Lege Artis Medicinae


MŰZES Györgyi

NOVEMBER 30, 2004

Lege Artis Medicinae - 2005;15(01 klsz)

[The cyclooxygenase (COX) metabolic pathway and prostaglandin production appear to play a causal role in the promotion and progression of human cancers. Recently COX-2 has received a great deal of interest since it is frequently overexpressed in a wide spectrum of cancers and precancerous lesions. Furthermore, elevated production of prostanoids (particularly PGE2) via COX-2 is associated with several pro-carcinogenic effects including increased proliferation, apoptosis resistance, tumor neoangiogenesis and invasiveness, host immunosuppression, and altered xenobiotic metabolism. Inhibitors of COX-1 and COX-2 (aspirin and most other nonsteroidal anti-inflammatory drugs) and of COX-2 alone (e.g. coxibs) have shown cancer preventive efficacy in epidemiological studies, experimental studies and in human clinical trials. Due to their improved side effect profile, COX-2 selective inhibitors appear to hold substantial promise for long-term administration in the setting of cancer prevention. Emerging data suggest that these agents may have potential in cancer treatment as well. In addition recent results indicate that COX-2 enzyme is also overexpressed in inflammatory processes of the central nervous system, e.g. in Alzheimer’s disease, so its suppression could offer a possible new therapeutic strategy even in the prevention and treatment of Alzheimer’s disease.]



Further articles in this publication

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[Changes to Gastroenterology Specialist Training Following Hungary’s Accession to the European Union]


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RÁCZ István

[Since its synthesis more than 100 years ago aspirin has become one of the most successful drug. Low-dose, long-term aspirin therapy reduces the risk of myocardial infarction, the frequency of cerebral stroke and also reduces the mortality of peripheral arterial diseases and systemic embolisms. With aspirin therapy becoming more and more widespread current knowledge is also getting more concerned about the gastrointestinal risks and beneficial effects. Aspirin therapy causes gastrointestinal damages by the inhibition of endogenous prostaglandin synthesis. The ion trapping effect and the injury of mucosal barrier as well as the inhibition of platelet aggregation are also responsible for gastrointestinal damages. According to epidemiological studies lowdose aspirin treatment increases the risk of acute upper gastrointestinal bleeding by 1.5-2.0 fold. However, endoscopic studies indicate that gastroduodenal ulcers may develop even in 10 percent of cases on long term aspirin treatment, most frequently in a symptom-free form. Older age as well as Helicobacter pylori infection increase the risk of aspirin induced ulcers. Beside Helicobacter pylori eradication therapy, preventive proton-pump-inhibitor treatment and the widespread of new non-toxic aspirin derivates may decrease the risk of gastrointestinal complications. Capsule endoscopy also seems to be a promising diagnostic tool for detecting aspirin induced small bowel erosions and ulcers. Long-term aspirin treatment increases the risk of acute bleeding from large bowel diverticulas especially with non-steroidal anti-inflammatory drug co-therapy present. Long-term, low-dose aspirin treatment is a promising method for the chemoprevention of colorectal cancers.]

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[Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation in patients with rheumatoid arthritis and osteoarthritis. However, they are also associated with a significant risk of gastrointestinal events with clinical and economic consequences. It is mandatory to rationalise the use of different NSAID treatment strategies in patients with varying degrees of gastrointestinal and cardiovascular risk. In patients for those aged <65 years with no previous gastrointestinal event and not concurrently on aspirin (low risk patients), the use of an NSAID should be considered as appropriate. For patients with a previous gastrointestinal event (high risk patients) or who concurrently received aspirin, an NSAID alone should be rated as inappropriate and either a coxib or selective cyclooxygenase-2 inhibitor, or an NSAID + proton pump inhibitor combination is considered as appropriate. Finally, for patients aged >65 years with a previous gastrointestinal event and on aspirin (patients with very high risk) a coxib in conjunction with a proton pump inhibitor is considered to be the best therapeutic strategy.]

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[Since the introduction of aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) proved to be the most commonly used drugs in the world. One of the major factors limiting their use is gastrointestinal toxicity. It has long been recognised that NSAID use is associated with serious, sometimes life-threatening adverse effects, like gastrointestinal ulcers, bleeding and perforation. Recent studies have indicated that the combination of NSAID and aspirin significantly increases the risk of complications. Aspirin is like a two-edged sword, balancing cardiovascular prevention with the risk of gastrointestinal side effects. Past history of ulcer carries the highest individual risk and other contributing factors include age, concurrent anticoagulation, cortocisteroid therapy, as well as high-dose or multipleforms of NSAID use. The mechanism of action of NSAID is to inhibit prostaglandin production through cyclooxygenase (COX). The inhibition of COX-2 isoenzyme reduces inflammatory-mediated prostaglandins, while the inhibition of COX-1 reduces the level of prostaglandins needed for normal protecting mechanism of the gastric mucosa. Non-selective NSAID has impact on both COX-enzymes, while selective COX-2-inhibitors (such as coxibs) exert their effects without affecting mucosal defence significantly. It is important to note that the risk of complications can not be reduced to zero by any therapeutic approach. The most appropriate treatment modality is to administer PPI co-therapy for the sake of gastro-protection, especially in high-risk cases. Histamine-2-receptor antagonists are not effective in reducing ulcer and complication in that particular group of patients. It has turned out that the inhibition of the synthesis of COX-2 by rofecoxib increases the risk of developing thromboembolic events and myocardial infaction. This has led to the withdrawal of Vioxx from the market on 30. 09. 2004. Studies conducted in recents years shed new light on numerous beneficial effects of NSAID other than alleviate pain, cure inflammatory processes and diminish higher temperature. The incidence of colon polyps and adenomas as well as cancers is reduced among people who are on maintanance NSAID therapy. The process of stone formation in the biliary tract is also reduced in patients who are on NSAID treatment. Development of Alzheimer's disease seems to be hindered, however, this finding can not yet be considered as evidence based.]

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[Gastrointestinal Protective Efficacy of Esomeprazole Comparative Studies in the International Literature]

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[Preclinical and clinical studies demonstrate that stress may be implicated in the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Our study aimed to investigate the effects of acute and chronic immobilization stress (IS) on the gene transcriptions of β-actin, amyloid precursor protein (APP) and mitogen activated protein kinase-1 (MAPK-1), proteins related to synaptic plasticity and neuronal degeneration. Male Wistar rats were exposed to IS for five hours daily for 3 days (acute stress) or through 7-14-21 days (chronic stress). At the end of exposure periods, total RNA was purified from the cortex and hippocampus. The amounts of β-actin, APP and MAPK-1 mRNA were determined with real time PCR method. Our results indicate that the mRNA expression of β-actin and APP followed a U-shaped time-response curve. Both acute and chronic IS caused a significant increase in β-actin and MAPK-1 mRNA expression. Significant APP mRNA elevation was observed only by the 3rd week after RS. Our findings demonstrate that both acute and chronic IS lead to gene transcriptional changes of β-actin, APP and MAPK-1. These proteins maintain the normal function of the cytoskeleton and the synaptic plasticity. The above changes may lead to cognitive deterioration, and the development of AD.]

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[Alzheimer’s disease is the most common form of dementia in mid- and late life. The 7-10% of the population over 65 and the 50-60% of the population over 85 are affected by this disease. On the contrary of its prevalence the pathogenesis of the disease is not well defined and there is no effective neuroprotective therapeutic agent. Three predominant neuropathological features of the Alzheimer’s disease brain are intracellular neurofibrillary tangles consisting mainly of the hyperphosphorylated protein t; the extracellular amyloid deposits (neuritic plaques) consisting of amyloid b peptide; and the extensive neuronal cell loss in the hippocampus and in portions of the cerebral cortex. The possible reason of the extensive neuronal cell loss can be the mitochondrial dysfunction observed in Alzheimer’s disease. Beyond the unclarified pathogenesis the causality of these characteristic neuropathologic phenomena are still unknown. In this study we would like to deal with two actual hypotheses, with the amyloid cascade and with the mitochondrial cascade hypotheses. We try to give an overview of these two hypotheses and to depict their interrelationship.]

Clinical Neuroscience

[The transcription of the amyloid precursor protein and tryptophan 2,3-dioxygenase genes are increased by aging in the rat brain]

KÁLMÁN Sára, PÁKÁSKI Magdolna, SZŰCS Szabina, GARAB Dénes, DOMOKOS Ágnes, ZVARA Ágnes, PUSKÁS László, BAGDY György, ZELENA Dóra, KÁLMÁN János

[Aging itself is considered as a major risk factor of dementia. The prevalence of the Alzheimer’s disease (AD) is increasing exponentially after the age of 65 and doubles every 5 years. The major aim of our present research was to examine the effect of aging on the transcription of certain genes associated with neurodegenerative disorders in the rat brain. The influence of the vasopressin (VP) hormone was also examined in the same experimental paradigm. Age dependent transcriptional changes of the following four genes were examined in the cerebral cortex: the first was the gene of the amyloid precursor protein (APP) which is abnormally cleaved to toxic beta-amyloid fragments. These aggregated peptides are the major components of the senile plaques in the AD brain. The second one was the mitogen-activated protein kinase (MAPK1) gene. The MAPK is involved in the abnormal hyperphosphorylation of the tau-protein which results in aggregated neurofibrillary tangles. The beta-actin gene was the third one. The protein product of this gene is considered to be involved in synaptogenesis, neuronal plasticity and clinical conditions like depression and AD. The last one was the gene of the tryptophan 2,3-dioxygenase (TDO2) enzyme. The activity of this enzyme is considered as a rate limiting factor in the metabolism of the neuro-immune modulator quinolinic acid (QUIN). The transciptional activity of young (2.5 months) and aged (13 months) Brattleboro rats with or without VP expression were compared by means of real time PCR technique. The cortical transciptional activity of the APP and TDO2 genes were increased in the aged animals as compared with the activity of the young ones, and this effect was independent on the presence of the VP. Our results indicate the importance of certain age dependent transcriptional changes might influence the mechanism of AD and other neurodegenerative disorders.]

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SZEKANECZ Éva, SZŰCS Gabriella, KISS Emese, SZABÓ Zoltán, SZÁNTÓ Sándor, TARR Tünde, SZÁNTÓ János, SZEKANECZ Zoltán

[INTRODUCTION - Survival data for rheumatoid arthritis (RA) have improved during the past years. Due to longer life expectancy, more attention has to be paid to prevention and treatment of long-term sequelae, including secondary malignancies. Incidence of malignant lymphoproliferative diseases and bronchial cancer is higher in a number of rheumatic diseases including RA. Some drugs nowadays very rarely used in RA - primarily cyclophosphamide and azathioprine - may further increase cancer risk. According to several large meta-analyses, biological therapy may also increase the risk of lymphomas, however, as these agents are used for the treatment of active, refractory arthritis, benefit may override such risks. PATIENTS AND METHODS - Altogether 516 RA patients managed at our department were assessed for the incidence and type of secondary malignancies. Although the absolute number of RA patients with a tumor was relatively small, we compared our cohort to the Health for All database and calculated standard incidence ratios (SIR). RESULTS - We identified 13 cases of malignancy (11 females and 2 males) in 516 RA patients (2.5%). In two patients, cancer developed before the onset of RA. RA patients with malignancy had an even higher female predominance (5.5 to 1) than usual. Mean age at onset of RA was 51.4 years, while age at the diagnosis of malignancy was 61.8 years. Mean duration of RA at the time of cancer diagnosis was 11.2 years. Five patients died, 4 due to the underlying malignancy. In the fifth patient, the tumor was considered cured but the patient died of amyloidosis. Among the 8 surviving patients, mean survival is 7.3 years until now, while overall survival of all 13 cancer patients is 4.7 years. Regarding types of malignancies, there were 6 cases of bronchial cancer, 2 cases of follicular thyroid cancer, and one cutaneous B cell lymphoma, one breast cancer, one gall bladder cancer, one colorectal cancer, and one pancreatic cancer. In comparison to the Health for All database, the overall SIR of all malignancies in RA was 1.12 (CI 0,91-1,33), varying between 2.2 and 70.7 among different tumor types. Only one cancer patient received cyclophosphamide therapy and some received methotrexate or anti-TNF agents. CONCLUSION - We identified 13 cases of malignancy among our RA patients. In RA, secondary tumors including bronchial cancer and lymphomas are more common than in the general population. Adequate treatment and monitoring of these patients may help us to lower the risk of malignancies secondary to RA]