Are COX-2 Inhibitors Active on Intracellular Oxidative Processes? A Study on In Vitro and Cellular Models

Book published by Nova Science Publishers, Inc. (2006)

In the last years, there has been an increasing interest of using cyclooxygenase-2 (COX-2) inhibitors to treat the inflammatory pain and chronic inflammatory diseases such as osteoarthritis and rheumatoid ... [more ▼]

In the last years, there has been an increasing interest of using cyclooxygenase-2 (COX-2) inhibitors to treat the inflammatory pain and chronic inflammatory diseases such as osteoarthritis and rheumatoid arthritis. The beneficial effects were to avoid the secondary adverse effects such as bleeding and gastric irritation, generally observed with aspirin and conventional NSAIDs. COX-1 is constitutively expressed in most tissues and involved in the regulation of normal homeostatic functions, while COX-2 is not detected in most tissues but induced by inflammatory stimuli. These outcomes motivated the commercial development of selective COX-2 inhibitors. Recent data suggested that the COX-2 enzyme can be expressed within atherosclerotic lesions and could play a crucial role in various types of cancers, by the way of its activity on the ROS production, gene transcription and prostaglandin (PGE2) production. Consequently, the COX-2 enzyme has become a real target for the study of various classes of compounds and specially the possible additional properties of COX-2 inhibitors. We and other groups have already investigated the pro or antioxidant profile of conventional NSAIDs and some COX-2 inhibitors. With the recent withdrawal of two compounds of the coxib’s family (rofecoxib and celecoxib), for adverse cardiovascular events, concerns regarding the safety of all COX-2 inhibitors have been raised. To answer to these concerns, different approaches were developed by studying on in vitro models, the potential inhibiting-or-stimulating activities on oxidative phenomena of new drugs with already recognized therapeutic effects. Preliminary data obtained with COX-2 inhibitors showed a moderate inhibiting effect on the intracellular oxidant processes and others a stimulating activity. New hypotheses for the treatment of inflammation are now suggested for compounds like nimesulide and its analogous, which are selective towards COX-2 with little activity on COX-1. Here, we reported the in vitro effects of some Cox-2 inhibitors, in comparison with traditional drugs (ibuprofen, diclofenac and aceclofenac) by using two cellular models: a human lung type II alveolar cell line (A549) and a human promonocyte cell line (THP-1). The direct interactions between the drugs and ROS were also investigated in cell-free systems. [less ▲]

New approaches and old controversies to postoperative pain control following cardiac surgery

in European Journal of Anaesthesiology (2006), 23(7), 539-550

Objective: To evaluate the effect of postoperative pain control in cardiac surgical patients on morbidity, mortality and other outcome measures. Background: New approaches in pain control have been ... [more ▼]

Objective: To evaluate the effect of postoperative pain control in cardiac surgical patients on morbidity, mortality and other outcome measures. Background: New approaches in pain control have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated in cardiac surgical patients. Methods: We searched Medline for the period of 1980 to the present using the key terms analgesics, opioid, non-steroidal anti-inflammatory drugs, cardiac surgery, regional analgesia, spinal, epidural, fast-track cardiac anaesthesia, fast-track cardiac surgery, myocardial ischaemia, myocardial infarction, postoperative care, accelerated care programmes, postoperative complications, and we examined and discussed the articles that were identified to be included in this review. Results: Pain management in cardiac surgery is becoming more important with the establishment of minimally invasive direct coronary artery bypass surgery and fast-track management of conventional cardiac surgery patients. Advances have been made in this area and encompass specific techniques, such as central neuraxial blockade or selective nerve blocks, and drugs (opioids, sedative-hypnotics and non-steroidal anti-inflammatory drugs). Ideally, these therapies provide not only patient comfort but also mitigate untoward cardiovascular responses, pulmonary responses, and other inflammatory and secondary sympathetic responses. The introduction of these newer approaches to perioperative care has reduced morbidity, but not mortality, in cardiac surgical patients. Conclusions: Understanding perioperative pathophysiology and implementation of care regimes to reduce the stress of cardiac surgery, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Reorganization of the perioperative team (anaesthesiologists, surgeons, nurses and physical therapists) will be essential to achieve successful fast-track cardiac surgical programmes. Developments and improvements of multimodal interventions within the context of 'fast-track' cardiac surgery programmes represents the major challenge for the medical professionals working to achieve a 'pain and risk free' perioperative course. [less ▲]

L'infusion intraveineuse de lidocaine réduit les besoins en propofol lors d'une AIVOC associant remifentanil et propofol.

in Annales Françaises d'Anesthésie et de Réanimation (2006), 25

Acute neutrophil activation in direct stenting: comparison of stable and unstable angina patients.

in International Journal of Cardiology (2006), 112(1), 59-65

BACKGROUND: Polymorphonuclear neutrophils have been implicated in the pathophysiology of atherosclerosis. A substantial body of evidence has emerged to implicate the role of specific leucocyte derived ... [more ▼]

BACKGROUND: Polymorphonuclear neutrophils have been implicated in the pathophysiology of atherosclerosis. A substantial body of evidence has emerged to implicate the role of specific leucocyte derived enzyme myeloperoxidase in atherogenesis, since its initiation through progression until destabilization. The aim of the study was to determine the presence of polymorphonuclear neutrophils activation after coronary stenting, to compare this activation between stable and unstable setting and to evaluate the kinetic relation of this activation with inflammatory response following atherosclerotic plaque rupture. METHODS: Myeloperoxidase, lactoferrin, elastase, C-reactive protein and cytokine plasma levels were assessed in 15 patients undergoing direct coronary stenting for unstable angina (Group A) and compared to 11 patients undergoing this procedure for stable angina (Group B). Serial sampling starting before arteriography and continued for 24 h was carried out in all patients. RESULTS: A significant elevation in myeloperoxidase and lactoferrin levels was observed after stenting in both group A (p<0.0001) and group B (p<0.0001), but was higher in group A. Interleukin-8, interleukin-12 and interleukin-6 levels increased temporarily after stenting in the 2 groups. Baseline values of C-reactive protein were similar in the 2 groups and a progressive increase was observed after the intervention. CONCLUSIONS: Direct coronary artery stenting is associated with an early polymorphonuclear neutrophils activation followed by release of inflammatory cytokines (interleukin-6, interleukin-8, interleukin-12) and C-reactive protein elevation in both stable and unstable patients. We conclude that stenting by itself is associated with myeloperoxidase liberation with a significantly enhanced response in unstable patients. [less ▲]

Brain response to one's own name in vegetative state, minimally conscious state and locked-in syndrome

in Archives of Neurology (2006), 63

Liver transplantation in Jehovah's witnesses

in Transplant International (2005), 18(8), 929-936

For religious reasons, Jehovah's witnesses refuse transfusion of blood products (red cells, platelets, plasma), but may accept organ transplantation. The authors developed a multidisciplinary protocol for ... [more ▼]

For religious reasons, Jehovah's witnesses refuse transfusion of blood products (red cells, platelets, plasma), but may accept organ transplantation. The authors developed a multidisciplinary protocol for liver transplantation in Jehovah's witnesses. In a 6-year period, nine Jehovah's witness patients were listed for liver transplantation. They received preoperative erythropoietin therapy, with iron and folic acid that allowed significant haematocrit increase. Two patients underwent partial spleen embolization to increase platelet count. Seven patients underwent cadaveric whole liver transplantation, and two right lobe living-related liver transplantation, using continuous circuit cell saving system and high dose aprotinin. No patient received any blood product during the surgical procedure. One patient suffering from deep anaemia after living-related liver transplantation was transfused as required by his family, but died from aspergillus infection. One 6-year-old child was transfused against her parent's will. The authors demonstrated that it is possible to increase haematocrit and platelet levels in cirrhotic patients awaiting liver transplantation. They were able to reduce intraoperative need for blood products, allowing liver transplantation in prepared Jehovah's witness patients. This experience may be beneficial for non-Jehovah's witness liver transplant recipients. [less ▲]

Catalytic activation of copper(II) salts on the reaction of peroxynitrite with propofol in alkaline medium

in Nitric Oxide (2005), 12(4), 252-260

We report here on the role of copper (II) salts on the acceleration of peroxynitrite (ONOO-) decomposition and ONOO- reaction with the anaesthetic agent propofol (2,6-diisopropylphenol) in alkaline medium ... [more ▼]

We report here on the role of copper (II) salts on the acceleration of peroxynitrite (ONOO-) decomposition and ONOO- reaction with the anaesthetic agent propofol (2,6-diisopropylphenol) in alkaline medium. We observed a strong acceleration of the ONOO- decomposition in alkaline medium in the presence of copper (I and II) salts. After 18 h of ONOO- reaction with propofol, we observed nitrosated, nitrated, and oxidized (quinone and diphenylquinone) derivatives of propofol, but in the presence of Cu(II) (20% molar vs ONOO-), the yields of quinone and nitrosopropofol strongly increased. We also observed that the temperature and the atmosphere influenced the effects of Cu(II) on ONOO- reactions with propofol: low temperatures promoted nitrosation and high temperatures promoted oxidation; O-2 atmosphere increased the general reactivity and the yield of nitrated and oxidized products. We highlighted the influence of Cu(II) salts on the radical character of the reaction by direct EPR technique. The exact mechanism of the Cu(II) catalysis remains unexplained, but we suggest the formation of a copper complex with propofol or, more probably, the oxidation of ONOO- into ONOO• by copper ions promoting the formation of quinone and nitrosopropofol according to a previously reported mechanism [M. Cudic, C. Ducrocq, Transformations of 2,6-diisopropylphenol by NO-derived nitrogen oxides, particularly peroxyrutrite, Nitric Oxide 4 (2000) 147-156]. © 2005 Elsevier Inc. All rights reserved. [less ▲]

Cerebral processing of auditory and noxious stimuli in severely brain injured patients: Differences between VS and MCS

in Neuropsychological Rehabilitation (2005), 15(3-4, Jul-Sep), 283-289

We review cerebral processing of auditory and noxious stimuli in minimally conscious state (MCS) and vegetative state (VS) patients. In contrast with limited brain activation found in VS patients, MCS ... [more ▼]

We review cerebral processing of auditory and noxious stimuli in minimally conscious state (MCS) and vegetative state (VS) patients. In contrast with limited brain activation found in VS patients, MCS patients show activation similar to controls in response to auditory, emotional and noxious stimuli. Despite an apparent clinical similarity between MCS and VS patients, functional imaging data show striking differences in cortical segregation and integration between these two conditions. However, in the absence of a generally accepted neural correlate of consciousness as measured by functional neuroirnaging, clinical assessment remains the gold standard for the evaluation and management of severely brain damaged patients. [less ▲]

La position de la SBAR à l'égard de la prémédication

in Acta Anaesthesiologica Belgica (2005), 56

The locked-in syndrome : what is it like to be conscious but paralyzed and voiceless?

in Progress in Brain Research (2005), 150(Boundaries of Consciousness: Neurobiology and Neuropathology), 495-511

The locked-in syndrome (pseudocoma) describes patients who are awake and conscious but selectively deefferented, i.e., have no means of producing speech, limb or facial movements. Acute ventral pontine ... [more ▼]

The locked-in syndrome (pseudocoma) describes patients who are awake and conscious but selectively deefferented, i.e., have no means of producing speech, limb or facial movements. Acute ventral pontine lesions are its most common cause. People with such brainstem lesions often remain comatose for some days or weeks, needing artificial respiration and then gradually wake up, but remaining paralyzed and voiceless, superficially resembling patients in a vegetative state or akinetic mutism, In acute locked-in syndrome (LIS), eye-coded communication and evaluation of cognitive and emotional functioning is very limited because vigilance is fluctuating and eye movements may be inconsistent, very small, and easily exhausted. It has been shown that more than half of the time it is the family and not the physician who first realized that the patient was aware. Distressingly, recent studies reported that the diagnosis of LIS on average takes over 2.5 months. In some cases it took 4-6 years before aware and sensitive patients, locked in an immobile body, were recognized as being conscious. Once a LIS patient becomes medically stable, and given appropriate medical care, life expectancy increases to several decades. Even if the chances of good motor recovery are very limited, existing eye-controlled, computer-based communication technology currently allow the patient to control his environment, use a word processor coupled to a speech synthesizer, and access the worldwide net. Healthy individuals and medical professionals sometimes assume that the quality of life of an LIS patient is so poor that it is not worth living. On the contrary, chronic LIS patients typically self-report meaningful quality of life and their demand for euthanasia is surprisingly infrequent. Biased clinicians might provide less aggressive medical treatment and influence the family in inappropriate ways. It is important to stress that only the medically stabilized, informed LIS patient is competent to consent to or refuse life-sustaining treatment. Patients suffering from LIS should not be denied the right tot die - and to die with dignity - but also, and more importantly, and pain and symptom management. In our opinion, there is an urgent need for a renewed ethical and medicolegal framework for our care of locked-in patients. [less ▲]