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Rofecoxib

Rofecoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID). It was marketed by Merck & Co. to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenorrhea. Rofecoxib was approved in the US by the US Food and Drug Administration (FDA) in May 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx. Rofecoxib was available by prescription in both tablets and as an oral suspension.

Rofecoxib gained widespread use among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

In September 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.

In 2005, the FDA issued a memorandum concluding that risks for serious cardiovascular (CV) events seem to be as great for nonselective NSAIDs as for COX-2–selective agents such as rofecoxib, according to long-term, controlled clinical trials. Based on data up to 2015, the FDA reasserted the likelihood of an increased risk of serious adverse CV events from COX-2–selective and nonselective NSAIDs, dependent on dose and duration.

In November 2017, Massachusetts-based Tremeau Pharmaceuticals announced its plan to return rofecoxib (TRM-201) to market as a treatment for hemophilic arthropathy (HA). Tremeau announced that the FDA had granted an orphan designation for TRM-201 (rofecoxib) for the treatment of HA, and that they had received FDA feedback on their development plan. HA is a degenerative joint disease caused by recurrent intra-articular bleeding. It is the largest cause of morbidity in patients with hemophilia and has no currently approved treatment options in the United States. Traditional NSAIDs are avoided in this population due to their effects on platelet aggregation and risk of gastrointestinal ulcers, and high potency opioids are the current standard of care in treating HA.

Mode of action
Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2. COX-1 mediates the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or "coxib".

Though the class of coxibs includes several agents, degrees of COX-2 selectivity vary among them, with celecoxib (Celebrex) being the least COX-2 selective, and rofecoxib (Vioxx), valdecoxib (Bextra), and etoricoxib (Arcoxia), being highly COX-2 selective.

At the time of its withdrawal, rofecoxib was the only coxib approved in the United States with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen.

Pharmacokinetics
The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%. Rofecoxib crossed the placenta and blood–brain barrier, and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) around 17 hours. The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib which are primarily excreted through urine.

Efficacy
Rofecoxib was approved by the FDA to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenorrhea. When it was marketed, it gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain.

Premenstrual acne
A 2003 placebo-controlled, small, short-term study in India of 80 women with premenstrual acne vulgaris, were given rofecoxib or placebo for two cycles of 10 days suggest that "rofecoxib is effective in the management of premenstrual acne.

Fabricated efficacy studies
On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated, overstating the analgesic effects of the drugs. No evidence has been found that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. Drug manufacturer Merck had no comment on the disclosure.

Side effects

In addition to the reduced incidence of gastric ulceration, rofecoxib exhibits no effect on bleeding time or platelet aggregation, even at supratherapeutic doses. Aside from these features, rofecoxib exhibits a similar adverse-effect profile to other NSAIDs.

VIGOR study and publishing controversy
The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., compared the efficacy and adverse-effect profiles of a supratherapeutic dose of rofecoxib (50 mg/day) vs. a common dose of naproxen (500 mg/BID), had indicated a significant four-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, relative risk 0.25) over a mean duration of 9 months. The elevated risk began during the second month on rofecoxib. No significant difference in the mortality from cardiovascular events was seen between the two groups, nor did any significant difference occur in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass).

Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect. The Martin Report excused senior management by stating they believed they were victims of Pfizer's alleged manipulation of test results to promote their product as a safer alternative. Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference, and some outside scientists warned Merck that this claim was implausible before VIGOR was published. No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.

The results of the VIGOR study were submitted to the US FDA in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four- to five-fold increase in myocardial infarctions (MIs) compared to patients on the comparator nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine in November 2000, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data. They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.

The editors charged that "more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article." These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the "aspirin not indicated" group) and the editors noted that the omission "resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups." The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statistically insignificant). The editors also noted a statistically significant (two-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection, thus were appropriately not included. (Using the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table were printed in the text of the article. The authors stood by the original article.

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).

Some scientists have accused the NEJM editorial board of making unfounded accusations. Others have applauded the editorial. Renowned research cardiologist Eric Topol, a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up". Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies".

On May 15, 2006, the Wall Street Journal reported that a late-night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that "the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine's own role in aiding Vioxx sales."

"Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article." The Journal stated that NEJM's "ambiguous" language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; "the New England Journal says it didn't attempt to have these mistakes corrected." Investigations revealed that Merck had several years worth of information suggesting an elevated risk of cardiac events, and Vice President Edward Scolnick took much of the blame for the suppression of this information.

The FDA reviewers were aware of the potential for cardiovascular risk in 1999 and it was argued that Merck had manipulated their EKG tests one week after the external review board provided their consultation to specifically exclude high risk factors from the trial subjects to avoid finding effect then predated the changes to their trials to almost three months earlier.

Alzheimer's disease
In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib. Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety.

APPROVe study
In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib, as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Other studies
Preapproval phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first 18 months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090", a preapproval trial, showed a three-fold increase in cardiovascular events compared to placebo, a seven-fold increase compared to nabumetone (another NSAID), and an eight-fold increase in heart attacks and strokes combined compared to both control groups. Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib's cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.

Other COX-2 inhibitors
In 2005, the FDA issued a memo concluding that along with the other approved COX-2 selective NSAIDs available at the time (i.e., celecoxib, and valdecoxib), rofecoxib was associated with an increased risk of serious adverse cardiovascular events compared to placebo. They also noted that the available data did not permit a rank ordering of these drugs with regard to cardiovascular risk.

Only Celebrex (generic name is celecoxib) is still available for purchase in the United States.

Regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:

 * Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
 * Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
 * Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

Other NSAIDs
Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older "trusted" NSAIDs such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.

Analyses in 2011 and 2013 by McGettigan and the Coxib and traditional NSAID Trialists (CNT) Collaborators, respectively, demonstrated that the risk of serious CV events was a dose dependent effect of COX-2 selective and nonselective NSAIDs, with the possible exception of naproxen, and high therapeutic doses of nonselective NSAIDs (e.g. ibuprofen 2400 mg/day, diclofenac 150 mg/day) carried similar CV risk when compared to a combined group of therapeutic and supra-therapeutic doses of COX-2 selective  NSAIDs (such as rofecoxib).

In 2014, Patrono and Baigent, summarizing all of the currently available data in a review article in Circulation, concluded that with the exception of GI toxicity, neither the efficacy nor the major cardiorenal complications of COX-2 selective NSAIDs appear to be influenced by their level of COX-2 selectivity. They concluded that the CV risk associated with NSAIDs was dependent on dose and duration.

This conclusion was further reinforced by the 2016 results of the celecoxib PRECISION trial, which showed no difference in CV event rates between the COX-2 selective NSAID celecoxib and the non-selective NSAIDs ibuprofen and naproxen.

Withdrawal
Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.

In addition to its own studies, on September 23, 2004, Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). One FDA analyst estimated that, based upon his mathematical model, Vioxx may have caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market. Senior FDA officials were quick to note, however, that this estimate was based solely on a mathematical model, and must be interpreted with caution.

On November 5, 2004, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk.

Merck-sponsored "Martin Report", 2006
In 2005, Merck spent $21 million US to retain John S. Martin Jr., a former US District Judge for the Southern District of New York, and colleagues at Debevoise & Plimpton LLP, to investigate Vioxx study results and communications conducted by Merck. The report, which Merck called the "Martin Report", was published in February 2006. The report found that Merck's senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team's overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and stated that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information were described as the result of oversight, not malicious behavior. The report did conclude that the Merck's marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics. Merck was satisfied with the findings of the report it had commissioned, and promised to consider the recommendations. The report was criticised in the press as self-serving. Merck insisted that the report was independent and Merck "had no effect at all on the findings and the conclusions". Merck hoped that the report would improve public perception of Merck.

FDA position
In 2005, advisory panels in both the US and Canada encouraged the return of rofecoxib to the market, stating that Rofecoxib's benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel stated that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.

Following the 2005 FDA Advisory Committee, the FDA issued a memo concluding that data from large long-term controlled clinical trials do not clearly demonstrate that COX-2 selective agents (including rofecoxib) have a greater risk of serious cardiovascular events than non-selective NSAIDs.

In 2015, the FDA reinforced this conclusion, stating that the available data support a dose and duration dependent class effect of an increased risk of serious adverse cardiovascular events for COX-2 selective and non-selective NSAIDs.

Litigation
By March 2006, there were over 10,000 cases and 190 class actions filed against Merck over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck's warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.

On August 19, 2005, a jury in Texas voted 10–2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award was capped at no more than US$26.1 million because of punitive damages limits under Texas law. Merck appealed and the verdict was overturned in 2008. On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston's injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005, in Houston. The trial ended on December 12, 2005, when Judge Eldon E. Fallon of U.S. District Court declared a mistrial because of a hung jury with an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas Courts of Appeals in San Antonio later ruled Garza's fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.

On April 5, 2006, a jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded McDarby $4.5 million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr. McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona.

In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale.

By November 2007 Merck announced that it agreed on a mass tort settlement of $4.85 billion between Merck and the lawyers of 27,000 individual lawsuits with a try-every-case strategy as opposed to a class action lawsuit if "85 percent of the plaintiffs sign up". After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees. Ultimately, the judge determined how the fees would be awarded to the plaintiff's attorneys. Judge Eldon E. Fallon of the United States District Court for the Eastern District of Louisiana additionally ordered the plaintiff lawyers to cap their fees at 32% of the settlement amount.

The above dispute over lawyer fees has caused scholars and observers to consider tort reform throughout the country. Articles on the subject include The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of Lawyers in Mass Tort Litigation and 10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts.

In November 2011, Merck announced a civil settlement with the US Attorney's Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx. Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck pleaded guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.

Possible return to market
In November 2017, Massachusetts-based Tremeau Pharmaceuticals announced its plan to return rofecoxib (TRM-201) to market as a treatment for hemophilic arthropathy (HA). Tremeau announced that the FDA had granted an orphan designation for TRM-201 (rofecoxib) for the treatment of HA, and that they had received FDA feedback on their development plan. HA is a degenerative joint disease caused by recurrent intra-articular bleeding. It is the largest cause of morbidity in patients with hemophilia and has no currently approved treatment options in the United States. Traditional NSAIDs are avoided in this population due to their effects on platelet aggregation and risk of gastrointestinal ulcers, and high potency opioids are the current standard of care in treating HA.

In March 2019 Tremeau announced that they had hired as chief development officer a former Merck employee who had been a product development team leader and also was responsible for executive oversight for numerous clinical trials for the COX-2 inhibitor VIOXX (rofecoxib). Tremeau also announced an upcoming clinical trial for rofecoxib and were seeking investigators.

On February 15, 2022, California-based BriOri Biotech announced that it had been issued a patent covering topical formulations of rofecoxib.

title: Rofecoxib


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Talk:The Art of Unix Programming

Free Speech AND Beer

 * In the spirit of the open source community, the author has made the book freely available online.

The spirit of the open source community is about collaborative development - ESR released this book under a license which prohibits modification. The term "open source" was invented to dispell the confusion between "free speech" and "free beer". Free Software and Open Source software are supposed to be free as in "free speech". ESR made this book available for free as in "free beer" - which is not what Open Source is about. He also violated his own rule of development by writing this book in a Cathederal style.

If someone would care to add a critique of the imaginary history that ESR has woven into this book, that'd be good. (I've done enough ESR exposing for one day.) Sometimes I think ESR edits these pages himself.Markvs 21:34, 11 May 2004 (UTC)

 * And the FSF doesn't allow modification of the text of the GPL, nor Richard Stallman of his philosophy essays. "Copyright (C) 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004 Free Software Foundation, Inc., 59 Temple Place - Suite 330, Boston, MA 02111, USA Verbatim copying and distribution of this entire article is permitted in any medium, provided this notice is preserved." - David Gerard 22:05, May 11, 2004 (UTC)

 * FSF allows modification of their technical documentation. Philosophical stuff misrepresent the author if it was modified - technical stuff will misrepresent the subject matter if it is not modifiable.  Software changes, the manuals need to be updated, or they'll be wrong.  Documentation bugs can be found by anyone familiar with the software, and they should be allowed to fix them.  Philosophical bugs cannot be judged by anyone but the author, so modification is not necessary.  If the GPL was modifiable, legal uncertaintly would be created (which "GPL" is this software under?), and more incompatible derivative licenses would be created by companies that want to claim to be using "the GPL".  (I won't defend the GNU Free Documentation License, I think it's a bad license, but if ESR wanted to claim that this book contained philosophical bits - which it does - the GFDL would have allowed him to mark them as "Invariant Sections", and the technical bits could have been modifiable.)

 * I think it's noteworthy that in the making of this book, ESR has ignored the two rules that he tells everyone else to follow (OpenSource + Bazaar), but if you think this should be omitted, I won't put it back. My wording was a bit weird, maybe "It's worth noting that this book is not Open Source." would've been better.Markvs 22:43, 11 May 2004 (UTC)

 * Look at the name of the book. "The Art Of". It's not technical documentation or a work like Stallman's biography - it's blowharding philosophy. I really don't see why it's at all remarkable that it's under something close to a "reproduce verbatim" license - David Gerard 23:05, May 11, 2004 (UTC)

 * Regarding your second point, If someone would care to add a critique of the imaginary history that ESR has woven into this book, that'd be good -- I don't think that would be appropriate for an encyclopaedia article, but I'd be curious if someone would elaborate on this elsewhere. -- Jon Dowland (talk) 13:19, 19 February 2008 (UTC)

 * By the way, aren't these terms self-contradictory? It says it's CC BY-ND 1.0 without NC "with the additional proviso that the right to publish it on paper for sale or other for-profit use is reserved to Pearson Education, Inc.". Is commercial use allowed or not? Ian (77.254.5.199 (talk) 13:59, 5 August 2009 (UTC))

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Talk:The Art of Unix Programming


text:
Daniello Bartoli

Daniello Bartoli, SJ (12 February 1608 – 13 January 1685) was an Italian Jesuit writer and historiographer, celebrated by the poet Giacomo Leopardi as the "Dante of Italian prose"

Ferrara
He was born in Ferrara. His father, Tiburzio was a chemist associated with the Este court of Alfonso II d'Este. When the papacy refused to recognize his illegitimate successor the court moved in 1598 under Cesare d'Este, Duke of Modena. During the Cinquecento and due to a host of writers including Ariosto and Tasso Renaissance Ferrara was the literary capital of Italian letters along with Florence, whereas the language of papal Rome was humanist Latin. His identity as a Ferrarese and a Lombard is touted in the pseudonym, Ferrante Longobardi which he used to sustain his independence from the linguistic tyranny of Florence in Il torto ed il diritto del "Non si può" (1655).

Vocation and Studies

Daniello was the youngest of three sons and barely fifteen when embraced a vocation to the Society of Jesus in 1623. Debarred by his superiors because of his manifest literary talents from the missions in the Indies he would later describe, he attained high distinction in science and letters. After a novitiate of two years at Novellara, Bartoli resumed his studies in Piacenza in 1625. In Parma (1626–29) he completed his philosophate and (1629–34) he taught grammar and rhetoric to the boys of the Jesuit collegio. Under Jesuit scientists Giovanni Battista Riccioli and Niccolo Zucchi the young Bartoli, together with his younger contemporary Francesco Maria Grimaldi was involved in noteworthy experiments and discoveries of the planetary heavens. Bartoli along with Zucchi is credited as having been one of the first to see the equatorial belts on the planet Jupiter on May 17, 1630. And in his old age he would return to the world of science. He was ordained a priest in 1634 and continued his studies in Milan and Bologna. In his thirties he was an esteemed preacher delivering the Lenten sermons at the principal Jesuits churches of Italy including Ferrara, Genoa, Florence and Rome. While in Ferrara he also published a collection of poems under the name of a nephew, as the Jesuits in Italy were not allowed to publish poetry. In his first published work he will quote from a number of these, anonymously. At 35 Bartoli pronounced his final vows as a professed Jesuit in Pistoia on July 31, 1643. In 1645 his treatise on the man of letters, L'huomo di lettere difeso ed emendato catapulted him to national celebrity and international fame as a leading contemporary writer of the High Baroque age. For the rest of the century his treatise was considered a masterpiece of erudition and eloquence. It  became a staple of the Italian printing industry and was much sought after and translated. During the process of her conversion to Roman Catholicism at the hands of the Jesuits in the 1650s Christina, Queen of Sweden specifically requested a copy of this celebrated work be sent to her in Stockholm. Heading to preach in Palermo he survived a shipwreck off Capri in 1646, but lost the manuscripts of his sermons. Because of his growing fame his superiors put an end to his decade as an itinerant preacher and brought him permanently to the order's headquarters in Rome. In 1648 his was appointed Jesuit historiographer and spent the next four decades writing his great history, as well as moral, spiritual and scientific treatises.

Baroque Rome

The remarkable success of Bartoli's literary debut coincided with the triumph of the High Baroque in Rome and it serves as a testament to the formative role of the Italian Jesuits as cultural entrepreneurs meditating between the sacred and the profane elements of the age. L'huomo di lettere (1645) became a cultural vademecum for the aspirations of a new generation of humanist intellectuals. Its eloquence and erudition found a lively balance between devotion to antiquity and consciousness of the modern. In Italy it was a bestseller. During the decades of Bartoli's life that followed, the work had editions and reprints nearly annually in Rome, Bologna, Florence, Milan and especially Venice. In the same period there were translations in French, German, English, Latin, Spanish and later Dutch. But history was his main task as a Jesuit man of letters. As such Bartoli represents the shift from the preceding Latin humanist historiography of Niccolò Orlandini and Francesco Sacchini to the illustrious Jesuit prose tradition he established in Italian when he undertook the official history of the first century of the Society of Jesus (1540). His monumental Istoria della Compagnia di Gesu (Rome, 1650–1673), in 6 folio vols. is the longest Italian classic. It begins with an authoritative, if somewhat ponderous, biography of the founder Ignatius Loyola. Particularly fascinating and exotic are his histories of Francis Xavier and the Jesuit missions in the East which describe India and the opening of the East, L'Asia (1653) in eight books. A shorter work on Akbar the Great and Rodolfo Acquaviva came out in 1653 and was added to the third edition of L'Asia in 1667. Part II of the first corner of the world he completed was Japan, Il Giappone (1660) in five books, and the Part III on China, La Cina appeared in four books (1663). To these he opened his projected Europa with the missions on the Jesuits in England,  L'Inghilterra (1667) and a final work on the opening years of the order in the Italy of St. Ignatius, Diego Laynez and Francis Borgia, L'Italia (1673). With these histories he alternated treatises on language use, Del torto e del diritto del non si può and moral works of like La Ricreazione del savio. In the 1660s the Lyons Jesuit Louis Janin, translator of L'huomo di lettere issued Latin translations of these histories. From 1671 to 1674 Bartoli served as Rector of the Collegio Romano in recognition of his international prestige as a writer. Indefatigible in his final years Bartoli produced 4 Jesuit biographies and three scientific treatises on pressure, sound, coagulation. His several works of spiritual reflection were brought together a folio edition, Le Morali in 1684. His final work, Pensieri sacri went to press after his death in Rome, January 13, 1685.

During the early nineteenth century, of Leopardi and of Manzoni, Bartoli became the literary paragon as a master of prose style. Outstanding among the numerous printings and anthologies of his works from that period is the standard octavo edition of his complete works beautifully printed by Giacinto Marietti, Turin, 1825-1842 in 34 volumes.

Literary writings and historical works

 * Dell'huomo di lettere difeso ed emendato 1645
 * La povertà contenta 1649
 * Della vita e dell'istituto di s. Ignatio, fondatore della Compagnia di Gesù 1650
 * Della vita del p. Vincenzo Caraffa, settimo generale della Compagnia di Gesù 1651
 * L'Asia 1653
 * Missione al gran Mogor del p. Rodolfo Acquaviva 1653
 * L'Eternità Consigliera 1653
 * Il torto ed il diritto del "Non si può" 1655 (under the pseudonym "Ferrante Longobardi")
 * La ricreazione del savio 1659
 * Il Giappone, parte seconda dell'Asia 1660
 * La Cina, terza parte dell'Asia 1663
 * La geografia trasportata al morale 1664
 * L'Inghilterra, parte dell'Europa 1667
 * L'huomo al punto, cioè l'huomo al punto di morte 1669
 * Dell'ultimo e beato fine dell'uomo 1670
 * Dell'ortografia italiana 1670
 * L'Italia, prima parte dell'Europa 1673
 * Della tensione e della pressione 1677
 * Del suono, dei tremori armonici, dell'udito 1679
 * Del ghiaccio e della coagulatione 1682
 * In addition to his magnum opus, the Istoria della Compagnia di Gesu for which he wrote 6 volumes, as Jesuit historiographer Bartoli produced 5 Jesuit Lives: Vincenzo Caraffa 1651, Robert Bellarmine 1678, Stanislas Kostka 1678, Francis Borgia 1681, and his teacher, the astronomer Niccolò Zucchi 1682.
 * Degli uomini e dei fatti della Compagnia di Gesu: Memorie storiche, an annalistic chronicle of the first Jesuit half century, (1540–1590), left in mss. at his death, was printed in five volumes by Marietti (Turin: 1847-56), in supplement to his 34 volume Opere.

References and online links
Notes

Select Bibliography

 * A. Belloni: Daniello Bartoli (1608-1685), Turín, 1931.
 * M. Scotti: Prose scelte di Daniello Bartoli e Paolo Segneri, Turín, 1967.
 * Daniello Bartoli, storico e letterato. Atti del Convegno Nazionale di Studi Organizzato dall'Accademia delle Scienze di Ferrara (18 settembre 1985), Ferrara, 1986.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * M. Scotti: Prose scelte di Daniello Bartoli e Paolo Segneri, Turín, 1967.
 * Daniello Bartoli, storico e letterato. Atti del Convegno Nazionale di Studi Organizzato dall'Accademia delle Scienze di Ferrara (18 settembre 1985), Ferrara, 1986.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * M. Scotti: Prose scelte di Daniello Bartoli e Paolo Segneri, Turín, 1967.
 * Daniello Bartoli, storico e letterato. Atti del Convegno Nazionale di Studi Organizzato dall'Accademia delle Scienze di Ferrara (18 settembre 1985), Ferrara, 1986.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * Daniello Bartoli, storico e letterato. Atti del Convegno Nazionale di Studi Organizzato dall'Accademia delle Scienze di Ferrara (18 settembre 1985), Ferrara, 1986.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * Daniello Bartoli, storico e letterato. Atti del Convegno Nazionale di Studi Organizzato dall'Accademia delle Scienze di Ferrara (18 settembre 1985), Ferrara, 1986.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.
 * Ditchfield, Simon Richard (2019) The Limits of Erudition: Daniello Bartoli SJ (1608-85) and the mission of writing history. In: Hardy, Nicholas and Levitin, Dmitri, (eds.) Confessionalisation and Erudition in Early Modern Europe. Proceedings of the British Academy. Oxford University Press, Oxford, pp. 218-239.

title: Daniello Bartoli


text:
Fredy Perlman

Fredy Perlman (1934–1985) was an American author, publisher, and activist. His best-known work, Against His-Story, Against Leviathan!, retells the historical rise of state domination (and domination generally) through a poetic investigation the Hobbesian metaphor of the Leviathan.

Early life
Perlman was born August 20, 1934, in Brno, Czechoslovakia, to Henry and Martha Perlman. His family immigrated first to Cochabamba, Bolivia to escape the Holocaust and later to the United States. Perlman received a master's degree from Columbia University and a PhD from University of Belgrade. He married Lorraine Nybakken in January 1958.

Career
His best-known work, Against His-Story, Against Leviathan (1983) rewrites the history of humanity as a struggle of free people ("zeks") resisting the sovereign nation-state (Leviathan). The book influenced the anarcho-primitivist author John Zerzan. Philosopher John P. Clark states that Against His-Story, Against Leviathan! describes Perlman's critique of what he saw as "the millennia-long history of the assault of the technological megamachine on humanity and the Earth." Clark also notes the book discusses "anarchistic spiritual movements" such as the Yellow Turban movement in ancient China and the Brethren of the Free Spirit in medieval Europe.

Death
Perlman died on July 26, 1985, while undergoing heart surgery in Detroit's Henry Ford Hospital. He was survived by his wife and a brother.

Selected publications

 * "Essay on Commodity Fetishism". Telos 6 (Fall 1970). New York: Telos Press.
 * "The Continuing Appeal of Nationalism"
 * Sound recording
 * "The Reproduction of Daily Life"
 * Against His-story! Against Leviathan!
 * Worker-Student Action Committees, France May '68 with Roger Gregoire
 * Manual for Revolutionary Leaders
 * Manual for Revolutionary Leaders Second Edition Including The Sources of Velli's Thoughts (Black & Red, Detroit, 1974)
 * "Ten Theses on the Proliferation of Egocrats"
 * "Obituary for Paul Baran"
 * "The Machine Against the Garden: Two Essays on American Literature and Culture"
 * "Chicago, 1968"
 * "Anything can happen"
 * Illyria Street Commune 1979 (AudioPlay)
 * Illyria Street Commune 1979 (Playscript on The Anarchist Library)
 * Illyria Street Commune 1979 (Playscript on The Anarchist Library)

title: Fredy Perlman


text:
A las Barricadas

"A las Barricadas" ("To the Barricades") was one of the most popular songs of the Spanish anarchists during the Spanish Civil War. "A las Barricadas" is sung to the tune of "Whirlwinds of Danger" ("Warszawianka"), composed by Józef Pławiński. The lyrics written by Valeriano Orobón Fernández in 1936 were partly based on the original Polish lyrics by Wacław Święcicki.

"The Confederation" referred to in the final stanza is the anarcho-syndicalist CNT (Confederación Nacional del Trabajo — "National Confederation of Labor"), which at the time was the largest labour union, the main anarchist organisation in Spain, and from 1936 to 1939 were a major force opposing Francisco Franco's military coup against the Spanish Republic.

Covering artists

 * Bandista (with the name "Haydi Barikata")
 * Jean-Marc Leclercq
 * Pascal Comelade
 * Victor Manuel and Ana Belén (as a duet piece).
 * Los Muertos de Cristo
 * Feminazgûl

title: A las Barricadas


text:
Talk:Bloomsbury Gang

From WP:VFD

 * Votes for deletion/Bloomsbury Gang

title: Talk:Bloomsbury Gang


text:
Hodometer

Hodometer may refer to:

 * Hodometer, an older name for an Odometer, a device for measuring the distance travelled by a vehicle
 * Hodometer, a Surveyor's wheel, a device for measuring distance. Also called a waywiser or perambulator.

title: Hodometer


text:
Celecoxib

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

Common side effects include abdominal pain, nausea, and diarrhea. Serious side effects may include heart attacks, strokes, gastrointestinal perforation, gastrointestinal bleeding, kidney failure, and anaphylaxis. Use is not recommended in people at high risk for heart disease. The risks are similar to other NSAIDs, such as ibuprofen and naproxen. Use in the later part of pregnancy or during breastfeeding is not recommended.

Celecoxib was patented in 1993 and came into medical use in 1999. It is available as a generic medication. In 2021, it was the 98th most commonly prescribed medication in the United States, with more than 7million prescriptions.

Medical uses
Celecoxib is indicated for the treatment of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis. It may be used in children with juvenile rheumatoid arthritis who are older than two years of age and weigh more than 10 kg (22 lb).

For postoperative pain, it is more or less equal to ibuprofen. For pain relief, it is similar to paracetamol (acetaminophen) at 3990 mg per day, which is the first line treatment for osteoarthritis.

Evidence of effects is not clear as a number of studies done by the manufacturer have not been released for independent analysis.

Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

Adverse effects

 * Cardiovascular events: NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Individual cardiovascular risk profiles should be evaluated prior to prescribing. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may impair response to thiazide or loop diuretics), and may contribute to cardiovascular events; monitor blood pressure and use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema or heart failure. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternative therapies should be considered for patients at high risk. The increased risk is about 37%.
 * Gastrointestinal events: NSAIDs may increase risk of serious gastrointestinal (GI) ulceration, bleeding, and perforation (may be fatal). These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with ≤325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (e.g., ulcer) occurs; concomitant gastroprotective therapy (e.g., proton pump inhibitors) is recommended. The increased risk is about 81%.
 * Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin time, partial thromboplastin time or platelet counts; it does not inhibit platelet aggregation at approved doses.

People with prior history of ulcer disease or GI bleeding require special precaution. Moderate to severe liver impairment or GI toxicity can occur with or without warning symptoms in people treated with NSAIDs.

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Allergy
Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in people with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs. NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy. Use should be discontinued at first sign of rash (or any other hypersensitivity).

Heart attack and stroke
A 2013 meta-analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo. In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen. As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly-used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxib's safety.

The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."

In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug. Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib. In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs". In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.

Drug interactions
Celecoxib is predominantly metabolized by cytochrome P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. If used concomitantly with lithium, celecoxib increases lithium plasma levels. If used concomitantly with warfarin, celecoxib may result in increased risk of bleeding complications. The risk of bleeding and gastric ulcers also increase further when selective serotonin reuptake inhibitors (SSRI) are used in combination with celecoxib. The drug may increase the risk of kidney failure with angiotensin-converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.

Anti-inflammatory
A highly selective reversible inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has analgesic and anti-inflammatory properties. Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Inhibition of COX-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis. COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation (and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.

Anti-cancer
For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues.

Celecoxib binds to Cadherin-11 (which may explain the reduction in cancer progression).

Structure-activity relationship

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib. A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).

Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency. To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2. This mutation appears to contribute to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.

History
It was initially marketed by Pfizer for arthritis. Celecoxib and other COX-2 selective inhibitors, valdecoxib, parecoxib, and mavacoxib, were discovered by a team at the Searle division of Monsanto led by John Talley.

Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University (BYU) discovered the COX-2 enzyme in 1988, and in 1991, BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. Monsanto's pharmaceutical division was later purchased by Pfizer, and in 2006, BYU sued Pfizer for breach of contract, claiming Pfizer did not properly pay contractual royalties back to BYU. A settlement was reached in April 2012, in which Pfizer agreed to pay $450 million. Other important discoveries in COX-2 were made at University of Rochester, which patented the discoveries. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.

According to the National Academy of Sciences, Philip Needleman, who was vice president of Monsanto in 1989 and president of Searle in 1993 oversaw research into COX-2 that led to the development of the anti-inflammatory drug celecoxib (Celebrex). He became senior executive vice president and chief scientist of Pharmacia from 2000 to 2003. Celecoxib was discovered and developed by G. D. Searle & Company and was approved by the FDA on 31 December 1998. It was co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle's favor (later Pfizer) in 2004. In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.

After the withdrawal of rofecoxib from the market in September 2004, celecoxib enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of rofecoxib, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. Sales reached $2 billion in 2006. Prior to its availability in generic form, it was one of Pfizer's "best-selling drugs, amounting to more than $2.5 billion in sales [by 2012], and was prescribed to 2.4 million" people in 2011. By 2012, 33 million Americans had taken celecoxib.

Pfizer resumed advertising Celebrex in magazines in 2006, and resumed television advertising in April 2007 with an unorthodox, $2 1/2$-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ad's comparisons misleading. Pfizer responded to Public Citizen's concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.

Fabricated efficacy studies
Pfizer and its partner, Pharmacia presented findings from their study that Celebrex was "better in protecting the stomach from serious complications than other drugs." This became Celebrex's main selling point. However, following federal investigations it was revealed that Pfizer and Pharmacia "only presented the results from the first six months of a year long study rather than the whole thing." These partial results were then published in The Journal of the American Medical Association. In 2001, the US Food and Drug Administration (FDA) released the full results of the Pfizer and Pharmacia study which showed that they had withheld crucial data. By 2012, a federal judge unsealed "thousands of pages of internal documents and depositions" in a "long-running securities fraud case against Pfizer."

In March 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. Although from 2002 to 2007 Pfizer underwrote much of Dr. Reuben's research and "many of his trials found that Celebrex and Lyrica, Pfizer drugs, were effective against postoperative pain," Pfizer was not aware of the fraudulent data. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Union's regulatory agencies prior to the drug's approval. Although Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator", the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings.

Brand names
Pfizer markets celecoxib under the brand name Celebrex, and it is available as oral capsules containing 50, 100, 200 or 400 mg of celecoxib.

It is legally available in many jurisdictions as a generic under several brand names. In the US, celecoxib was covered by three patents, two of which expired on 30 May 2014, and one of which (US RE44048 ) was due to expire 2 December 2015. On 13 March 2014, that patent was found to be invalid for double patenting. Upon the patent expiry on 30 May 2014, the FDA approved the first versions of generic celecoxib.

In the US, Celebrex is marketed by Viatris after Upjohn was spun off from Pfizer.

Psychiatry
On the theory that inflammation plays a role in the pathogenesis of major mental disorders, celecoxib has been trialed for a number of psychiatric disorders, including major depression, bipolar disorder, and schizophrenia.

Bipolar disorder
A meta-analysis considering trials of celecoxib as an adjunctive treatment in bipolar disorder was inconclusive citing low evidence quality.

Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.

Cancer prevention
The use of celecoxib to reduce the risk of colorectal cancer has been investigated, but neither celecoxib nor any other drug is indicated for this use. Small-scale clinical trials in very high-risk people (belonging to FAP families) showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken. Results show a 33 to 45% polyp recurrence reduction in people treated with celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups. Aspirin shows a similar (and possibly larger) protective effect,  has demonstrated cardioprotective effects and is significantly cheaper, but no head-to-head clinical trials have compared the two drugs.

Cancer treatment
Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are going on to determine whether celecoxib might be useful for this latter condition. However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, COX-2. The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX-2 became contentious.

Certainly, the inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of celecoxib. However, whether inhibition of COX-2 also plays a dominant role in this drug's anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX-2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX-2. Karen Seibert and colleagues have published research showing antiangiogenic and antitumor activity of celecoxib in animal models.

Additional support for the idea that other targets besides COX-2 are important for celecoxib's anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures. Some of these analogs retained COX-2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing the inhibition of COX-2 was not required for the anticancer effects. One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.

title: Celecoxib


text:
Talk:Professional video camera

General Cleanup
I've made a lot of edits and added some new sections, specifically a narrative for the history section to improve on the timeline list that was there before, and EFP as a category. Also moved some fo the pictures, and will be adding a remote camera section.

This article could use some more work, better illustrations and photos, more cites ( I added the Zettl text, which supports pretty much everything I've added or edited.) for history. The list of wikipedia refs is disorganized and not helpful, and could be cleaned up. The time line list in history should be pruned, added to, and cited better. —Preceding unsigned comment added by StevenBradford (talk • contribs) 08:11, 19 February 2009 (UTC)

I have made some small minor changes to reflect a better accuracy in the article: Rewrote a the Studio Camera section a little to emphasize that studio cameras are versatile today (not like in previous generations). Also corrected the analogue vs digital sentence. If there are some studios running analogue today, they will be in trouble as you just don't get spares. Almost every broadcaster is digital in one sense or another. Also, I have added the fibre optic cable to the Outside Broadcast camera section. —Preceding unsigned comment added by 41.243.8.201 (talk) 15:56, 17 March 2010 (UTC)

Professional Vs Broadcast Cameras
Professional cameras are the cheaper version of ENGs like the camcorder. The Digital Betacam is a broadcast camera and is of superior quality and is quite expensive in comparison. The article does not differentiate between these two categories. Thanks --mnb 15:23, 17 December 2007 (UTC)

Needs new info
There is no mention of newer HD cams or photos of them like HDxcam by Sony that are standard on reality shows. Cost = 20,000- 100,000 dollars.

Also need a list of TV shows, Films and what cameras they use.

http://www.hdcameraguide.com/guide/camera_selector/reality-tv http://www.quora.com/Reality-Television/What-kind-of-camera-s-does-MTV-use-for-their-reality-shows

"Jon Lawrence, I have provided production oversight ... I have provided production oversight for north of $24 million in cable television production either as Exec in Charge of Production, as Line Producer or Production Manager. I have also Co-Ep'd and Produced new media series for both Comedy Central, and MyDamnChannel. Television 1 vote by Brandon Fletcher This varies wildly. Each individual production company chooses the cameras used in production; as long as the finished program master is in the format required by the network deliverables, pretty much anything goes.

Typically, prod co's will choose one of several well-proven field cameras for their shows. The choices are made by the Director of Photography (if there is one) or by the show producers, and also depend on the budget of the show.

The most oft-used workhorses are:

(mid-to-high budget reality)

 * Panasonic HDX900
 * Sony HDW F900
 * Panasonic SDX900

(low-to-mid budget reality)

 * Panasonic HVX200
 * Sony EX1 & EX3

There are a few other makes and models, but another point of consideration is how many of the same cameras are available at a given time when you're shooting. If you need, say, 12 matched cameras, your ability to get those will be limited to only a few models since rental houses can't stock a deep inventory of all models.

DSLR's are typically NOT used for reality at this point for a variety of reasons."  --Ericg33 (talk) 09:05, 17 July 2011 (UTC)

JordoCo's recent edits
JordoCo has been editting this and a lot of related articles, inserting odd language, over- and inappropriate linking, too-specific stuff, etc. I revert some of the more recent bits here, but the rest of his changes need a good going over or revert, too. Anyone around to look at it? Dicklyon (talk) 23:57, 2 August 2011 (UTC)

I agree, they're odd, and often peripheral to the topic. I'll try to go through and see what I catch. That last one was a doozy.--StevenBradford (talk) 18:47, 3 August 2011 (UTC)

Mention of the "iconoscope" but not of the "image dissector" which was electronic and invented earlier
I noticed in the Chronology section that it refers to the "iconoscope" but it does not mention about Philo Farnsworth's "image dissector" - considered the inventor of Electronic Television: http://en.wikipedia.org/wiki/Philo_Farnsworth. The image dissector as far as I can see from the wikipedia article came before the "iconoscope" by a few years. It was initially designed in 1920 and it transmitted its first image in 1927 and demonstrated to the public in 1928. It seems it wasn't as sensitive as the iconoscope but I would think it is worth mentioning. — Preceding unsigned comment added by Tes68 (talk • contribs) 05:50, 11 August 2013 (UTC)

title: Talk:Professional video camera


text:
Cabinet counties

The Cabinet counties are ten counties in the southern part of the U.S. state of Michigan named after President Andrew Jackson and people who served in his Cabinet. The Michigan Territorial legislature created twelve counties on October 29, 1829, naming eight of them after members of the recently elected Jackson's cabinet. Cass County was also created in 1829 and named for Lewis Cass, the Territorial Governor at the time. Cass later served in Jackson's Cabinet, making a case for it to be included as a cabinet county. Livingston County was created in 1833 and named for Edward Livingston, Jackson's Secretary of State at the time.

The generally accepted reason for the naming of these counties after Jackson Administration members is that the Michigan Territory was trying to gain support of these officials in its border dispute with Ohio over the Toledo Strip.

In one of his last acts in office, Jackson signed the 1837 bill making Michigan the 26th state.

 * Barry County, Michigan, named for U.S. Postmaster General William T. Barry
 * Berrien County, Michigan, named for U.S. Attorney General John M. Berrien
 * Branch County, Michigan, named for U.S. Secretary of the Navy John Branch
 * Calhoun County, Michigan, named for U.S. Vice President John C. Calhoun
 * Cass County, Michigan, named for Jackson's second Secretary of War, Lewis Cass
 * Eaton County, Michigan, named for Secretary of War John Eaton
 * Ingham County, Michigan, named for U.S. Secretary of the Treasury Samuel D. Ingham
 * Jackson County, Michigan, named for Andrew Jackson himself
 * Livingston County, Michigan, named for Jackson's second Secretary of State, Edward Livingston
 * Van Buren County, Michigan, named for U.S. Secretary of State (later Vice President and then President) Martin Van Buren

title: Cabinet counties


text:
Malpeque

Malpeque can refer to several different things:

Electoral districts

 * Malpeque (electoral district), a federal electoral district in Prince Edward Island, Canada

Geography

 * Malpeque Bay, a bay in Prince Edward Island, Canada

Settlements

 * Malpeque, an unincorporated rural community in Prince Edward Island, Canada
 * Malpeque Bay, Prince Edward Island, an incorporated rural municipality in Prince Edward Island, Canada

Structures

 * Malpeque Outer Range Lights, a set of lighthouses operated by the Canadian Coast Guard in Prince Edward Island, Canada
 * Malpeque Harbour Approach Range Lights, a set of lighthouses operated by the Canadian Coast Guard in Prince Edward Island, Canada

title: Malpeque