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ID PMID Title PublicationDate abstract
10807792 Chronic neutropenia mediated by fas ligand. 2000 May 15 Chronic neutropenia, often associated with rheumatoid arthritis, is a characteristic finding in large granular lymphocyte (LGL) leukemia. The mechanism of neutropenia is not known. Normal neutrophil survival is regulated by the Fas-Fas ligand apoptotic system. We hypothesized that neutropenia in LGL leukemia is mediated by dysregulated expression of Fas ligand. Levels of Fas ligand in serum samples from patients with LGL leukemia were measured with a Fas ligand enzyme-linked immunosorbent assay. The effects of serum from patients with LGL leukemia on apoptosis of normal neutrophils were determined by flow cytometry and morphologic assessment. High levels of circulating Fas ligand were detected in 39 of 44 serum samples from patients with LGL leukemia. In contrast, Fas ligand was undetectable in 10 samples from healthy donors. Serum from the patients triggered apoptosis of normal neutrophils that depended partly on the Fas pathway. Resolution of neutropenia was associated with disappearance or marked reduction in Fas ligand levels in 10 of 11 treated patients. These data suggest that high levels of Fas ligand are a pathogenetic mechanism in human disease. (Blood. 2000;95:3219-3222)
10729374 A novel dual regulator of tumor necrosis factor-alpha and interleukin-10 protects mice fro 2000 Mar 17 A pyrimidylpiperazine derivative, N-[1-(4-¿[4-(pyrimidin-2-yl)piperazin-1-yl]methyl¿phenyl)cycloprop yl] acetamide (Y-39041), is a dual cytokine regulator of tumor necrosis factor (TNF)-alpha and interleukin-10 production. Lipopolysaccharide-induced TNF-alpha release in BALB/c mice was inhibited by the oral treatment with the compound at 10-100 mg/kg (about 80% suppression) while interleukin-10 release was augmented (about 10-fold increase at 30 mg/kg). In addition, Y-39041 (30 mg/kg, p.o.) completely protected mice from lipopolysaccharide-induced death by the treatment before and after lipopolysaccharide injection. The finding that Y-39041 suppresses TNF-alpha production and stimulates interleukin-10 production at the same time provides new insights for the treatment of septic shock, rheumatoid arthritis and Crohn's diseases.
10708598 CBP: A target molecule of HTLV-1 Tax in synoviocyte activation. 2000 Mar 16 Previous studies have shown that human T-cell leukemia virus type 1 (HTLV-1) Tax is a key molecule of synoviocyte activation in HTLV-1 associated arthropathy (HAAP). To clarify the molecular mechanism of HTLV-1 Tax-induced transcriptional activation in synoviocytes from HAAP, we investigated the role of cyclicAMP (cAMP)-regulated enhancer (CRE) binding protein (CREB)-binding protein (CBP), as a target molecule of HTLV-1 Tax. Activation of cyclic AMP (cAMP)/protein kinase-A (PK-A) pathway resulted in a significantly high response of CRE promoter in synoviocytes from patients with HAAP as well as in Tax-transiently transfected synoviocytes from patients with rheumatoid arthritis (RA). Mammalian two-hybrid analysis showed that the recruitment of CBP was responsible for CREB activation. Furthermore, PK-A activation induced CBP-Tax complex in synoviocytes from HAAP and the complex contained CREB. These findings demonstrated that complex formation of CBP and Tax is critical for enhanced CREB activity in synoviocytes from HAAP.
10685365 Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in 1999 Oct Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.
10645148 [Mixed connective tissue disease--etiology, pathogenesis, clinical significance, treatment 1999 Some patients have features of more than one rheumatic disease and thus do not fit into traditional classification. Patients with combination of clinical finding similar to those of systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), polymyositis, rheumatoid arthritis (RA) and with unusually high titers of circulating antinuclear antibody with specificity for nuclear ribonucleoprotein (RNP) are considered to have mixed connective tissue disease (MCTD). The overlap was described by Sharp and colleagues in 1972. During the post 20 years many studies exposed the clinical correlates of this antibody system (now called anti U1RNP). Controversy arose about whether MCTD was a distinct entity or would be better defined as subset of SLE. Anti RNP antibodies precipitate three proteins uniquely associated with U1RNP. Clinical correlates considered to be distinctive of MCTD are associated with 68 kD antigen specificity. Its to be expected that T cells receptors and HLA molecules are involved in the generation of these antibodies. Several observations have indicated, that 68 kD anti U1RNP antibody response in associated with HLA DR 4 and DR2 phenotype. Several studies have pointed a role of viruses initiating an antibody response against URNPs. Initial observations of MCTD suggested infrequent renal disease, a good response to corticosteroids and favourable prognosis. Future study has shown that some patients may require aggressive and prolonged pharmacologic therapy and that pulmonary involvement is common. Pulmonary hypertension associated proliferative vascular lesions may be serious complication with not always favourable prognosis.
10467068 Coronary artery aneurysms: A 25-patient study. 1999 Sep Coronary artery aneurysm is a rare disorder, characterized by abnormal dilatation of a localized portion or diffuse segments of the coronary artery. We studied clinical demographics, catheterization findings, and clinical outcomes in an Asian patient cohort with documented coronary artery aneurysms. Compared to a Caucasian adult population, our patient cohort had a lower incidence of coronary artery aneurysm (0.25% vs. 2.6%), and more patients with nonobstructive coronary artery aneurysms (70%); age, gender, and coronary distribution were comparable. The initial presentation of myocardial infarction occurred in five patients (5/17, 30%) with nonobstructive coronary artery aneurysms; however, none who were receiving preventive medications consisting of anticoagulant and antiplatelet agents subsequently developed myocardial infarction. We conclude that the incidence of coronary artery aneurysms with or without associated significant coronary stenosis seems to be lower in the Asian population. In contrast, the incidence of nonobstructive coronary artery aneurysms is considerably high and should not be thought of as a relatively benign disease entity if not treated with preventive medications. Rheumatoid arthritis-related vasculitis might be a cause of coronary artery aneurysm. Surgical intervention is based on the severity of coronary artery stenosis. The result of medical treatment has been compatible with long-term survival. Cathet. Cardiovasc. Intervent. 48:31-38, 1999.
10403806 Doxycycline induces Fas/Fas ligand-mediated apoptosis in Jurkat T lymphocytes. 1999 Jul 5 Tetracyclines have been used in the treatment of chronic inflammatory diseases associated with local infiltration of inflammatory cells and matrix destruction as observed in rheumatoid arthritis and periodontal disease. Fas/Fas ligand (FasL)-mediated apoptosis plays an important role in maintaining T lymphocyte homeostasis and modulating immune response. The present study demonstrates that doxycycline inhibits Jurkat T lymphocyte proliferation and induces apoptosis. The phytohemagglutinin (PHA)-activated Jurkat cells are more susceptible to doxycycline-induced apoptosis. Furthermore, doxycycline-induced apoptosis is associated with increased Fas/FasL expression in Jurkat cells. The increase of apoptosis in Jurkat cells treated with doxycycline is consistent with the increase of FasL expression. These results suggest that doxycycline may downregulate the inflammatory process in certain diseases by eliminating activated T lymphocytes through Fas/FasL-mediated apoptosis.
9972127 Effect of an inhibitor of matrix metalloproteinases on spontaneous osteoarthritis in guine 1998 Nov Recently discovered chemically modified tetracyclines have been found to be effective inhibitors of matrix metalloproteinase (MMP)-mediated connective tissue destruction in a variety of pathologic processes, including rheumatoid arthritis and osteoarthritis (OA). Since the histologic techniques used in our laboratory have been validated in Hartley guinea pigs, which have a high incidence of OA-like changes in the proximal tibia, we have used two tetracyclines which have potent inhibitory capacity against various MMPs, doxycycline (Dox) and a compound known as chemically modified tetracyclines (CMT-7). These were given by mouth to a group of guinea pigs for 4 to 8 months, and we assessed the effect of the compound on morphologic and biochemical aspects of OA. We found that prophylactic CMT-7 given orally decreases OA changes in the knee joints both in vitro and in vivo in the guinea pig OA model. Cartilage fibrillation and destruction, in addition to subchondral bone sclerosis and cyst formation, were all decreased in the central compartment of the medial condyle, which is most affected by OA compared with controls. Also collagen, hyaluronan and proteoglycancontent in cartilage was higher in the CMT-7 treated group compared with controls. In contrast, OA changes were not decreased in the Dox group. Our results confirm that various tetracyclines have reduced the severity of OA in animal models, indicating the therapeutic potential of this class of compounds in the future.
9952118 Clinical results of the transoral operation for lesions of the craniovertebral junction an 1999 Jan BACKGROUND: We treated 20 cases of craniovertebral junction lesions via a transoral approach. Developmental abnormalities of the craniovertebral junction accounted for 15 cases; there were 3 cases of tumor, 1 case of osteomyelitis, and 1 case of rheumatoid arthritis. METHODS: The transoral transpharyngeal approach was used in all cases. In 17 non-tumoral patients the anterior margin of the atlas and the odontoid process were resected. In one patient with a ventral clivus chordoma, both a transoral and a transnasal transsphenoidal approach was used for partial resection of the tumor mass. In two cases the median transpharyngeal approach was combined with a jaw-facial incision. In one case a metastatic adenocarcinoma, and in another a neurinoma of the accessory nerve straddling the posterior fossa and the pharyngeal region were removed. RESULTS: After operation four cases developed craniovertebral joint instability and required posterior cervical fusion or external fixation with a halo brace. Follow-up ranged from 2 to 44 months. In most patients neurologic function slowly improved. One worsened, and one died of respiratory failure after operation. Two patients with malignant tumors died during the follow-up period. CONCLUSION: In patients with developmental malformations, transoral decompression will result in some neurologic improvement and arrest the progress of symptoms. Patients with tumors are likely to show a good neurologic outcome when transoral surgery is performed in the early stage of the condition.
9718899 Psychometric properties of the maternal worry scale for children with chronic illness. 1998 Aug OBJECTIVE: To develop and evaluate the psychometric properties of a scale termed the Maternal Worry Scale (MWS) designed to measure maternal worry about children with chronic illnesses. METHOD: The sample consisted of 140 mothers of young children (mean age 8.2 years, 64% female) with a chronic illness (juvenile rheumatoid arthritis, diabetes, or sickle cell disease). Maternal worry, depression, and anxiety, as well as information about the child's health and behavior, were assessed through structured interviews. RESULTS: The MWS had good internal consistency (alpha = .94) and test-retest reliability (r = .84). Analyses indicated a single-factor structure for the MWS. Estimates of construct validity were quite positive: the MWS was moderately correlated with parental depression (r = .34-.39), anxiety (r = .27), and maternal report of child behavior problems (r = .25 [externalizing], r = .46 [internalizing]). CONCLUSIONS: The results suggest that the MWS is a useful, reliable, and valid scale for measuring worry of mothers raising children with chronic health conditions.
9536954 Inhibition of phenolsulphotransferase by salicylic acid: a possible mechanism by which asp 1998 Feb BACKGROUND: Recent epidemiological evidence has shown that chronic use of aspirin decreases susceptibility to bowel cancer. Animal studies have shown that sulphotransferase inhibitors coadministered with sulphation activated carcinogens dramatically reduce the incidence of cancer. AIMS: To investigate the effect of the main aspirin breakdown product, salicylic acid, on the P and M isoforms of phenolsulphotransferase from human platelets and colonic mucosa. METHODS: Platelets were obtained from healthy blood donors and isolated within 24 hours after donation. Samples of colonic mucosa were obtained at resection for non-malignant disease. Phenolsulphotransferase activity was measured in cellular homogenates using a standard radiolabelling assay. RESULTS: Salicylic acid consistently and selectively inhibited the P form of phenolsulphotransferase at subtherapeutic concentrations in both tissue samples. A 50% inhibition of sulphation by the P phenolsulphotransferase occurred at salicylic acid concentrations of about 40 and 130 microM in platelets and bowel mucosa respectively. M phenolsulphotransferase was virtually unaffected by salicylic acid up to a concentration of 1.5 mM (the therapeutic plasma concentration for salicylates when treating rheumatoid arthritis is about 1-2 mM). CONCLUSION: The action of salicylic acid on P phenolsulphotransferase, by preventing the excessive activation of carcinogens, is a possible additional pathway by which aspirin can reduce cancer risk.
9450622 Matrix metalloproteinases in skin. 1997 Oct Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases collectively capable of degrading essentially all extracellular matrix components. These enzymes can be produced by several different types of cells in skin such as fibroblasts, keratinocytes, macrophages, endothelial cells, mast cells, and eosinophils and their activity can be specifically inhibited by TIMPs (tissue inhibitors of metalloproteinases), which bind to active MMPs with 1:1 stoichiometry. In general, MMPs are not constitutively expressed in skin but are induced temporarily in response to exogenous signals such as various cytokines, growth factors, cell matrix interactions and altered cell-cell contacts. At present, more evidence is accumulating that MMPs play an important role in proteolytic remodeling of extracellular matrix in various physiologic situations, including developmental tissue morphogenesis, tissue repair, and angiogenesis. On the other hand, MMPs play an important pathogenetic role in excessive breakdown of connective tissue components, e.g. in rheumatoid arthritis, osteoarthritis, chronic ulcers, dermal photoageing, and periodontitis, as well as in tumor cell invasion and metastasis. In this review we discuss the role of MMPs and TIMPs in human skin based on new observations on the regulation of the expression of MMPs, on their substrate specificity, and MMP expression in physiologic and pathologic conditions of skin involving matrix remodeling. Furthermore, therapeutic modalities based on regulating MMP activity will be reviewed.
9407113 Dissection of C1q capability of interacting with IgG. Time-dependent formation of a tight 1997 Dec 26 C1q-bearing immune complexes have been observed in diseases such as rheumatoid arthritis and human immunodeficiency virus infection-associated neuropathy. For the purpose of understanding better the phenomenon of C1q-bearing immune complexes, we investigated the constancy of the C1q-IgG interaction. An enzyme-linked immunosorbent assay was developed in which wells were coated with IgG to mimic antigen-complexed IgG. Serial dilutions of C1q were applied for distinct time intervals, and bound C1q was detected either directly or after exposure to one of several elution buffers. Our results show that a part of C1q attached to IgG forms a tight association that is not reversible under treatment with buffers containing usually protein-protein interaction-dissociating reagents such as 3 M NaCl, 5 M urea, sodium dodecyl sulfate, or beta-mercaptoethanol. The formation of the highly stable C1q-IgG complex was found to be time-, temperature-, and pH-dependent and to proceed with bound C1q even in the absence of free C1q in the supernatant. In ligand blotting experiments we demonstrate for the first time directly that all three chains of C1q can individually bind IgG. Altogether, our results provide a suitable explanation for the formation and persistence of C1q-bearing immune complexes.
19570000 Subcutaneous bioavailability of a PRIMATIZED IgG1 anti-human CD4 monoclonal antibody is do 1998 IDEC-CE9.1/SB-210396 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-cell surface marker, CD4. This antibody has been evaluated as a potential treatment for rheumatoid arthritis and asthma, in which T cell activation is believed to play an important role in orchestrating inflammation and tissue damage. Human CD4+ murine CD4 knock-out transgenic mice (HuCD4+) have proven most useful in studying the pharmacology of CE9.1, since this antibody cross-reacts only with chimpanzee CD4 and the disposition of the antibody is highly dependent on the presence and distribution of human CD4. In the present study, the distribution and pharmacokinetics of [(3)H]CE9.1 were investigated after subcutaneous (sc) administration to HuCD4+ and murine CD4 knock-out (CD4-) transgenic mice (doses of 0.4 and 100 mg/kg). After a low sc dose to HuCD4+ mice, no absorption of CE9.1 into the systemic circulation was observed. By contrast, high systemic exposure was noted following a comparable sc dose to CD4- mice. Based on evidence that absorption of large proteins occurs primarily via the lymphatics (Supersaxo et al., Pharm. Res. 7:167, 1990), it is proposed that specific binding of CE9.1 to the CD4 molecule on lymphocytes in the regional lymph node(s) prevented the mAb from entering the systemic circulation. Saturation of CD4 binding following a high sc dose to HuCD4+ mice resulted in systemic exposure comparable to that observed at lower doses in CD4- mice. Furthermore, absorption of a low sc dose of [(3)H]CE9.1 was increased 30-fold by administration 7 h earlier of a high sc dose of unlabeled CE 9.1.
9392445 Circadian rhythm in experimental granulomatous inflammation is modulated by melatonin. 1997 Sep Biological rhythms are detected in a variety of physiological and pathological conditions in man and animals, such as rheumatoid arthritis and asthma. Here we describe a circadian rhythm in experimental infectious and non-infectious granuloma. After 30 days of BCG (Bacillus Calmette-Guerin) or nystatin inoculation in the left hind foot of C57B1/6 mice, there is an oscillation with a period of approximately 24 hr in the variation of paw thickness, indicating a circadian rhythm. The acrophase occurred during the light phase, between 9:00 and 13:00 hr, while the nadir occurred in the dark phase, between 21:00 and 01:00 hr. The vascular permeability around the granulomatous lesions was higher at 12:00 hr than at 24:00 hr. This is in agreement with the observation that the thickness of a paw with granulomatous lesion is larger during the light phase. This rhythmic variation was eliminated by either pinealectomy or superior cervical ganglionectomy, which greatly reduce melatonin levels in the blood. Nocturnal replacement of melatonin in pinealectomized mice led to the re-establishment of the circadian rhythm. Thus, the rhythm of the granulomatous lesion is due to the rhythmic melatonin release by the pineal gland. This approach opens new questions regarding the modulation of chronic inflammation in inflammatory diseases that present rhythmic symptoms throughout the day.
9337621 Oxyradical-mediated clastogenic plasma factors in psoriasis: increase in clastogenic activ 1997 Oct Psoriasis is a common skin disorder characterized by hyperproliferation and incomplete differentiation of epidermal keratinocytes. Psoralen plus UVA (PUVA) is one of the treatments proposed for this disease. We had reported previously that exposure of regular blood cultures from healthy donors to PUVA leads to chromosomal breakage via the formation of transferable clastogenic materials, a phenomenon inhibitable by superoxide dismutase. In the present paper we show that these clastogenic factors (CF) are also formed in vivo. The CF were found in about 50% of the psoriasis patients studied (14 out of 31). In PUVA-treated psoriasis patients, the clastogenic activity of the plasma increased significantly between the first and the last (16th) exposure to PUVA. We hypothesize that CF formation in psoriasis is similar to that in other diseases accompanied by oxidative stress, in particular chronic inflammatory diseases with autoimmune reactions such as lupus erythematosus, progressive systemic sclerosis, rheumatoid arthritis and others. Increased superoxide production by phagocytes, formation of lipid peroxidation products and release of cytokines are considered to be responsible for the superoxide-stimulating and chromosome-damaging properties of patients' plasma. During PUVA therapy, superoxide generated via the interaction of psoralen with UVA may contribute to CF formation in addition to superoxide from inflammatory cells. An increased risk of cancer and leukemia is observed in diseases accompanied by CF formation. Therefore CF may contribute to the well-known risk of photocarcinogenesis by PUVA therapy. This additional risk may be preventable by antioxidants and superoxide scavengers.
9264388 Concomitant manifestation of systemic lupus erythematosus and low-grade non-Hodgkin's lymp 1997 Aug We describe a patient presenting with systemic lupus erythematosus (SLE) and concomitant low-grade (Ig) non-Hodgkin's lymphoma of the B cell type (B-NHL). Although the association of autoimmune disorder and lymphoma is well conceived, there is only scarce information available as to the simultaneous occurrence of both disease conditions in one patient. As in this patient diagnosis of Ig B-NHL was also based on the detection of a monoclonal population of CD5+ B lymphocytes, and given that the polyclonal expansion of CD5+ B cells has been previously reported in rheumatoid arthritis (RA), Sjogren's syndrome (SS) and single cases of SLE, the observations we made in this patient led us to discuss the role of the CD5+ population in the development of rheumatic disorders and concomitant lymphoid malignancy. Moreover, since impaired production rates of interleukin 3 (IL-3) and interleukin 4 (IL-4) have been associated with an abnormal expansion of CD5, lymphoma cells and seeing that soluble interleukin 2 receptor (sIL-2R) serum levels were found to be positively correlated with disease activity both in SLE and Ig B-NHL, these parameters were investigated and related to the patient's disease state throughout the entire clinical observation period.
9194227 MR imaging of supra-acetabular insufficiency fractures. 1997 May OBJECTIVE: Diagnosis of insufficiency fractures in the pelvis is difficult, especially in patients with prior malignancy, irradiation, steroid therapy or osteoporosis. This report shows the MR imaging appearance of supra-acetabular insufficiency fractures and how they can be differentiated from metastatic disease. DESIGN AND PATIENTS: Twelve patients (four men, eight women, average age 72.8 years) at risk for pelvic insufficiency fractures and who had pelvic or hip pain were studied with MR imaging. Indications were possible recurrent tumor or previous radiation to the pelvis (7 patients); osteoporosis from steroid use in rheumatoid arthritis (two patients); to exclude osteonecrosis of the hip (two patients); or to rule out a hip fracture (one patient). RESULTS: A characteristic linear region of low signal intensity on both T1- and T2-weighted sequences was found in the supra-acetabular region paralleling the superior acetabulum in a curvilinear are in 92% (11/12) of cases, and oblique in origin in 8% (1/11). Diffuse bands of high signal on T2-weighted images indicated surrounding edema. In two cases, MR findings obviated biopsy. One patient underwent a biopsy prior to the imaging studies being reviewed. All patients were treated conservatively and did well. DISCUSSION: Attention to insufficiency fractures has previously focused on characteristic locations in the sacrum and pubic bones. Supra-acetabular insufficiency fractures also occur and are difficult to diagnose without a high degree of suspicion. MR imaging is a useful tool for diagnosing supra-acetabular insufficiency fractures. The characteristic MR imaging appearance of these fractures can preclude additional diagnostic studies and therapy in most instances.
9051055 Methotrexate management of immune-mediated cochleovestibular disorders. 1997 Feb Immune-mediated cochleovestibular disorders continue to present a management challenge to the otolaryngologist. The traditional treatment of these disorders, corticosteroids and/or cyclophosphamide (Cytoxan), has been associated with serious and occasionally life-threatening complications. In this study we report our experience in treating 25 patients with immune-mediated cochleovestibular disorders with methotrexate, a less toxic immunosuppressive agent that has been used extensively in patients with rheumatoid arthritis. Mean duration of treatment was 12.9 months, and adverse reactions were acceptable and reversible. Hearing improved in 69.6% of patients, and vestibular symptoms subsided or improved in 80% of patients. The results of this study suggest that methotrexate treatment is effective in a substantial number of patients with immune-mediated cochleovestibular disorders and has acceptable adverse reactions. A prospective, randomized study is needed to compare the efficacy of methotrexate with that of other immunosuppressive agents.
9035019 Tissue selective inhibition of prostaglandin biosynthesis by etodolac. 1997 Feb Inflammation is a complex process involving numerous mediators. Because prostaglandins (PG) have been implicated as mediators in all stages of inflammation, inhibition of their synthesis provides the basis for the therapeutic effects of nonsteroidal antiinflammatory drugs (NSAID). Treatment with NSAID is usually accompanied by gastric side effects, attributed to interference with the formation of cytoprotective PG in gastric mucosa. An ideal NSAID should inhibit PG synthesis at the site(s) of inflammation but not in gastric mucosa. Experimental and clinical data support the view that this criterion has been met by etodolac, a structurally distinct NSAID. Thus, in rats and humans with rheumatoid arthritis, longterm daily administration of etodolac at effective antiinflammatory dosages (3 mg/kg in rats; 600 mg in humans) had no effect on PGF2 and prostacyclin levels in gastric mucosa. In contrast, significant decreases in gastric PG levels occurred with antiinflammatory doses of aspirin, naproxen, and piroxicam. Cyclooxygenase (COX), the pivotal enzyme in PG biosynthesis, exists in 2 isoforms: constitutive COX-1, which produces the PG required for maintenance of normal cell activity (e.g., gastric cytoprotection), and COX-2, which is induced in restricted tissue-specific fashion (e.g., by inflammatory stimuli). The antiinflammatory action of NSAID may result from inhibition of COX-2, whereas their gastric side effects may result in large part from inhibition of COX-1; thus, a preferred NSAID should inhibit COX-2 but not COX-1. Results show that etodolac has 10-fold selectivity for COX-2 and indicate that etodolac's pharmacotherapeutic efficacy can be explained by its demonstrably selective inhibition of COX-2, amplified by its favorable tissular pharmacokinetics. The sparing of COX-1 activity in gastric mucosa gives rise to etodolac's noted gastric tolerance.