A randomized placebo-controlled trial comparing the efficacy of etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of patients with osteoarthritis.

OBJECTIVE: We compared the efficacy of etoricoxib 30 mg to placebo and ibuprofen 2400 mg for the treatment of osteoarthritis (OA) of the hip and knee. DESIGN: In this 12-week, randomized, double-blind, placebo- and active-comparator-controlled trial, 548 patients (median age 63 years) with OA of the hip or knee were randomized to receive placebo, etoricoxib 30 mg q.d., or ibuprofen 800 mg t.i.d. Demonstration of etoricoxib's efficacy vs placebo and comparison of its efficacy to ibuprofen were assessed using three co-primary endpoints: Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain Subscale (WOMAC-PS); WOMAC Physical Function Subscale (WOMAC-PFS); and Patient Global Assessment of Disease Status (PGADS). Each primary endpoint utilizes a 0-100 mm visual analog scale. To demonstrate comparable efficacy of etoricoxib vs ibuprofen, the 95% confidence intervals (CIs) for the difference in the least squares (LS) mean change over 12 weeks for all three co-primary endpoints had to fall within +/-10 mm. Safety and tolerability data were collected throughout the study. RESULTS: Mean baseline values for the three co-primary endpoints ranged from 62.52 to 70.14 mm. Both etoricoxib and ibuprofen demonstrated superior (P< or =0.002) efficacy for all primary endpoints. The LS mean (mm) changes (95% CI) over 12 weeks for etoricoxib and ibuprofen, respectively, compared to placebo were given as follows: WOMAC-PS: -11.66 (-16.31, -7.01) and -7.62 (-12.30, -2.94); WOMAC-PFS: -10.15 (-14.74, -5.57) and -7.23 (-11.85, -2.61); PGADS: -11.65 (-16.81, -6.50) and -8.11 (-13.30, -2.92). The efficacy of etoricoxib 30 mg was comparable to ibuprofen 2400 mg. All treatments were similarly well tolerated. CONCLUSION: Treatment with etoricoxib 30 mg q.d. provides superior efficacy vs placebo and comparable clinical efficacy vs ibuprofen 2400 mg (800 mg t.i.d.) for the treatment of OA of the hip and knee.

Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis.

OBJECTIVES: To assess the efficacy and safety of etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). METHODS: Two 1-year randomised, double blind, parallel group two-part base studies (part I 12 weeks; part II 40 weeks), followed by an 86-week extension, in patients with OA (hip or knee) were conducted at 80 clinical centres (19 countries). The studies had identical designs. Patients taking placebo in part I received etoricoxib or naproxen (1:1 ratio) in part II and the extension; patients taking etoricoxib or naproxen in part I continued to receive the same treatment throughout the entire length of the studies. Co-primary efficacy end points were patient global assessment of disease status, and WOMAC questionnaire pain subscale and physical function subscale (100 mm VAS). Efficacy over 138 weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. RESULTS: 997 patients entered (615 completed) the base studies. Of these patients, 463 patients entered the extensions. A total of 161 and 152 patients in the etoricoxib and naproxen groups, respectively, completed 138 treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of treatment. For etoricoxib and naproxen, respectively, WOMAC pain assessments were 67 and 67 mm (baseline); 28 and 29 mm (1 year), and 34 and 33 mm (138 weeks). Results for the other efficacy end points were similar to those seen with the WOMAC pain assessments. Both etoricoxib and naproxen were generally well tolerated. CONCLUSION: Both etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.

Efficacy of cyclo-oxygenase-2 inhibition by etoricoxib and naproxen on the axial manifestations of ankylosing spondylitis in the presence of peripheral arthritis.

OBJECTIVE: The combined efficacy of selective and non-selective cyclo-oxygenase-2 (COX-2) inhibition on the axial manifestations of ankylosing spondylitis (AS) in the presence or absence of chronic peripheral arthritis was evaluated. METHODS: In a post hoc subgroup analysis of a 6 week, randomised, double blind, placebo controlled trial, 387 patients with active axial AS were randomised to receive etoricoxib 90 mg or 120 mg once a day, naproxen 500 mg twice daily, or placebo. Randomisation was stratified by the presence or absence of chronic peripheral arthritis. The primary outcome measure was the time weighted average change from baseline of spine pain intensity. Efficacy data from the three groups receiving active treatment (the NSAID/COX-2 inhibitor group) were combined to improve precision. An analysis of covariance model was used to evaluate the effect of peripheral disease on treatment response. RESULTS: 93 patients were allocated to receive placebo and 294 to active treatment (naproxen or etoricoxib). The combined NSAID/COX-2 inhibitor group had a significant treatment response compared with the placebo group for all efficacy measures, both in patients with and without peripheral arthritis. A significantly greater difference in mean patient assessment of spine pain was found between active and placebo treatments in patients without compared with those with peripheral arthritis (p = 0.005; -32.5 mm v -17.0 mm, respectively). Similar differences, although not statistically significant, were seen for other end points. CONCLUSION: NSAIDs and COX-2 inhibitors have a clinically relevant symptomatic effect on axial AS irrespective of the presence of peripheral arthritis. In this exploratory analysis spinal improvement appeared to be greater in patients without peripheral disease.

Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.

BACKGROUND: In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs. METHODS AND RESULTS: CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen. CONCLUSIONS: This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.

Efficacy of single-dose and multidose rofecoxib in the treatment of post-orthopedic surgery pain.

To determine the efficacy of rofecoxib in post-orthopedic surgery pain, we conducted a double-blind, randomized, placebo- and active-comparator-controlled, parallel-group trial. Two hundred eighteen patients enrolled. Day 1 patients received placebo, rofecoxib 50 mg, or naproxen sodium 550 mg. Days 2 through 5, the placebo and naproxen sodium groups received placebo, and the rofecoxib group received rofecoxib 25 or 50 mg. Rofecoxib 50 mg was superior to placebo (P < .05) and similar to naproxen sodium for all single-dose measures of pain relief. Days 2 through 5, the rofecoxib 50 mg group used less supplemental narcotic analgesia (P = .005) and reported less pain on global evaluations (P = .041) when compared with the placebo group; the efficacy of rofecoxib 25 mg fell between that of placebo and rofecoxib 50 mg for these endpoints (P < or = .267). Rofecoxib 50 mg once daily effectively treated post-orthopedic surgery pain.

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

BACKGROUND: Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS: We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS: Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

Montelukast, a leukotriene receptor antagonist, in combination with loratadine, a histamine receptor antagonist, in the treatment of chronic asthma.

BACKGROUND: Montelukast sodium, a potent, oral, specific leukotriene-receptor antagonist, has demonstrated clinical efficacy in the treatment of chronic asthma. Loratadine, a selective histamine type 1 (H(1))-receptor antagonist, has demonstrated antiallergic properties. Leukotriene-receptor antagonists given concomitantly with H(1)-receptor antagonists have been shown to have additive effects in the prevention of bronchospasm in antigen-challenge models. OBJECTIVE: To determine whether montelukast plus loratadine provides improved efficacy to montelukast alone in the treatment of chronic asthma. METHODS: The efficacy of montelukast alone vs montelukast-loratadine was studied in a 10-week, multicenter, randomized, double-blind, 2 x 2 crossover study. After a 2-week placebo run-in period, patients received montelukast sodium (10 mg) plus loratadine (20 mg), or montelukast sodium (10 mg) plus placebo once daily for 2 weeks. After a 2-week placebo washout period, patients were crossed over to receive 2 weeks of the other active treatment regimen, followed by another 2-week placebo washout period. RESULTS: Montelukast given concomitantly with loratadine caused significant improvement in percentage of change from baseline in forced expiratory volume in 1 second (FEV(1)) compared with montelukast alone (13.86% vs 9.72%; P =.001). The average additional effect of loratadine (least square mean difference in percentage of change from baseline in FEV(1)) was 4.15% (95% confidence interval, 1.65%-6.65%). Key secondary end points (mean daily beta-agonist use, daytime and nighttime symptom scores, morning and evening peak expiratory flow rate, and the Patient Global Evaluation) all showed significant improvement with montelukast-loratadine (P<.05). CONCLUSION: Montelukast-loratadine significantly improved end points of asthma control during a 2-week treatment period.

Isolation and characterization of an oligomerization-negative mutant of HIV-1 integrase.

The yeast two-hybrid method was used to screen mutagenized DNAs to isolate a variant of the human immunodeficiency virus type 1 integrase (IN) that does not interact with the wild-type IN. The responsible mutation, leading to a single amino acid change (V260E) in the C-terminal domain of IN, blocks IN-IN multimerization but has only small effect on binding to a host interacting protein, INI1 (hSNF5). Binding studies in vitro confirmed the defect in multimerization of the mutant IN. Biochemical analyses of the mutant IN enzyme expressed in bacteria detected only subtle changes in its properties, suggesting that the yeast system is a sensitive reporter of correct IN conformation. Mutant virus carrying the V260E substitution was blocked in replication at the time of DNA integration, consistent with IN multimerization being important for its activity in vivo.

The morphology of the immature HIV-1 virion.

Newly released HIV-1 particles exhibit an immature morphology, previously reported to be characterized by a doughnut/ring-shaped structure. In this study we showed that among immature extracellular virus particles not only were particles with doughnut-shaped morphology present, but particles with a crescent morphology were also observed. These particles occurred with different frequencies, depending on whether they were in the cell or in cell-free fractions. The crescent-shaped particles were more abundant in the cell-free fractions, whereas the particles in the cell fraction mainly exhibited doughnut-shaped morphology. The crescent-shaped structure may represent an assembly intermediate.

The role of Gag in human immunodeficiency virus type 1 virion morphogenesis and early steps of the viral life cycle.

The phenotypes of a series of mutant human immunodeficiency virus type 1 proviruses with linker insertion and deletion mutations within the gag coding region were characterized. These mutants, with mutations in the matrix, capsid, and p2 coding regions, produced replication-defective virion particles with defects in the early steps of the viral life cycle. To investigate this phenotype further, the abilities of mutant virion particles to enter T cells, initiate and complete reverse transcription, and transport the newly transcribed proviral DNA were investigated. Only 4 of 10 of the mutants appeared to make wild-type levels of viral DNA. Biochemical analyses of the mutants revealed the middle region of CA as being important in determining virion particle density and sedimentation in velocity gradients. This region also appears to be critical in determining the morphology of mature virion particles by electron microscopy. Particles with aberrant morphology were uninfectious, and only those mutants which displayed cone-shaped cores were capable of carrying out the early steps of the viral life cycle. Thus, the normal morphology of human immunodeficiency virus type 1 appears to be critical to infectivity.

Sequences in the human immunodeficiency virus type 1 U3 region required for in vivo and in vitro integration.

A series of mutants with alterations in the U3 region of the human immunodeficiency virus type 1 long terminal repeat were made, and the effects of these mutations were evaluated both in vitro and in vivo. When the subterminal 6 to 8 nucleotides of the U3 long terminal repeat were mutated, the resulting provirus was unable to efficiently replicate in vivo, and a mutant oligonucleotide which mimicked the mutation could not be efficiently cleaved but could be joined to target DNA by wild-type recombinant integrase protein in vitro. These results suggest that this region is important in the specific recognition of the viral DNA by the integrase protein.

Linker insertion mutations in the human immunodeficiency virus type 1 gag gene: effects on virion particle assembly, release, and infectivity.

The phenotypes of a series of mutant human immunodeficiency virus type 1 proviruses with linker insertion and deletion mutations within the gag coding region were characterized. These mutants were tested for their ability to make and release viral particles in COS7 cells and for their viability in vivo. Of the 12 mutant proviruses, 4 did not make extracellular virion particles when transfected into COS7 cells. All four of these mutants had mutations in the C-terminal domain of CA. These mutants appeared to have defects both in the ability to accumulate high-molecular-weight intracellular structures containing Gag and Pol products and in the ability to release virion particles. Seven of the mutant proviruses retained the ability to make, release, and process virion particles from COS7 cells. These particles contained the Env glycoprotein, viral genomic RNA, and the mature products of the Gag and Gag-Pol polyproteins, yet they were noninfectious or poorly infectious. The defect in these mutants appears to be in one of the early steps of the viral life cycle. Thus, multiple regions throughout Gag appear to be important in mediating the early steps of the viral life cycle.

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

A high frequency (greater than or equal to 65%) of thymomas induced by mink cell focus-forming virus 69L1 in AKR/J mice contain proviral integrations which are clustered 0.7-kilobase upstream of the c-myc oncogene predominantly in the opposite transcriptional orientation. Blot hybridization experiments showed that on the average there was only a twofold elevation of steady-state c-myc RNA in the thymomas as compared with levels in normal AKR/J thymocytes. Such an increase would not appear to be sufficient as a mechanism of oncogene activation in this system. In contrast, S1 nuclease analysis of transcripts initiated from the two known c-myc promoters indicated a strong shift in promoter usage in virtually all thymomas tested. In normal thymus the ratio of transcripts initiated from the proximal promoter P1 to the distal promoter P2 was 0.2 to 0.3. In contrast, most of the thymomas tested (18 of 23) showed an average P1/P2 ratio of 1.2 regardless of whether or not proviral integrations could be detected within a 21-kilobase EcoRI fragment containing the three c-myc exons. We conclude that alterations in P1/P2 ratios are good indicators of c-myc deregulation in thymic lymphomas.

Early clonality and high-frequency proviral integration into the c-myc locus in AKR leukemias.

Blot hybridization of thymocyte DNA from AKR/J mice was used to detect new proviral junction fragments as markers of clonality at different stages of viral leukemogenesis and to detect DNA rearrangements at the c-myc locus due to proviral insertion. Clonal populations of thymocytes were observed in mink cell focus-forming virus-injected mice as early as 35 days postinjection, at a stage distinguishable from frank leukemia by flow cytometric analysis and transplantation bioassay. Specific proviral integrations in the c-myc locus were detected in 15% of these early clones and in up to 65% of late-developing thymomas and frank leukemias. Thus, in this system c-myc activation appears to be a common mechanism in T-cell leukemogenesis.

Sequence homology between two membrane transport ATPases, the Kdp-ATPase of Escherichia coli and the Ca2+-ATPase of sarcoplasmic reticulum.

We have determined the DNA sequences of the genes encoding the three structural proteins of the Kdp-ATPase, an ATP-driven potassium transport system of Escherichia coli. Regions of the predicted amino acid sequence of KdpB, the phosphorylated protein of the system, are homologous to regions of the Ca2+-ATPase of rabbit sarcoplasmic reticulum. The phosphorylated aspartate residue of the latter is within a region of homology.