A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and placebo in healthy elderly subjects.

BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2 specific inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs are often used for short-term treatment of pain. AIM: To compare the short-term upper gastrointestinal mucosal effects of naproxen with the new COX-2 specific inhibitor, valdecoxib, or placebo, in elderly subjects. METHODS: In this multicentre, double-blind, randomized, study, elderly subjects (65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper gastrointestinal mucosal injury was evaluated post-treatment by EGD (day 7). RESULTS: Subjects receiving naproxen (11/60, 18%) had significantly more gastroduodenal ulcers post-treatment than those receiving placebo (2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant finding was observed for gastric ulcer rates. All treatments had similar adverse event rates and clinical laboratory findings. CONCLUSIONS: Valdecoxib, even at supratherapeutic doses, was associated with an ulcer rate significantly lower than naproxen but similar to placebo in healthy elderly subjects, despite the short duration of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated as placebo.

Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial.

OBJECTIVE: To compare the efficacy and upper gastrointestinal (GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac 75 mg slow release (SR) twice daily in treating rheumatoid arthritis (RA). METHODS: Seven hundred and twenty-two patients with adult-onset RA were enrolled into this 26-week, randomized, multicentre, double-blind, parallel-group study (246 in the valdecoxib 20 mg daily arm, 237 in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75 mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per day) was similar across all groups: 5.4% in the diclofenac group, 5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib 40 mg group. Efficacy was measured by the Patient's Assessment of Arthritis Pain [visual analogue scale (VAS)] and the modified Health Assessment Questionnaire (mHAQ) at baseline and at weeks 2, 6, 8, 12, 18 and 26 of treatment, or at early termination. Upper GI safety was evaluated by endoscopy at the end of treatment, which took place no more than 2 days after the last dose of study medication or at early termination. RESULTS: Valdecoxib 20 and 40 mg daily were comparable to diclofenac 75 mg SR twice daily in treating the signs and symptoms of RA. No significant differences were observed between treatment groups with respect to mean changes from baseline in the Patient's Assessment of Arthritis Pain (VAS) or mHAQ. The incidence of gastroduodenal ulcers in patients receiving valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was significantly lower (P < 0.001) than in patients receiving diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily was also associated with significantly improved GI tolerability (P = 0.035) compared with diclofenac. CONCLUSIONS: Single daily doses of valdecoxib 20 and 40 mg provided efficacy comparable to that of diclofenac, with a superior upper GI safety profile in the long-term treatment of RA patients.

Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen.

OBJECTIVE: To compare the efficacy of the COX-2 specific inhibitor valdecoxib with the conventional NSAID naproxen and placebo in treating rheumatoid arthritis (RA). METHODS: This multi-centre, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of valdecoxib 10 mg (n=209), 20 mg (n=212) or 40 mg once daily (q.d.) (n=221) with naproxen 500 mg b.i.d. (n=226) or placebo (n=222), in treating the signs and symptoms of RA. Efficacy was assessed by the number of patients responding to treatment according to the American College of Rheumatology-Responder Index (ACR-20). RESULTS: ACR-20 response was recorded for all randomized patients who received a single dose of study medication (above). Valdecoxib, at all administered doses, produced significant improvements in the ACR-20 Responder Index at weeks 2, 6 and 12 compared with placebo (P

CD4 and its role in infection of rabbit cell lines by human immunodeficiency virus type 1.

Human CD4 (HuCD4) is the principal receptor for human immunodeficiency virus type 1 (HIV-1) in human cell infection. Susceptibility of rabbit cell lines to infection with HIV-1 raised questions concerning whether a CD4 homolog serves as HIV-1 receptor on rabbit cells. Sequence comparisons of rabbit CD4 (RbCD4) cloned from a rabbit thymus cDNA library showed that 6 of the 18 residues implicated in HIV-1 binding by CD4 differ between the human and rabbit proteins. No correlation between RbCD4 expression by rabbit cell lines and their ability to support HIV-1 infection was seen. Transfection of RbCD4-negative, HTLV-I-transformed cell lines with HuCD4 significantly enhanced HIV-1 infectivity, suggesting that these lines lack a receptor present on other RbCD4-negative lines that produce high levels of p24 in their native state. Inhibition of HIV-1 infection with soluble HuCD4 was demonstrated for all rabbit lines tested, but complete inhibition was obtained only with a rabbit T-cell line expressing RbCD4 and with HuCD4 transfectants. The results suggest that HIV-1 infection of the RbCD4-positive line proceeds through a receptor similar to HuCD4 but that an additional receptor or receptors may serve this purpose in RbCD4-negative lines.

A monocyte-derived factor interferes with detection of reverse transcriptase in HIV-1 infection.

Culture supernatants from the rabbit macrophage cell line 6083 infected with a retrovirus, human immunodeficiency virus type 1 (HIV-1), were negative for reverse transcriptase (RT) expression although the line was shown to be productively infected by all other criteria tested. Supernatants from uninfected cultures of 6083, the human monocyte line U937, and from freshly isolated peripheral human monocytes, were found to contain a monocyte-derived inhibitory factor (MDIF) which interferes with a standard assay for RT. MDIF is a heat-labile activity of approximately of 40 kD. Both substrates and products of the reverse transcriptase assay are degraded by MDIF which is not affected by reduction and alkylation of disulfide bonds. MDIF is inhibited by the addition of a particular thioated oligonucleotide (S-dG30) to the reaction mixture but this addition also inhibits RT. The optimum method to minimize MDIF interference in the RT assay is by addition of ethylene glycol bis-(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA); MDIF requires divalent cations for activity and has a strong preference for calcium which is preferentially chelated by EGTA. The potential presence of this inhibitory activity should be considered when using RT levels as a measure of retroviral infection.

The effect of thyroidectomy on bone mineral content in perimenopausal women.

To examine the effects of total thyroidectomy on skeletal mineral content we performed dual photon densitometry of the spine and hip in 18 patients with well differentiated thyroid cancer treated with total thyroidectomy and post-thyroidectomy 131-I thyroid remnant ablation. Study subjects were 18 Caucasian females, 45-55 years old, no more than 3 years post-menopausal, 4-20 years (mean 9.7) post-thyroidectomy and 131-I ablation. All subjects were free of disease by all criteria and receiving slightly supra-physiological doses of thyroxine. These subjects were compared with 16 carefully age and sex matched controls without thyroid disease. Patients and controls did not differ significantly in: age (mean-range) 50.2 (45-55) vs 48.7 (45-54) years, height 165.1 (152.4-177.8) vs 164.6 (157.5-172.7) cm, or weight 76.7 (49.1-122.7) vs 71.3 (54.5-104.5) kg. Neither did they differ in (mean +/- SEM): serum calcium 9.45 +/- 0.44 vs 9.49 +/- 0.36 mg/dl, serum inorganic phosphate 3.51 +/- 0.67 vs 3.60 +/- 0.43 mg/dl, serum creatinine 0.84 +/- 0.14 vs 0.91 +/- 0.11 mg/dl or PTH 151.7 +/- 71.0 vs 162.4 +/- 52.0 pg/ml. The T12 index was significantly greater in patients on exogenous thyroxine, 12.0 +/- 2.3 vs 8.7 +/- 1.3 (p less than 0.005) although TSH values performed with a standard sensitivity rather than a super sensitive TSH assay were not significantly different 1.8 +/- 0.9 vs 3.2 +/- 1.6 microU/ml. Lumbar vertebral (L2-4) mineral content was not different between patients and controls, 1.245 +/- 0.900 g/cm2 vs. 1.238 +/- 0.166 g/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Histochemical evaluation of lymphocytes in hypogammaglobulinemia. Decreased number of 5'-nucleotidase-positive cells.

With the use of a histochemical technique, 5'-nucleotidase activity was examined in peripheral blood lymphocytes from patients with primary hypogammaglobulinemia. Our current study demonstrates that the decrease in 5'-nucleotidase activity in congenital agammaglobulinemia, previously demonstrated by a radiochemical assay, is associated with a reduction in the number of cells containing 5'-nucleotidase rather than with a decrease of the enzyme activity per cell. Both sheep erythrocyte rosette-forming and nonrosette-forming PBMs have reduced percentages of 5'-nucleotidase-containing cells in subjects with the enzyme deficiency. The reduced percentage of 5'-nucleotidase-containing mononuclear cells in patients with congenital agammaglobulinemia was evident in both monocyte-contaminated and monocyte-depleted cell preparations.

Hypoxanthine salvage in man: its importance in urate overproduction in the Lesch-Nyhan syndrome.

1. A daily urinary excretion of 0.8 percent of the administered radioactivity results from the turnover of the labeled adenine nucleotide pool. 2. A 4-fold increase of urinary radioactivity excretion occurs in patients with the Lesch-Nyhan syndrome and support the role of impaired hypoxanthine salvage in the purine overexcretion associated with HGPRT deficiency. 3. Our data do not support the possibility that the increased radioactivity excretion in the HGPRT deficient subjects results from an elevated rate of adenine nucleotide degradation.