Increasing amounts of experimental and clinical data support the role of selective cyclooxygenase (COX)-2 inhibition in anti-inflammatory processes and the involvement of COX-1 inhibition in the side ...effects. associated with non steroidal anti-inflammatory drug use. This review will focus on the differences in the structure of the COX-1 and COX-2 molecules, particularly the active site and how they are bound by various NSAIDs to achieve COX-2 selectivity. This COX-2 selectivity will then be characterized in pharmacological assays in vitro and in animal models in vivo. Finally, clinical information available for this new class of selective inhibitors will be discussed.
Ambroxol and bromhexine are shown to be scavengers of both Superoxide and hydroxyl radicals as determined by pulse radiolysis experiments. The dismutation of Superoxide was accelerated 3-fold by ...bromhexine and 2.5-fold by ambroxol over the rate of spontaneous dismutation. The reaction constants of hydroxyl radicals with bromhexine and ambroxol were determined by competition kinetics to be 1.58 ± 0.15 × 10
10 M
−1s
−1 and 1.04 ± 0.1 × 10
10 m
−1s
−1, respectively. N-acetyl-L-cysteine also reacted with hydroxyl radicals (1.28 ± 0.14 × 10
10 M
−1s
−1) but not with Superoxide radical. These effects may be clinically relevant in the treatment of oxidant-associated lung damage induced by inflammatory agents and/or environmental pollutants.
Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 ...(HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.
This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B(2) endpoints in ...healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB(2). These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2) levels, and that meloxicam is selective for COX-2.
Meloxicam provides a case study in the evolution of the cyclooxygenase (COX) hypothesis. Meloxicam was initially characterized in standard animal models of inflammation at a time when its improved ...pharmacologic profile in relation to other nonsteroidal anti-inflammatory drugs (NSAIDs) could not be explained. The subsequent discovery of COS-2 provided a reasonable working hypothesis. Meloxicam was investigated in several in vitro test systems in which it consistently demonstrated preferential COX-2 inhibition. These observations suggested that meloxicam would have a COX-1-sparing effect in vivo. Pharmacologic studies have confirmed the COX-1-sparing effect in animal models and in human subjects and suggest that the improved gastrointestinal and renal safety profile of this drugs may be related to this COX-2-sparing effect. The pharmacologic studies, taken together with the in vitro data, suggest the validity of the COX hypothesis as an estimator of NSAID efficacy and safety. Although further studies have suggested that meloxicam could affect inflammatory processes in other ways than by COX-2 inhibition, the clinical significance of these in vitro findings has yet to be determined. Moreover, accumulating evidence suggests a role for COX-2 in Alzheimer's disease and colorectal cancer. NSAIDs such as meloxicam could therefore be of potential benefit in the prevention or treatment of these diseases.
The general pharmacologist in the pharmaceutical industry is challenged to generate physiologically relevant data on possible safety liabilities or on secondary therapeutic uses as early as possible ...in drug development. This implies the need for efficient use of usually only small supplies of test article. For this reason, we have developed a new animal model combining various elements to provide a broad spectrum of data focussing on the so-called vital physiological functions: cardiovascular, respiratory, and central nervous system. This system uses rats chronically implanted with transmitters for the measurement of arterial pressure, ECG, and body temperature. Modification of the transmitters also allows for the simultaneous assessment of locomotor activity. Studies are performed with these rats in plethysmographs placed directly over the antenna units thus allowing for the additional assessment of respiratory function in the same studies. Using this system, we can generate simultaneously a wide range of relevant physiological parameters in conscious rats with a modest requirement for test article. Such an approach is highly useful for getting early safety readouts of potential drug development candidates as well as for detecting possible secondary therapeutic actions of a drug.
Myoelectric activity patterns of the upper gastrointestinal tract were recorded using chronically implanted electrodes in conscious rabbits. A cyclical pattern of intense spiking activity occurring ...on almost every slow wave for 10-15 min, corresponding to the regular spiking phase or phase III of the migrating myoelectric complex (MMC), was recorded. This activity was detected by electrodes implanted distal to the ligament of Treitz on the proximal jejunum at a frequency of 9.4-10.6/24 hr. The MMC pattern occurred in both fed and fasted animals, regardless of the presence of cecotrophy. Initiation of phase III activity on the jejunum persisted after transplantation of the pancreatic duct opening to the proximal duodenum 5 cm from the pylorus and when gastric contents emptied directly into the proximal jejunum through a large gastrojejunostomy. It is concluded that the MMC pattern of the rabbit small intestine is persistently initiated in the proximal jejunum distal to the pancreatic and biliary ducts. The jejunal origin of the MMC in the rabbit is reminiscent of that seen transiently 8-10 hr after a meal in dogs during the change from fed to the fasted pattern of gastrointestinal motor activity.
Numerous in vitro assay systems have been developed for testing and comparing the relative inhibitory activities of nonsteroidal anti-inflammatory drugs (NSAIDs) against cyclooxygenase (COX)- 1 and ...COX-2, the two COX isoforms responsible for prostaglandin biosynthesis. Despite variability among these systems, which precludes direct comparison of data, analysis of the ratio of inhibition of COX-2 to COX-1 by NSAIDs suggests that inhibitors can be classified based on their COX selectivity. Standard NSAIDs can be classified as preferential COX-2 inhibitors; other compounds currently under development are highly specific for COX-2. Although in vitro systems are important in characterizing activity, the clinical relevance of these data should be carefully considered. Models based on in vitro data can be constructed and maybe compared with, but are no substitute for, in vivo results when they become available.
Five-lipoxygenase-activating protein (FLAP) is usually described as an essential protein to activate the leukotriene (LTs) synthesis via the 5-lipoxygenase pathway. In the enterocyte model HT29 cl.19 ...A cell line, 5-lipoxygenase metabolism was found despite the lack of FLAP expression. Therefore HT29 cl.19A represents an original mammalian model to study FLAP-dependent leukotriene synthesis. In FLAP cDNA transfected HT29 cl.19 A cells, FLAP expression led to an increase in cyclooxygenase pathway products (mainly PGE
2) without an increase in 5-lipoxygenase metabolism. This increase in PGE
2 synthesis was associated with a cyclooxygenase-2 up-regulation in comparison to untransfected HT29 cl.19A cells. These results suggest a possible interaction between the two major pathways of arachidonic acid metabolism.
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