Non-PCa Prescription Drugs: Celebrex

Shortly before Dr. John Vane, the Nobel Prize winner, whose work contributed to the development of the COX-2 inhibitor drugs, died in 2004, he might have become aware that experts were predicting the demise of that entire class of drugs, following the withdrawl of Vioxx from the Market a few weeks earlier.

"The 3-year clinical trial called APPROVe (Adenomatous Polyp Prevention of Vioxx), which was halted in late September (2 months before it was scheduled to end), was evaluating the efficacy of rofecoxib in preventing the recurrence of colorectal polyps among patients with a history of colorectal adenomas. It revealed an increased relative risk for serious cardiovascular events, including heart attacks and strokes, beginning after 18 months of treatment among patients taking rofecoxib that was about twice that of patients taking placebo. The results for the first 18 months of the study did not show any increased risk." [1]

(Strange that there was no increased risk for the first 18 months.)

I remember arthritis sufferers panicking because the new COX-2 inhibitors were the only pain killers that gave many of them relief.

Well, Pfizer was permitted by the FDA to keep Celebrex on the market, provided that it did a study. The study, now ended, (conveniently timed for after the drug became generic,) seems to absolve the drug from the charge of having excess cardiovascular risk.

The first thing to note is that Celebrex was found to be no riskier than chronic use of ibuprofen or naproxen. That's setting the bar low. In contrast, the Vioxx study compared the drug to placebo.

There was a two-third dropout rate during the study.

Only 20% of the participants had heart disease, making it a low-risk population.

& the Celebrex dose was comparatively much lower that the high dose used in the Vioxx study:

"Patients were randomly assigned, in a 1:1:1 ratio, to receive celecoxib (100 mg twice a day), ibuprofen (600 mg three times a day), or naproxen (375 mg twice a day) with matching placebo. At subsequent visits, for patients with rheumatoid arthritis, investigators could increase the dose of celecoxib to 200 mg twice a day, the dose of ibuprofen to 800 mg three times a day, or the dose of naproxen to 500 mg twice a day for the treatment of symptoms. For patients with osteoarthritis, increases in the doses of ibuprofen and naproxen were permitted; however, regulatory dosing restrictions precluded dose escalation for celecoxib in these patients. Esomeprazole (20 to 40 mg) was provided to all patients for gastric protection."

Anyway, Celebrex is now considered to be safe.

...

Four months ago I posted:

"Foods/Supplements-Vitamins: Arachidonic acid [AA]",

which contains a section on COX-2 inhibitors [3] - specifically Celebrex.

Three intervention studies are mentioned (details below signature). Doses used were 400 mg twice daily - four times that used in the new study.

Study [3c] - the STAMPEDE study - concluded that:

"Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting."

...

Also in my post, I mention how "PCa cells chronically activate NF-kB (nuclear factor-kappaB). NF-kB, when activated, causes the transcription of many pro-survival proteins ..."

IMO, it's a mistake to focus on COX-2. COX-2 inhibitors do not inhibit COX-1, which means that they do not inhibit NF-kB. NF-kB activation leads to COX-1, COX-2, 5-LOX, 12-LOX & 15-LOX. These enzymes act on arachidonic acid to produce a range of products - see [4] for details. Each can be inhibited selectively, perhaps, but the proper target is NF-kB.

-Patrick

[1] cmaj.ca/content/171/9/1027....

[2] nejm.org/doi/full/10.1056/N...

[3] "COX-2 Inhibitors.

There have been three intervention studies using Celecoxib (celebrex), a selective COX-2 inhibitor:

[3a] (2006 - U.S.)

"To assess the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in prostate-specific antigen (PSA) doubling time (PSADT) as the primary outcome variable."

"Participants had histologically confirmed prostate cancer, no recent hormone therapy, rising serum PSA after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases. Patients were randomly assigned to celecoxib (400 mg by mouth twice daily) or placebo. Treatment continued until disease progression or until adverse effects stopped treatment. A positive outcome was defined as post-treatment PSADT of more than 200% baseline PSADT with no new metastases."

"The study was terminated early after information about the cardiovascular safety of celecoxib prompted review of ongoing clinical studies."

However:

"Eight (20%) of 40 men in the placebo group and 15 (40%) of 38 men in the celecoxib group had post-treatment PSADT of more than 200% of baseline PSADT with no new metastases"

"Mean PSA velocity increased by 3.0% for the placebo group and decreased by 3.4% for the celecoxib group ..."

"Although the primary efficacy objective was not met, this study provides some evidence for biologic activity of celecoxib in prostate cancer. Compared with placebo, celecoxib significantly decreased mean PSA velocity and tended to increase the proportion of men who doubled their PSADT."

[3b] (2009 - U.S. - Johns Hopkins)

"Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy."

"Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies."

[3c] (2012 - International - the STAMPEDE study)

"Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A)."

"At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94"

"Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting."

[4]

"- The enzymes cyclooxygenase-1 and -2 (i.e. prostaglandin G/H synthase 1 and 2 {PTGS1 and PTGS2}) metabolize arachidonic acid to Prostaglandin G2 and prostaglandin H2, which in turn may be converted to various prostaglandins, to prostacyclin, to thromboxanes, and to the 17-carbon product of thromboxane metabolism of prostaglandin G2/H2, 12-Hydroxyheptadecatrienoic acid (12-HHT).[8][9]

"- The enzyme 5-lipoxygenase metabolizes arachidonic acid to 5-hydroperoxyicosatetraenoic acid (5-HPETE), which in turn is metabolized to various leukotrienes (i.e. leukotriene B4, leukotriene C4, leukotriene D4, and leukotriene E4 as well as to 5-hydroxyicosatetraenoic acid (5-HETE) which may then be further metabolized to 5-HETE's more potent 5-keto analog, 5-oxo-eicosatetraenoic acid (5-oxo-ETE) (also see 5-Hydroxyicosatetraenoic acid.[10]

"- The enzymes 15-lipoxygenase-1 (ALOX15 and 15-lipoxygenase-2 (ALOX15B metabolize arachidonic acid to 15-hydroperoxyicosatetraemoic acid (15-HPETE) which may then be further metabolized to 15-hydroxyicosatetraenoic acid (15-HETE) and lipoxins;[11][12][13] 15-Lipoxygenase-1 may also further metabolize 15-HPETE to eoxins in a pathway analogous to (and presumably using the same enzymes as used in) the pathway which metabolizes 5-HPETE to leukotrienes.[14]

"- The enzyme 12-lipoxygenase (ALOX12) metabolizes arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE0 which may then be metabolized to 12-hydroxyeicosatetraenoic acid (12-HETE) and to hepoxilins.[15]"

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