Effects of ibuprofen on molecular markers of cartilage and synovium turnover in patients with knee osteoarthritis.

OBJECTIVE: The aim of this study was to evaluate the effect of ibuprofen on the urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) and urinary glucosyl galactosyl pyridinoline (Glc-Gal-PYD), two new molecular markers of cartilage and synovial tissue metabolism, respectively, in patients with knee osteoarthritis (OA). METHODS: We studied 201 patients with knee pain and radiographic evidence of knee OA who were on treatment with non-steroidal anti-inflammatory drugs (NSAIDs) prior to study initiation. After an initial screening visit, patients were withdrawn from their pre-study NSAID and, following a flare of their OA symptoms, were randomised to ibuprofen (2400 mg/day) or placebo. Urinary CTX-II and Glc-Gal-PYD levels were measured at time of randomisation (baseline) and after 4-6 weeks of treatment. RESULTS: After 4 to 6 weeks, urinary CTX-II (+17%, p = 0.023) and Glc-Gal-PYD (+10%, p = 0.020) increased significantly from baseline in the placebo group whereas marginal or no increase was observed in the ibuprofen group (CTX-II +2%, NS and Glc-Gal-PYD +4%, p = 0.045). For urinary CTX-II, the difference in the change from baseline between placebo and ibuprofen treated groups was significant (13%, p = 0.017). At baseline, urinary levels of CTX-II and Glc-Gal-PYD were higher in patients with knee swelling (n = 127) than in those without (n = 74) (p<0.02 for both markers). When patients were stratified according to presence or absence of knee swelling at baseline, the increases over 4-6 weeks of urinary CTX-II and Glc-Gal-PYD in the placebo group were restricted to patients with knee swelling (+22% from baseline, p = 0.001 and +12%, p = 0.011, for urinary CTX-II and Glc-Gal-PYD respectively). In patients with knee swelling who were treated with ibuprofen this increase was not observed and the difference from placebo was significant for urinary CTX-II (p = 0.014). CONCLUSION: In patients with a flare of knee OA, specifically in patients with evidence of joint inflammation documented by knee swelling, there was a significant increase in markers reflecting cartilage and synovium metabolism that could partly be prevented by high doses of ibuprofen. These data suggest that patients with a flare of knee OA are characterised by increased cartilage and synovial tissue degradation, which may be partly prevented by high doses of NSAIDs.

Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis.

OBJECTIVES: To evaluate the clinical efficacy and tolerability of etoricoxib in the treatment of osteoarthritis (OA) of the knee and define the clinically active dose range for further clinical trials. METHODS: This two-part, randomized, double-blind, placebo- and active comparator-controlled trial was conducted in 617 adults with knee OA. In Part 1 (6 weeks), patients received placebo, etoricoxib 5, 10, 30, 60 or 90 mg q.d. In Part 2 (8 weeks), patients received etoricoxib 30, 60 or 90 mg q.d. or diclofenac 50 mg t.i.d., predetermined at Part 1 allocation. Efficacy and safety were evaluated. Primary efficacy end-points were the Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain subscale, Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status. RESULTS: At 6 weeks, etoricoxib 5, 10, 30, 60 and 90 mg each demonstrated clinical efficacy superior to placebo. Maximal efficacy was seen with 60 mg. In Part 2, etoricoxib 30, 60 and 90 mg were generally similar to diclofenac. Patients receiving etoricoxib 30, 60 or 90 mg in Parts I and II had sustained effects over 14 weeks. All treatments were well tolerated. CONCLUSIONS: Etoricoxib 60 mg once daily showed maximal efficacy in treating OA in this study. Etoricoxib 5-90 mg once daily was generally well tolerated in OA patients for up to 14 weeks.

Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet.

BACKGROUND: This study compared directly the renal effects of two selective cyclooxygenase (COX)-2 inhibitors (rofecoxib and celecoxib) with naproxen (dual COX-1/COX-2 inhibitor) and placebo in healthy elderly subjects on a sodium-replete diet. METHODS: A total of 67 elderly subjects stabilized in the clinic for weight and urinary sodium on a controlled 200-mEq sodium diet were randomized in a double-blind fashion to receive rofecoxib, 25 mg daily (n = 17); celecoxib, 200 mg twice daily (n = 17); naproxen, 500 mg twice daily (n = 17); or matching placebo (n = 16) for 28 days. Subjects were sequestered in the clinic for the first 14 treatment days on the controlled diet. RESULTS: Daily urinary sodium excretion during the first 72 hours of treatment (primary endpoint) significantly decreased in rofecoxib, celecoxib, and naproxen groups compared with baseline (P < or =.05). Rofecoxib and celecoxib decreases in urinary sodium excretion rates that were comparable with each other, on the basis of predefined boundaries (-39.5 versus -27.1 mEq/d, respectively) and to naproxen (-40.6, mEq/d). Rofecoxib, celecoxib, and naproxen increased mean systolic blood pressure to a similar degree (3.4, 4.3, and 3.1 mm Hg, respectively, versus -1.3 mm Hg for placebo) after 14 days of treatment; small changes also occurred in diastolic blood pressure (0.3, 0.8, and -0.4 mm Hg, respectively, versus -1.4 mm Hg for placebo). Changes from baseline in creatinine clearance, body weight, and urinary potassium excretion among active treatments were similar. After 28 days of treatment, findings were generally consistent with those at 14 days. No subject reported edema or discontinued treatment as the result of an adverse experience. CONCLUSION: In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

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.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children.

Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. We evaluated the safety and tolerability and the GH-insulin-like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth velocity < 10th percentile for age, height < 10th percentile for age, and a maximum GH response of < or = 10 microg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day -1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x h/L (range, 1.3 to 35.6) for the GH area under the concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001), 12 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/L (range, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis.

Substance P is localised in brainstem regions associated with emesis. Based on studies in the ferret, it was postulated that a neurokinin-1 (NK1) receptor antagonist would have antiemetic activity as monotherapy in humans receiving chemotherapy. L-758,298 is a water-soluble, intravenous (i.v.) prodrug for L-754,030, a potent and selective NK1 receptor antagonist. This double-blind, randomised, active-agent (ondansetron)-controlled study enrolled 53 cisplatin-naïve patients and evaluated the prevention of both acute (0-24 h) and delayed (days 2-7) emesis after cisplatin treatment (50-100 mg/m(2)). All patients received i.v. L-758,298 (60 or 100 mg) (n=30) or ondansetron (32 mg) (n=23) before cisplatin and efficacy was evaluated up to day 7 post-cisplatin. Nausea was assessed by means of a four-point ordinal scale at intervals over the 7 day period. In the acute period, the proportion of patients without emesis in the L-758,298 and ondansetron groups was 37 and 52%, respectively (no significant difference between the groups). Comparing the distribution of average nausea scores over the entire first 24 h revealed no significant difference between the groups. In the delayed period, the proportion of patients without emesis in the L-758,298 and ondansetron treatment groups was 72 and 30%, respectively (P=0.005). The distribution of average nausea scores in the delayed period was lower in the L-758,298 group compared with the ondansetron group (P=0.15 for the entire delayed period and P=0.043 for day 2 only). No serious adverse events were attributed to L-758,298. A single dose of L-758,298 substantially suppressed the delayed nausea and vomiting characteristic of high dose cisplatin and also appeared to reduce acute emesis post-cisplatin. The data also support the proposition that the underlying mechanism(s) of acute and delayed emesis are different.

Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production.

BACKGROUND & AIMS: Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. METHODS: Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2. RESULTS: Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo). CONCLUSIONS: Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.

Renal effects of COX-2-selective inhibitors.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat a variety of inflammatory diseases, these agents may cause deleterious effects on kidney function, especially with respect to solute homeostasis and maintenance of renal perfusion and glomerular filtration. NSAIDs act by reducing prostaglandin biosynthesis through inhibition of cyclooxygenase (COX) which exists as two isoforms (COX-1 and COX-2). NSAID-induced gastrointestinal toxicity is generally believed to occur through blockade of COX-1 activity, whereas the anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. However, the situation in the kidney may be somewhat different. Recent studies have demonstrated that COX-2 is constitutively expressed in renal tissues of all species; this isoform may, therefore, be intimately involved in prostaglandin-dependent renal homeostatic processes. Drugs that selectively inhibit COX-2 might, therefore, be expected to produce effects on renal function similar to nonselective NSAIDs which inhibit both COX-1 and COX-2. This assertion is borne out by recent clinical studies showing that the COX-2 inhibitors rofecoxib and celecoxib procedure qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention, and their consequences similar to nonselective NSAIDs. It, therefore, seems unlikely that these COX-2 inhibitors (and perhaps their successors) will offer renal safety benefits over nonselective NSAID therapies, and, at this juncture, it is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors, share a similar risk for adverse renal effects.

Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women.

GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.

Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers.

The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.

Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.

OBJECTIVE: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor. METHODS: Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. RESULTS: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. CONCLUSION: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

Single dose methodology to assess the influence of an alpha1-adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia.

AIMS: To establish methodology which rapidly and reliably assesses the effect of an alpha1-adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH. METHODS: Twenty-five patients with BPH enrolled in a double-blind, placebo-controlled, two-period crossover study. Patients were either withdrawn from their current alpha1-adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s-1 off therapy (or < 10 ml s-1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s-1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two-period crossover. Uroflowmetry was performed predose and once postdose (4.5-5.5 h postdose) on day 1, and once postdose (4.5-5.5 h postdose) on day 8 of each treatment period. RESULTS: After a single dose of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s-1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s-1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference). CONCLUSIONS: Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for 'responsiveness' to an alpha1-adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.

The effect of rofecoxib on the pharmacodynamics and pharmcokinetics of warfarin.

OBJECTIVE: The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin. METHODS: Two single-dose (12.5 or 50 mg of rofecoxib with 25 mg or 30 mg of oral warfarin, respectively, on day 7 of each period) trials (N = 12 men) and 1 steady-state warfarin trial (25 mg rofecoxib; N = 15, 13 men and 2 women) were completed as two-period, randomized, balanced, crossover, double-blind designs. The prothrombin time international normalized ratio (INR) and S(-) and R(+) warfarin enantiomers were assessed during 144 hours after the single warfarin doses. In the steady-state warfarin trial, after the attainment of a stable INR (1.4-1.7), the stable warfarin dose was co-administered with rofecoxib (25 mg) and placebo over two 21-day periods. After the dose of warfarin on day 21, INR and S(-) and R(+) warfarin were assessed during 24 hours. RESULTS: Compared with placebo, rofecoxib slightly increased the INR by approximately 5% (90% confidence interval on the geometric ratio, 1.03, 1.08) and 11% (1.04, 1.19) for the two single-dose warfarin trials with 12.5 and 50 mg of rofecoxib, respectively. In the steady-state warfarin study with 25 mg of rofecoxib, the INR was increased by 8% (1.02, 1.15). Rofecoxib had no significant effect (versus placebo) on the pharmacokinetics of S(-) warfarin. However, in the 3 studies, treatment with 12.5, 25, and 50 mg of rofecoxib was associated with a 27%, 38%, and 40% increase in the area under the plasma concentration-time curve of the biologically less active R(+) warfarin. CONCLUSIONS: Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR. The approximately 8% increase in INR at steady state with warfarin co-administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin.

Concurrent administration of the erythromycin breath test (EBT) and oral midazolam as in vivo probes for CYP3A activity.

Given the prominent role of CYP3A in the metabolism of drugs, it is important to identify whether new chemical entities will affect this enzyme system and produce clinically relevant drug interactions. This study evaluated concomitant administration of intravenous [14C N-methyl] erythromycin (3 microCi) (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and of systemic plus presystemic CYP3A activity, respectively. Twelve males received the probes in a two-period crossover fashion: one period included the probes on two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given orally 2 hours prior to the probes. The within-subject CV for EBT (%14CO2/h) and midazolam AUC0-last was 4.9% and 16.9%, respectively. Ketoconazole reduced %14CO2/h by 43% and increased midazolam AUC0-last by approximately fivefold. In a nonrandomized third period (N = 5), ketoconazole was given simultaneously with midazolam (no EBT); midazolam AUC0-last was similar whether ketoconazole was given 2 hours prior to or simultaneously with the midazolam. The low midazolam dose was generally well tolerated; mild sedation was occasionally seen. Concurrent administration of the EBT and oral midazolam is a sensitive and reproducible tool to screen new chemical entities for potentially important CYP3A interactions.

Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group.

OBJECTIVE: To determine the efficacy and safety of the cyclooxygenase 2 (COX-2) specific inhibitor, rofecoxib in patients with osteoarthritis (OA) of the knee. METHODS: Rofecoxib, 25 mg or 125 mg once daily, was compared with placebo in a 6 week, double blind, parallel group, randomized, multicenter study of 219 patients with knee OA. RESULTS: Both doses of rofecoxib produced clinically significant improvement as assessed by primary (e.g., WOMAC Pain Subscale 0-100 mm, decrease from baseline: placebo: 7.1 mm; rofecoxib 25 mg: 28.1 mm, rofecoxib 125 mg: 28.0 mm; p < 0.001 rofecoxib vs placebo) and secondary efficacy (p < 0.05) criteria compared with placebo. Clinical improvement with the 25 mg dose was similar to that with the 125 mg dose. Both rofecoxib doses were generally well tolerated. CONCLUSION: Specific inhibition of COX-2 by 25 and 125 mg rofecoxib, administered once daily, resulted in clinically meaningful improvements in patients with OA. This study confirms that COX-2 derived prostanoids are important clinical mediators of pain and other symptoms of knee OA and that inhibition of COX-1 is not required to provide clinical benefit.

Substance P-induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man.

AIMS: Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. METHODS: Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min-1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298. RESULTS: L-758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (-0.49 to +0.49) ml 100 ml-1 min-1, 1. 0 (-3.2 to +5.2) mmHg and 1.9 (-5.9 to +9.7) beats min-1, respectively. Twenty-four hours after 1.43 mg of L-758,298, there was approximately 34-fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml-1. L-758 298 was generally well tolerated without serious adverse events. CONCLUSIONS: Substance P induced forearm vasodilatation is mediated by the endothelial cell NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.