, but several reports point out that its use in ultra-low doses (ULD) has prothrombotic properties. In this study, we evaluate the effect of portal hypertension in rats on platelet aggregation in an in vivo arterial thrombosis model induced by a laser beam. Portal hypertension was produced by calibrated stenosis of the portal vein. ASA in ULD was injected to both control and portal hypertensive groups. Platelet aggregation induced by ADP, prothrombin time, activated partial thromboplastin time, fibrinogen and induced hemorrhagic time test were also performed. Portal hypertensive rats showed a diminished number of emboli and duration of embolization in the laser procedure and an increase in induced hemorrhagic time. These changes were reverted by one injection of ASA at ULD. This observation could be of importance for primary prevention or the treatment of recurrence in upper digestive tract hemorrhage in portal hypertensive patients.