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.

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.

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.