OBJECTIVE: To consider the relevance of the duration of a clinical trial in ankylosing spondylitis: long-term (i.e. 1 yr) vs short-term (i.e. 6 weeks) assessment of a non-steroidal anti-inflammatory drug (NSAID)-placebo controlled study. METHODS: The design was a prospective, multicentre, double-blind, placebo-controlled study of 6 weeks duration with a 12 months double-blind extension. Study drugs were placebo (n = 121) or active NSAID (n = 352). A decrease of at least 50% in pain and/or global assessment and/or functional impairment during the study defined the response to treatment. The percentage of patients discontinuing the study drug over time (life table analysis) permitted the evaluation of both the efficacy and toxicity. RESULTS: Among the 473 recruited patients, the percentage of responders was similar at 1 yr and week 6 with a highly statistically significant difference in favour of the active NSAID groups when compared to placebo (at 1 yr, 17% in the placebo group vs 37, 50 and 43% in the piroxicam 20 mg, meloxicam 15 mg and meloxicam 22.5 mg, respectively, for the patient's overall assessment) without any statistically significant difference between the three active groups. However, evaluation of the patients discontinuing the study drug during the 1 yr of the study permitted the detection of a statistically significant difference between the active NSAID groups. A lower percentage of patients taking meloxicam 22.5 mg had to discontinue the study drug when compared to either meloxicam 15 mg or piroxicam 20 mg (37% vs 53% and 53%, respectively, P < 0.05). By 52 weeks, drug-related upper gastrointestinal adverse events occurred in 13, 32, 20 and 18% in the placebo, piroxicam 20 mg, meloxicam 15 mg and meloxicam 22.5 mg groups, respectively. Some of the adverse events occurred only after week 6. CONCLUSION: This study suggests that a 1 yr trial might be of optimum value compared to a 6 week assessment in order to define better the efficacy and tolerability of NSAIDs in ankylosing spondylitis. (+info)
(2/359) Realities of diagnosing Helicobacter pylori infection in clinical practice: a case for non-invasive indirect methodologies.
BACKGROUND: The current, arbitrarily defined gold standard for the diagnosis of H. pylori infection requires histologic examination of two specially stained antral biopsy specimens. However, routine histology is potentially limited in general clinical practice by both sampling and observer error. The current study was designed to examine the diagnostic performance of invasive and non-invasive H. pylori detection methods that would likely be available in general clinical practice. METHODS: The diagnostic performance of rotating clinical pathology faculty using thiazine staining was compared with that of an expert gastrointestinal pathologist in 38 patients. In situ hybridization stains of adjacent biopsy cuts were also examined by the expert pathologist for further comparison. Receiver operator characteristic (ROC) analysis was performed to evaluate whether the diagnostic performance of the expert pathologist differed depending upon the histologic method employed. A similar analysis was made to evaluate the diagnostic performance of pathology trainees relative to the expert. In the absence of an established invasive gold standard, non-invasive testing methods (rapid serum antibodies, formal Elisa antibodies and carbon-14 urea breath testing) were evaluated in 74 patients by comparison with a gold standard defined using a combination of diagnostic tests. RESULTS: Using either rapid urease testing of biopsy specimens or urea breath testing as the gold standard for comparison, the diagnostic performance of the rotating clinical pathology faculty was inferior to that of the expert gastrointestinal pathologist especially with regard to specificity (e.g., 69 percent for the former versus 88 percent, with the latter relative to rapid urease testing). Although interpretation of in situ hybridization staining by the expert appeared to have an even higher specificity, ROC analysis failed to show a difference. The mean ROC areas for thiazine and in situ hybridization staining for trainee pathologists relative to the expert were 0.88 and 0.94, respectively. In untreated patients, urea breath testing had a sensitivity and specificity of 100 percent as compared with thiazine staining with a sensitivity of 83 percent and a specificity of 97 percent. Post-therapy, breath testing had a sensitivity of 100 percent but a specificity of only 86 percent as compared with invasive testing with a sensitivity and specificity of 100 percent. Rapid serum antibody testing and formal Elisa antibody testing agreed in 93 percent of cases (Kappa 0.78) with the rapid test being correct in three of the four disagreements. CONCLUSIONS: The current study illustrates a number of realities regarding H. pylori diagnosis. There is no diagnostic gold standard in general clinical practice. Accurate interpretation of specially stained slides is a learned activity with a tendency towards overdiagnosis early on. Urea breath testing is likely to be the diagnostic method of choice for untreated patients in general clinical practice although antibody testing is almost as accurate. Rapid antibody tests are at least as accurate as formal Elisa antibody tests. Urea breath testing is useful for confirming cure after therapy, but false-positive results may occur in some patients. (+info)
(3/359) Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'-methylhydroxylation by quinidine and hydroquinidine in vitro.
In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased Km and increased Vmax of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both Km and Vmax of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations. (+info)
(4/359) Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects.
We evaluated whether therapeutic blood levels of meloxicam are associated with selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 and platelet COX-1 were obtained in vitro after the incubation of meloxicam with whole blood samples. Moreover, 11 healthy volunteers received placebo or 7.5 or 15 mg/day meloxicam, each treatment for 7 consecutive days, according to a randomized, double-blind, crossover design. Before dosing and 24 h after the seventh dose of each regimen, heparinized whole blood samples were incubated with lipopolysaccharide (10 microgram/ml) for 24 h at 37 degrees C, and prostaglandin E2 was measured in plasma as an index of monocyte COX-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 min was assessed as an index of platelet COX-1 activity. The administration of placebo did not significantly affect plasma prostaglandin E2 (21. 3 +/- 7.5 versus 19.1 +/- 4 ng/ml, mean +/- S.D., n = 11) or serum thromboxane B2 (426 +/- 167 versus 425 +/- 150 ng/ml) levels. In contrast, the administration of 7.5 and 15 mg of meloxicam caused dose-dependent reductions in monocyte COX-2 activity by 51% and 70%, respectively, and in platelet COX-1 activity by 25% and 35%, respectively. Although the IC50 value of meloxicam for inhibition of COX-1 was 10-fold higher than the IC50 value of COX-2 in vitro, this biochemical selectivity was inadequate to clearly separate the effects of meloxicam on the two isozymes after oral dosing as a function of the daily dose and interindividual variation in steady-state plasma levels. (+info)
(5/359) Salt-induced hypertension in Dahl salt-resistant and salt-sensitive rats with NOS II inhibition.
Although recent evidence suggests that reduced nitric oxide (NO) production may be involved in salt-induced hypertension, the specific NO synthase (NOS) responsible for the conveyance of salt sensitivity remains unknown. To determine the role of inducible NOS (NOS II) in salt-induced hypertension, we treated Dahl salt-resistant (DR) rats with the selective NOS II inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) for 12 days. Tail-cuff systolic blood pressures rose 29 +/- 6 and 42 +/- 8 mmHg in DR rats given 150 and 300 nmol AMT/h, respectively (P < 0.01, 2-way ANOVA) after 7 days of 8% NaCl diet. We observed similar results with two other potent selective NOS II inhibitors, S-ethylisourea (EIT) and N-[3-(aminomethyl)benzyl]acetamidine hydrochloride (1400W). Additionally, AMT effects were independent of alterations in endothelial function as assessed by diameter change of mesenteric arterioles in response to methacholine using videomicroscopy. We, therefore, conclude from these data that NOS II is important in salt-induced hypertension. (+info)
(6/359) Effect of thiazinotrienomycin B, an ansamycin antibiotic, on the function of epidermal growth factor receptor in human stomach tumor cells.
Thiazinotrienomycin B (TT-B), an ansamycin isolated from fermentation broths of Streptomyces sp. MJ672-m3, inhibited the growth in vitro of human stomach tumor SC-6 cells over 10 times more strongly than the growth of other human tumor cells, such as HeLa (cervix), T24 (bladder) and LX-1 (lung). The extent of growth inhibition by TT-B of SC-6, but not of LX-1 nor T24, was lowered in a competitive manner by raising serum concentrations in the culture medium. TT-B inhibited the cell cycle progression of SC-6 at an early stage of the progression from G0/G1 to S. The inhibition was again competitive with serum concentrations in the culture medium. No direct inhibition of DNA synthesis was observed at the concentration range which caused the cell cycle arrest. TT-B and anti-epidermal growth factor receptor (anti-EGFR) were antagonistic to each other in inhibiting the cell cycle progression of SC-6 from G0/G1 to S, suggesting that the two compounds share the same target, EGFR. The kinase activity of EGFR was little inhibited by TT-B in a cell-free system. (+info)
(7/359) Natriuretic response to increased pressure is preserved with COX-2 inhibitors.
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)
(8/359) Topographic targeting and pathfinding errors of retinal axons following overexpression of ephrinA ligands on retinal ganglion cell axons.
In the retinotectal projection, the Eph receptor tyrosine kinase ligands ephrinA2 and ephrinA5 are differentially expressed not only in the tectum, but also in a high-nasal-to-low-temporal pattern in the retina. Recently, we have shown that retrovirally driven overexpression of ephrinA2 on retinal axons leads to topographic targeting errors of temporal axons in that they overshoot their normal termination zones in the rostral tectum and project onto the mid- and caudal tectum. The behavior of nasal axons, however, was only marginally affected. Here, we show that overexpression of ephrinA5 affects the topographic targeting behavior of both temporal and nasal axons. These data reinforce the idea that differential ligand expression on retinal axons contributes to topographic targeting in the retinotectal projection. Additionally, we found that ectopic expression of ephrinA2 and ephrinA5 frequently leads to pathfinding errors at the chiasm, resulting in an increased stable ipsilateral projection. (+info)