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Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs due to their high efficacy in the treatment of pain, fever, inflammation and rheumatic disorders. However, their use is associated with the occurrence of adverse effects at the level of digestive tract, ranging from dyspeptic symptoms, gastrointestinal erosions and peptic ulcers to more serious complications, such as overt bleeding or perforation. To overcome problems related to NSAID-induced digestive toxicity, different therapeutic strategies can presently be considered, including the co-administration of drugs endowed with protective activity on the upper gastrointestinal tract, such as the proton pump inhibitors, or the prescription of coxibs, which have been clinically developed as anti-inflammatory/analgesic drugs characterized by reduced damaging activity on gastrointestinal mucosa. The availability of different treatment options, to reduce the risk of NSAID-induced adverse digestive effects, has fostered intensive preclinical and clinical research aimed at addressing a number of unresolved issues and to establish rational criteria for an appropriate use of coxibs in the medical practice. Particular attention is being paid to the management of patients with high degrees of digestive risk, resulting by concomitant treatment with low-dose aspirin for anti-thrombotic prophylaxis or ongoing symptomatic gastroduodenal ulcers. The present review discusses the most relevant lines of evidence concerning the position of coxibs in the therapeutic strategies for gastrointestinal protection in patients who require NSAID therapy and hold different levels of risk of developing adverse effects at the level of digestive tract. [Copyright &y& Elsevier]

Abstract: Celosomy is a term used for a group of congenital anomalies characterized by opening of the somatic wall with evisceration. The most common types of celosomy are gastroschisis and omphalocele. They have been associated with maternal age, cigarette smoking, environmental pollution, as well as prenatal exposure to vasoconstrictors and recreational drugs. The aim of this study was to evaluate the effect of prenatal exposure to various selective and non-selective cyclooxygenase-2 (COX-2) inhibitors on the abdominal wall defects in rat. A retrospective statistical analysis was performed on the basis of data collected in our laboratory in the years 1997–2004, during different teratological studies with COX-inhibitors (aspirin, DFU, DuP-697, ibuprofen, paracetamol, piroxicam, propyphenazone, tolmetin). Out of 6744 live born fetuses celosomy was revealed only in four animals exposed to different non-selective COX inhibitors. A single case of gastroschisis was also found in a rat exposed to the selective COX-2 inhibitor. The fetal body weight was significantly lower in COX-exposed group of fetuses when compared with untreated control. It was also significantly decreased in non-malformed fetuses prenatally exposed to COX inhibitors when compared with untreated control. The fetal body weight and length were lower in fetuses born with gastroschisis than with omphalocele. However, when animals with both anomalies were pooled in one group the mean fetal body weight was marginally lower (p =0.0523) when compared with non-malformed group, while no statistically significant differences were found for fetal length. The pooled statistical analysis done for the concurrent and our own historic data showed that only aspirin statistically increased the risk of abdominal wall defects in rat fetuses. The expected ratio for aspirin is 56.41 per 10,000 offsprings (p <0.05), which is over 10-times higher than ratio for all non-selective COX inhibitors, including aspirin (6.01/10,000; p <0.05). No differences were found for selective COX-2 inhibitors. It could be stressed that aspirin, unlike other non-selective and selective COX-2 inhibitors increases the risk of the abdominal wall defects, which are observed more often in growth-retarded fetuses. [Copyright &y& Elsevier]

The aim of the study was to evaluate the toxicity of non-selective (tolmetin, ibuprofen and piroxicam) and selective (DFU) cyclooxygenase-2 inhibitors on pregnant and non-pregnant rats. The drugs were administered orally once (DFU, piroxicam) or three times (tolmetin, ibuprofen) a day from days 8 through 21 of gestation experiment in three doses. The initial dose was similar to the human antiinflammatory one and set as 8.5 mg/kg (tolmetin, ibuprofen), 0.3 mg/kg (piroxicam) and 0.2 mg/kg (DFU). The middle dose was increased 10 times and the highest one 100 times the initial dose. The highest dose for ibuprofen was set at 200 mg/kg due to high mortality. On gestation/experimental day 21 animals were sacrificed, blood was collected and abdominal organs were taken for pathological examination. Activity of alanine and asparate aminotransferases and levels of total protein and urea were determined. Stomach, small and large intestines, and liver were grossly and histologically examined. Dose-dependent mortality, signs of gastrointestinal toxicity, and significant changes of biochemical parameters were found in groups exposed to non-selective COX inhibitors in both pregnant and non-pregnant rats. Mild regressive structural hepatic changes were observed. Significant decrease of protein level in non-pregnant rats treated with high DFU dose, and occasionally observed gastrointestinal changes were the only changes noted in groups exposed to the selective COX-2 inhibitor. Tolerability of non-selective COX inhibitors was lower in both pregnant and non-pregnant groups when compared with DFU. Insignificant mortality and histological changes were noted between pregnant and non-pregnant groups. [Copyright &y& Elsevier]