Aimee Dallob

Characterization of rofecoxib as a cyclooxygenase‐2 isoform inhibitor and demonstration of analgesia in the dental pain model

Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX‐1) and inducible (COX‐2) isoforms of cyclooxygenase. The induction of COX‐2 after inflammatory stimuli has led to the hypothesis that COX‐2 inhibition primarily accounts for the therapeutic properties of NSAIDs.

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.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia

BACKGROUND Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

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

AbstractObjective: 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 (VioxxTM), 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.

Characterization of Etoricoxib, a Novel, Selective COX‐2 Inhibitor

Etoricoxib is a potent selective COX‐2 inhibitor in man. Ex vivo whole‐blood assays assessed COX‐2 inhibition after oral administration of etoricoxib in single (5–500 mg) and multiple (25–150 mg) once‐daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2 synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of etoricoxib 120 mg qd on the COX‐1‐mediated antiplatelet effects of low‐dose aspirin (ASA) was also assessed. The mean (time)–weighted average inhibition (WAI) of lipopolysaccharide (LPS)–stimulated PGE2(COX‐2 assay) versus placebo was dose related after single (range: 3.1%–99.1%) and multiple doses (range: 52.5%–96.7%). PGE2 remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS‐stimulated PGE2 showed a strong relationship with etoricoxib plasma concentrations; ex vivo, IC50 was almost identical to in vitro. Multiple dosing of etoricoxib (up to 150 mg qd) showed no important effects on serum TXB2, bleeding time, or platelet aggregation (COX‐1‐mediated effects). The nonselective nonsteroidal anti‐inflammatory (NSAID) naproxen significantly inhibited (∼78%) ex vivo prostaglandin synthesis in gastric mucosa; etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low‐dose ASA, as assessed by serum TXB2 and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, etoricoxib is a potent selective inhibitor of COX‐2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.

Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects.

We determined cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 inhibition in healthy middle‐aged subjects (41–65 years) randomly assigned to four 7‐day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double‐blind, randomized, 4‐period crossover study. Maximum inhibition of thromboxane B2 (cyclo‐oxygenase‐1 activity) in clotting whole blood on day 7 (0–24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide‐induced prostaglandin E2 in whole blood (cyclo‐oxygenase‐2 activity) was assessed on day 7 (0–24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B2 versus each comparator (P < .001); placebo 2.4% (95% confidence interval: −8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E2 synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2, whereas etoricoxib and celecoxib significantly inhibit cyclo‐oxygenase‐2 and do not substantially inhibit cyclo‐oxygenase‐1.

Pharmacological evidence for a role of lipoxygenase products in platelet-activating factor (PAF)-induced hyperalgesia

Platelet-activating factor (PAF), a potent inflammatory mediator, decreases the nociceptive threshold in the rat hindpaw. Pain sensitivity, measured by the applied pressure necessary to induce vocalization, was increased maximally at 3 and 4 hr after injection of synthetic PAF. The hyperalgesic response to PAF was specifically inhibited by agents that interfere with the lipoxygenase pathway of arachidonic acid metabolism and was not affected by cyclooxygenase inhibitors. BW-755C (3-30 mg/kg, p.o.) and L-615,919 (0.01-0.3 mg/kg, p.o.) significantly reduced PAF-induced hyperalgesia, whereas indomethacin had no effect. The finding that L-615,919, a specific 5-lipoxygenase inhibitor, was a potent inhibitor of this model of hyperalgesia leads to speculation that leukotrienes are important mediators of inflammatory pain.

Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation

Injection of brewers yeast into the rat paw results in edema and a subsequent hyperalgesia. The edema was accompanied by an increase in 5-lipoxygenase products, and the hyperalgesia coincided with the formation of both cyclooxygenase and 5-lipoxygenase products. When administered perorally, indomethacin inhibited cyclooxygenase product formation, phenidone inhibited 5-lipoxygenase product formation, and 3-amino-1-(m-[trifluoromethyl]-phenyl)-2-pyrazoline (BW 755C) inhibited formation of products of both pathways. These compounds were also effective analgesic agents. The correlation of these effects with the suppression of hyperalgesia suggests the participation of products from both cyclooxygenase and 5-lipoxygenase pathways in the mediation of hyperalgesia.

Cerebrospinal Fluid Biomarkers Distinguish Postmortem-Confirmed Alzheimer's Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimers disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.

Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD2 receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC50 of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC50 for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC50 does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.