Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts.
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In this study, we use primary embryonic fibroblasts derived from cyclooxygenase-deficient transgenic embryos to further investigate the role of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), in the process of neoplastic transformation. Cells with either, neither, or both of the cyclooxygenases were transformed by Ha-ras and/or SV40. Our results show that when a cyclooxygenase enzyme is present, the transformed cells have marked increases in COX-2 and/or COX-1 expression. Nevertheless, each type of cell, deficient in either or both cyclooxygenases, can be readily transformed at almost equal efficiency. Different nonsteroidal antiinflammatory drugs (NSAIDs) were used to examine their possible antineoplastic effects on the transformed cells, which have various levels of expression of COX-1 or COX-2. Our results show that NSAIDs suppress the colony formation in soft agar in a dosage-dependent manner in the absence of the cyclooxygenase(s). Thymidine incorporation and apoptosis analyses further demonstrate that the NSAIDs are effective in the cyclooxygenase-null cells. Our findings with cyclooxygenase knockout cells confirm recent reports that some of the antiproliferative and antineoplastic effects of NSAIDs are independent of the inhibition of either COX-1 or COX-2. They also show that transformation is independent of the status of cyclooxygenase expression, suggesting that the involvement of the cyclooxygenases in tumorigenesis may occur at later steps. (+info)
Natriuretic response to increased pressure is preserved with COX-2 inhibitors.
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Elevation of renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion increases sodium excretion. This natriuretic response is blunted by the nonspecific inhibition of the cyclooxygenase (COX) enzymes. The present study tested the hypothesis that the natriuretic response to increased RIHP during direct renal interstitial volume expansion is dependent on COX-1 but not COX-2. RIHP and fractional excretion of sodium (FE(Na)) were measured before and after direct renal interstitial volume expansion in control rats (n=7), rats infused with the COX-1 inhibitor piroxicam (n=6, 1.5 mg/kg), and rats infused with the COX-2 inhibitors NS-398 (n=5, 1.5 mg/kg) and meloxicam (n=6, 0.3 mg/kg). In control animals, direct renal interstitial volume expansion significantly increased RIHP (Delta2.3+/-0.5 mm Hg, P<0. 05) and FE(Na) (Delta1.1+/-0.3%, P<0.05). Likewise, in animals infused with NS-398 or meloxicam, direct renal interstitial volume expansion significantly increased RIHP (Delta1.8+/-0.6 mm Hg, P<0.05, and Delta1.7+/-0.3 mm Hg, P<0.05) and FE(Na) (Delta1.5+/-0.4%, P<0. 05, and Delta1.1+/-0.3%, P<0.05), respectively. In contrast, infusion of piroxicam significantly blunted the natriuretic response to direct renal interstitial volume expansion (DeltaFE(Na) 0.3+/-0. 2%), even though RIHP was increased (Delta1.9+/-0.6 mm Hg, P<0.05). Infusion of piroxicam but not NS-398 or meloxicam blunted the natriuretic response to increased renal interstitial hydrostatic pressure, suggesting that the natriuretic response to increased blood pressure may be preserved during inhibition of COX-2. (+info)
Prediction of pharmacokinetic drug/drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants.
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CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin, phenprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxylation of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lornoxicam and the oral anticoagulants are potential inhibitors of their metabolism. Their inhibitory potency was investigated in microsomes from six human livers. An approach to predict pharmacokinetic interactions of lornoxicam from in vitro inhibition data was developed. Where possible, the forecasts were verified by comparison with data from clinical interaction studies. The following increases in steady-state plasma concentrations or areas under the plasma concentration-time curve of the oral anticoagulants by concomitant lornoxicam medication were predicted (values in parentheses are for healthy volunteers): (S)-warfarin, 1. 58-fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-fold); racemic-phenprocoumon, 1.11-fold (1.18-fold); and (S)-phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation was competitively inhibited in vitro by both phenprocoumon (K(i) = 1.2 +/- 0.4 microM) and acenocoumarol (K(i) = 5.5 +/- 3.5 microM). The present results indicate that relatively close predictions of the interactions of lornoxicam with oral anticoagulants from in vitro data are possible under the assumption that hepatic lornoxicam concentrations are similar to its total plasma concentrations. The degree of pharmacokinetic interactions exhibited by oral anticoagulants and lornoxicam is dependent on the respective contribution of CYP2C9 to their total clearance. (+info)
Inhibitory effects of combined administration of antibiotics and anti-inflammatory drugs on lung tumor development initiated by N-nitrosobis(2-hydroxypropyl)amine in rats.
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The effects of antibiotics and anti-inflammatory drugs on the promotion stage of lung carcinogenesis initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats were investigated in two experiments with a similar protocol. In experiment 1, rats received tap water containing 2000 p.p.m. BHP for 12 weeks followed by basal diet or basal diet containing 0.02% erythromycin (EM), 0. 04% ampicillin (ABPC), 1.5% sho-saiko-to, 0.02% EM plus 1.5% sho-saiko-to or 0.04% ABPC plus 1.5% sho-saiko-to for 8 weeks after BHP administration. The development of adenocarcinomas (AC), squamous cell carcinomas (SqC) and adenosquamous carcinomas (ASqC) was completely inhibited in rats given ABPC plus sho-saiko-to and the numbers of lung lesions including alveolar hyperplasias, adenomas and carcinomas were decreased in rats given EM plus sho-saiko-to or ABPC plus sho-saiko-to. Neutrophil and macrophage infiltration into alveolar spaces of the lung were also markedly suppressed. In experiment 2, rats received BHP in the same manner as in experiment 1 and basal diet or basal diet containing 0.04% ABPC, 0.006% piroxicam, 0.04% ABPC plus 0.006% piroxicam and 0.04% ABPC plus 0.75% ougon for 8 weeks. The incidence and number of carcinomas, including ACs, SqCs and ASqCs were decreased in rats given ABPC plus piroxicam or ABPC plus ougon. Bacteria, mainly Escherichia coli, were detected in broncho-alveolar lavage of rats receiving BHP. The results suggest that chronic inflammation might be involved in the progression of lung carcinogenesis by BHP in rats and its suppression may therefore be useful as a chemopreventive strategy in lung cancer clinics. (+info)
Criteria for selecting and using non-steroidal anti-inflammatory drugs in primary health care.
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BACKGROUND: Numerous non-steroidal anti-inflammatory drugs (NSAIDs) are commercially available in Spain. This makes proper selection and use of these drugs difficult for GPs. OBJECTIVE: To find out the criteria which GPs use to choose among the drugs in this group and to evaluate other criteria related to the clinical management of NSAIDs. METHOD: A survey questionnaire was distributed among all the GPs of the reformed network in the health area of Tarragona (Spain). RESULTS: The doctors questioned chose a limited number of NSAIDs. Major preferences were diclofenac and piroxicam. The main criteria for selection were: efficacy and safety of the drug; previous and/or current gastrointestinal pathology of the patient; the difference between acute and chronic use; and the type of inflammatory process. There were a large number of combinations of routes of administration. The histamine H2 antagonists were the prophylactic drugs which were used most for gastropathy. CONCLUSION: Sometimes the main criteria for choosing between the drugs in this study do not reflect the drugs that are used in clinical practice. Some of the criteria used by GPs for selecting and using NSAIDs should be reviewed. (+info)
Effect of oral and i.v. tenoxicam in postoperative pain after total knee replacement.
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We have evaluated the effect of oral and i.v. tenoxicam on postoperative pain after unilateral total knee replacement in a double-blind, randomized, controlled study. Tenoxicam was administered to two groups of patients, either before (40 mg orally) or after (40 mg i.v.) surgery, then at 24 h after surgery (40 mg i.v.) and at the end of each day for 8 days (20 mg orally). A third group were given placebo at all times. All patients had access to PCA morphine for the first 48 h and then co-dydramol tablets for the duration of the study. We studied 101 patients, mean age 67 yr. There was no significant reduction in the requirement for PCA morphine for the duration of the study in either of the treatment groups, or for co-dydramol in the first 2 days, but tenoxicam significantly reduced the need for co-dydramol over the remaining 7 days. There were no significant differences in mobility between groups. There was a high incidence of adverse events reported, with a similar number in each of the three groups. (+info)
Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers.
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The interaction between mutations in the tumor-suppressor genes Apc and p53 was studied in congenic mouse strains to minimize the influence of polymorphic modifiers. The multiplicity and invasiveness of intestinal adenomas of Apc(Min/+) (Min) mice was enhanced by deficiency for p53. In addition, the occurrence of desmoid fibromas was strongly enhanced by p53 deficiency. The genetic modifier Mom1 and the pharmacological agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function. Mom1 showed no influence on the development of desmoid fibromas, whereas the combination of piroxicam and difluoromethylornithine exerted a moderate effect. The ensemble of tumor suppressors and modifiers of a neoplastic process can be usefully analyzed in respect to tissue specificity and synergy. (+info)
An open comparative study of dispersible piroxicam versus soluble acetylsalicylic acid for the treatment of osteoarticular painful attack during sickle cell crisis.
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We compared the efficacy and tolerability of oral piroxicam 1 mg/kg/day with soluble aspirin given at 100 mg/kg/day taken four-hourly in 58 patients with sickle cell anaemia and severe ostcoarticular painful attacks requiring hospitalization in a randomized, paralleled study. Main investigational criteria were pain relief, limitation of movement, fever, and insomnia or agitation. Both groups were well-matched at the commencement of therapy but most patients on piroxicam showed remarkable and significant pain relief and improvement in other parameters within 24 h. Unwanted effects were absent in the piroxicam-treated group whereas those treated with aspirin experienced nausea and vomiting. There were no significant changes in liver function tests with both forms of treatment. Oral piroxicam is an effective and safe treatment in the management of the osteoarticular painful crisis in sickle cell anaemia. It might prevent the use of parenteral analgesics and hospitalization and reduce the loss of school hours in patients who are being treated for bone pain crises that characterize sickle cell anaemia. (+info)