Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new rofecoxib research articles will be listed here shortly after becoming available to us.
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Medical research on rofecoxib
Nonaspirin NSAIDs, Cyclooxygenase 2 Inhibitors, and the Risk for Stroke.
Stroke. 2008 Apr 24;
Roumie CL, Mitchel EF, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR
BACKGROUND AND PURPOSE: There is limited information regarding the cerebrovascular safety of cyclooxygenase 2 inhibitors (coxibs) and noncoxib nonsteroidal antiinflammatory drugs (NSAIDs). We determined whether specific NSAIDs, including coxibs, are associated with risk of stroke. METHODS: Retrospective cohort study among Tennessee Medicaid enrollees aged 50 to 84 years between January 1, 1999 and December 31, 2004. Noninstitutionalized persons with continuous enrollment in Medicaid and no stroke or other serious medical illness in the year before cohort entry were included. The 7 most common NSAIDs were examined: celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, diclofenac, and indomethacin. Nonuse of NSAIDs was the reference group. Because new use is less susceptible to bias, we conducted a similar analysis confined to new users. The outcome was hospitalization for an incident cerebrovascular event: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. RESULTS: The cohort included 336 906 persons, with 989 826 person-years of follow-up, and 4354 stroke hospitalizations. There were 4.51 strokes per 1000 person years in the nonuse group, 5.15 strokes per 1000 person years (adjusted HR 1.28, 95% CI 1.06, 1.53) with rofecoxib use, and 5.95 strokes per 1000 person years (adjusted HR 1.41, 95% CI 1.04, 1.91) with valdecoxib use. New use of rofecoxib and valdecoxib led to 6.06 (adjusted HR 1.46 95% CI 1.08, 1.98) and 6.19 (adjusted HR 1.39, 95% CI 0.74, 2.59) strokes per 1000 person years respectively. No other NSAID significantly increased the risk of incident stroke. CONCLUSIONS: Our results indicate an increased risk of stroke with current use of two highly selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.
[What is new about nonsteroidal antiinflamatory drugs?]
Pol Merkur Lekarski. 2007 Dec; 23(138): 454-8
Dzielska-Olczak M
NSAIDs contain nonselective cyclooksygenase inhibitors (for COX-1 and COX-2), inhibitors to the preferential COX-2, the coxibs (sulphonamides, methylsulphones, phenylacethic acid derivatives) with 1000 fold selectivities for COX-2. COX-2 enzyme isoform are constitutively expressed in normal gastric tissue in animals and humans, in the cardiovascular system, renal, central nervous system and other. COX-2 is involved in the ischemic preconditioning mechanism and sulphones have a prooxidant activity. COX-2 inhibitors increased risk for thrombotic cardiovascular events. Long-term study VIGOR, CLASS, TARGET MEDAL revealed that celecoxib, rofecoxib, lumiracoxib, etoricoxib significantly reduced the risk of major gastrointestinal effects (ulcers, perforations, bleeding) than nonselective NSAIDs, but the rates of complicated upper gastrointestinal events were similar for etoricoxib and diclofenac. Only in VIGOR trial incidence of cardiovascular events was greater. No evidence that concomitant ASA reduced risk for cardivascular events. Potential differences in cardiovascular outcomes with the selective COX-2 inhibitors may be due to differences in the drugs molecular structures, pharmacokinetics and pharmacodynamics. In the "prothrombotic environment" contribution disorders in the balance between thromboxan A2 and prostacyclin, increased aggregation plaque, hypertension, endothelial cell dysfunction, impaired angiogenesis. Moreover COX-2 may plays a crucial role in atherosclerotic plaque stability or instability. The cardiovascular risk may be dose related and depends on duration therapy, variable selectivity for COX-2.
Thermodynamic behavior of glassy state of structurally related compounds.
Eur J Pharm Biopharm. 2008 Feb 14;
Kaushal AM, Bansal AK
Thermodynamic properties of amorphous pharmaceutical forms are responsible for enhanced solubility as well as poor physical stability. The present study was designed to investigate the differences in thermodynamic parameters arising out of disparate molecular structures and associations for four structurally related pharmaceutical compounds - celecoxib, valdecoxib, rofecoxib, and etoricoxib. Conventional and modulated temperature differential scanning calorimetry were employed to study glass forming ability and thermodynamic behavior of the glassy state of model compounds. Glass transition temperature of four glassy compounds was in a close range of 327.6-331.8K, however, other thermodynamic parameters varied considerably. Kauzmann temperature, strength parameter and fragility parameter showed rofecoxib glass to be most fragile of the four compounds. Glass forming ability of the compounds fared similar in the critical cooling rate experiments, suggesting that different factors were determining the glass forming ability and subsequent behavior of the compounds in glassy state. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches towards development of stable glassy pharmaceuticals.
JAMA. 2008 Apr 16; 299(15): 1813-7
Psaty BM, Kronmal RA
Sponsors have a marketing interest to represent their products in the best light. This approach conflicts with scientific standards that require the symmetric and comparable reporting of safety and efficacy data. Selective reporting of the results of clinical trials can misrepresent the risk-benefit profile of drugs. We summarize how the sponsor represented mortality findings associated with rofecoxib in clinical trials of patients with Alzheimer disease or cognitive impairment. We reviewed documents that became available during litigation related to rofecoxib involving Merck & Co, including internal company analyses and information provided by the sponsor to the FDA. We also evaluated information in 2 published articles that reported results of these trials. In one article (reporting results of protocol 091) published in 2004, 11 "non-drug related deaths" were reported (9 deaths among 346 rofecoxib patients and 2 deaths among 346 placebo patients). In another article (reporting results of protocol 078) published in 2005, 39 deaths were reported among patients taking study treatment or within 14 days of the last dose (24 among 725 rofecoxib patients and 15 among 732 placebo patients) and an additional 22 deaths in the off-drug period (17 in rofecoxib patients and 5 in placebo patients). However, these articles did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is "well tolerated." In contrast, in April 2001, the company's internal intention-to-treat analyses of pooled data from these 2 trials identified a significant increase in total mortality (hazard ratio [HR], 4.43; 95% CI, 1.26-15.53 for protocol 091, and HR, 2.55; 95% CI, 1.17-5.56 for protocol 078), with overall mortality of 34 deaths among 1069 rofecoxib patients and 12 deaths among 1078 placebo patients (HR, 2.99; 95% CI, 1.55-5.77). These mortality analyses were neither provided to the FDA nor made public in a timely fashion. The data submitted by the sponsor to the FDA in a Safety Update Report in July 2001 used on-treatment analysis methods and reported 29 deaths (2.7%) among 1067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients. This on-treatment approach to reporting minimized the appearance of any mortality risk. In December 2001, when the FDA raised safety questions about the submitted safety data, the sponsor did not bring these issues to an institutional review board for review and revealed that there was no data and safety monitoring board for the protocol 078 study. The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary.
JAMA. 2008 Apr 16; 299(15): 1800-12
Ross JS, Hill KP, Egilman DS, Krumholz HM
CONTEXT: Authorship in biomedical publication provides recognition and establishes accountability and responsibility. Recent litigation related to rofecoxib provided a unique opportunity to examine guest authorship and ghostwriting, practices that have been suspected in biomedical publication but for which there is little documentation. OBJECTIVE: To characterize different types and the extent of guest authorship and ghostwriting in 1 case study. DATA SOURCES: Court documents originally obtained during litigation related to rofecoxib against Merck & Co Inc. Documents were created predominantly between 1996 and 2004. In addition, publicly available articles related to rofecoxib identified via MEDLINE. DATA EXTRACTION: All documents were reviewed by one author, with selected review by coauthors, using an iterative process of review, discussion, and rereview of documents to identify information related to guest authorship or ghostwriting. DATA SYNTHESIS: Approximately 250 documents were relevant to our review. For the publication of clinical trials, documents were found describing Merck employees working either independently or in collaboration with medical publishing companies to prepare manuscripts and subsequently recruiting external, academically affiliated investigators to be authors. Recruited authors were frequently placed in the first and second positions of the authorship list. For the publication of scientific review papers, documents were found describing Merck marketing employees developing plans for manuscripts, contracting with medical publishing companies to ghostwrite manuscripts, and recruiting external, academically affiliated investigators to be authors. Recruited authors were commonly the sole author on the manuscript and offered honoraria for their participation. Among 96 relevant published articles, we found that 92% (22 of 24) of clinical trial articles published a disclosure of Merck's financial support, but only 50% (36 of 72) of review articles published either a disclosure of Merck sponsorship or a disclosure of whether the author had received any financial compensation from the company. CONCLUSIONS: This case-study review of industry documents demonstrates that clinical trial manuscripts related to rofecoxib were authored by sponsor employees but often attributed first authorship to academically affiliated investigators who did not always disclose industry financial support. Review manuscripts were often prepared by unacknowledged authors and subsequently attributed authorship to academically affiliated investigators who often did not disclose industry financial support.
Drug safety surveillance in China and other countries: a review and comparison.
Value Health. 2008 Mar; 11 Suppl 1: S130-6
Du W, Guo JJ, Jing Y, Li X, Kelton CM
OBJECTIVES: Drug safety and postmarketing surveillance have become important public health issues in China. This study reviews the relatively new drug safety surveillance system in China and compares it with the systems in the United States and Europe. METHODS: An extensive literature review was conducted in the following four areas: 1) the organizational structure of the State Food and Drug Administration (SFDA) in China; 2) the development of an adverse drug reaction (ADR) monitoring system in China; 3) regulatory issues related to drug safety in China; and 4) similarities and differences between drug safety surveillance in China and surveillance in the United States and Europe. RESULTS: The SFDA oversees an extensive network of drug safety "watchdogs," including the China National Center for ADR Monitoring and 32 regional centers throughout China. China's system has faced a number of recent challenges. It has had to respond quickly to the withdrawal of various high-profile drugs like Vioxx (rofecoxib) and Baycol (cerivastatin) from other markets. Together with China's Ministry of Health, the SFDA has faced several unique drug safety events. Three of those events, involving the injectable form of the heartleaf houttuyinia herb (Yu Xing Cao), Armillarisni A injections, and clindamycin glucose infusions (Xinfu), are discussed. The rapid development of drug safety surveillance in China is manifested in extensive organizational structure, development of large databases, and laws and regulations supporting drug safety. The two major laws are the China Drug Administration Law issued in February 2001 and the Regulation for the Administration of ADR Reporting and Monitoring issued in March 2004. The study also discusses and compares recent developments in drug safety surveillance in the United States and the European Union. These developments will most likely have implications for the Chinese system in the near future. CONCLUSIONS: While postmarketing surveillance guidelines are not yet available in China, we fully expect their eventual issuance after adaptation to the particular culture and clinical practices in China.
Br J Pharmacol. 2008 Apr; 153(8): 1762
Huntjens DR, Strougo A, Chain A, Metcalf A, Summerfield S, Spalding DJ, Danhof M, Pasqua OD
Health Technol Assess. 2008 Apr; 12(11): 1-178
Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS
OBJECTIVES: To review the clinical effectiveness and cost-effectiveness of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis (OA) and rheumatoid arthritis (RA). DATA SOURCES: Electronic databases were searched up to November 2003. Industry submissions to the National Institute for Health and Clinical Excellence (NICE) in 2003 were also reviewed. REVIEW METHODS: Systematic reviews of randomised controlled trials (RCTs) and a model-based economic evaluation were undertaken. Meta-analyses were undertaken for each COX-2 selective NSAID compared with placebo and non-selective NSAIDs. The model was designed to run in two forms: the 'full Assessment Group Model (AGM)', which includes an initial drug switching cycle, and the 'simpler AGM', where there is no initial cycle and no opportunity for the patient to switch NSAID. RESULTS: Compared with non-selective NSAIDs, the COX-2 selective NSAIDs were found to be equally as efficacious as the non-selective NSAIDs (although meloxicam was found to be of inferior or equivalent efficacy) and also to be associated with significantly fewer clinical upper gastrointestinal (UGI) events (although relatively small numbers of clinical gastrointestinal (GI) and myocardial infarction (MI) events were reported across trials). Subgroup analyses of clinical and complicated UGI events and MI events in relation to aspirin use, steroid use, prior GI history and Helicobacter pylori status were based on relatively small numbers and were inconclusive. In the RCTs that included direct COX-2 comparisons, the drugs were equally tolerated and of equal efficacy. Trials were of insufficient size and duration to allow comparison of risk of clinical UGI events, complicated UGI events and MIs. One RCT compared COX-2 (celecoxib) with a non-selective NSAID combined with a gastroprotective agent (diclofenac combined with omeprazole); this included arthritis patients who had recently suffered a GI haemorrhage. Although no significant difference in clinical GI events was reported, the number of events was small and more such studies, where patients genuinely need NSAIDs, are required to confirm these data. A second trial showed that rofecoxib was associated with fewer diarrhoea events than a combination of diclofenac and misoprostol (Arthrotec). Previously published cost-effectiveness analyses indicated a wide of range of possible incremental cost per quality-adjusted life-year (QALY) gained estimates. Using the simpler AGM, with ibuprofen or diclofenac alone as the comparator, all of the COX-2 products are associated with higher costs (i.e. positive incremental costs) and small increases in effectiveness (i.e. positive incremental effectiveness), measured in terms of QALYs. The magnitude of the incremental costs and the incremental effects, and therefore the incremental cost-effectiveness ratios, vary considerably across all COX-2 selective NSAIDs. The base-case incremental cost per QALY results for COX-2 selective NSAIDs compared with diclofenac for the simpler model are: celecoxib (low dose) 68,400 pounds; celecoxib (high dose) 151,000 pounds; etodolac (branded) 42,400 pounds; etodolac (generic) 17,700 pounds; etoricoxib 31,300 pounds; lumiracoxib 70,400 pounds; meloxicam (low dose) 10,300 pounds; meloxicam (high dose) 17,800 pounds; rofecoxib 97,400 pounds; and valdecoxib 35,500 pounds. When the simpler AGM was run using ibuprofen or diclofenac combined with proton pump inhibitor (PPI) as the comparator, the results change substantially, with the COX-2 selective NSAIDs looking generally unattractive from a cost-effectiveness point of view (COX-2 selective NSAIDs were dominated by ibuprofen or diclofenac combined with PPI in most cases). This applies both to 'standard' and 'high-risk' arthritis patients defined in terms of previous GI ulcers. The full AGM produced results broadly in line with the simpler model. CONCLUSIONS: The COX-2 selective NSAIDs examined were found to be similar to non-selective NSAIDs for the symptomatic relief of RA and OA and to provide superior GI tolerability (the majority of evidence is in patients with OA). Although COX-2 selective NSAIDs offer protection against serious GI events, the amount of evidence for this protective effect varied considerably across individual drugs. The volume of trial evidence with regard to cardiovascular safety also varied substantially between COX-2 selective NSAIDs. Increased risk of MI compared to non-selective NSAIDs was observed among those drugs with greater volume of evidence in terms of exposure in patient-years. Economic modelling shows a wide range of possible costs per QALY gained in patients with OA and RA. Costs per QALY also varied if individual drugs were used in 'standard' or 'high'-risk patients, the choice of non-selective NSAID comparator and whether that NSAID was combined with a PPI. With reduced costs of PPIs, future primary research needs to compare the effectiveness and cost-effectiveness of COX-2 selective NSAIDs relative to non-selective NSAIDs with a PPI. Direct comparisons of different COX-2 selective NSAIDs, using equivalent doses, that compare GI and MI risk are needed. Pragmatic studies that include a wider range of people, including the older age groups with a greater burden of arthritis, are also necessary to inform clinical practice.
J Pharmacol Exp Ther. 2008 Apr 2;
Brzozowski T, Konturek PC, Chlopicki S, Sliwowski Z, Pawlik M, Ptak-Belowska A, Kwiecien S, Drozdowicz D, Pajdo R, Slonimska E, Konturek SJ, Pawlik WW
1-methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit anti-thrombotic and anti-inflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) or administered 75% ethanol. MNA (6.25 - 100 mg/kg i.g.) led to a dose- dependent rise in the plasma MNA level, inhibited gastric acid secretion and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow (GBF) and plasma CGRP levels, the preservation of PGI2 generation (measured as 6-keto-PGF1alpha) and an overexpression of mRNAs for COX-2 and CGRP in the gastric mucosa. RO 324479 which is the selective antagonist of IP/PGI2 receptors reversed the effects of MNA on gastric lesions and GBF. MNA- induced gastroprotection was attenuated by suppression of COX-1 (SC-560) and COX-2 (rofecoxib) activity, capsaicin denervation, and by the pretreatment with CGRP8-37 or capsazepine. Addition of exogenous PGI2 or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing SOD activity in the gastric mucosa, while pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanism involving cooperative action of PGI2 and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity and reduction in lipid peroxidation.
Br J Clin Pharmacol. 2008 Apr 1;
McGettigan P, Han P, Jones L, Whitaker D, Henry D
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Pharmaco-epidemiological studies have shown that in susceptible individuals, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors increase the risk of developing congestive heart failure (CHF). * Recently published studies have found lower relative risk (RR) estimates than the initial studies published in 1998-2000. * It is unclear whether the level of risk is elevated equally in first time and recurrent cases of CHF. WHAT THIS STUDY ADDS * This study found low-level, statistically nonsignificant elevations of risk with NSAIDs and COX-2 inhibitors. * There was a much higher level of recent use of NSAIDs/COX-2 inhibitors among first-time cases than among recurrent cases of CHF. * The dilution of the RR over successive studies, and the differences between first-time and recurrent cases noted here, suggest that prescribing doctors have heeded advice about the cardiovascular risks of NSAIDs and extended this practice to selective COX-2 inhibitors. AIMS To quantify the association between treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors and hospitalization due to congestive heart failure (CHF); to determine if the risk varies between first and subsequent episodes of CHF. METHODS We conducted a case-control study of the relationship between recent use of NSAIDs and COX-2 inhibitors and hospitalization with CHF. Cases (n = 530) were patients admitted to hospital with a primary diagnosis of CHF. Controls (n = 1054) were subjects without CHF who were admitted to the same hospitals as the cases. They were frequency matched to cases on the basis of age and sex. Structured interviews were used to obtain information on a number of study factors, including recent use of NSAIDs and COX-2 inhibitors. Relative risks (RRs) were estimated from exposure odds ratios, adjusted for a range of potential confounders. RESULTS Overall, NSAIDs and COX-2 inhibitors had been taken by 249 (23.6%) controls in the week before admission to hospital. Use of any NSAID/COX-2 inhibitor was recorded in 81/285 (28.4%) first-time cases compared with 38/245 (15.5%) in recurrent cases: difference 12.9% (95% confidence interval 5.9, 19.8) (P = 0.0004). The adjusted RRs for first hospital admission for CHF with different drug exposures were: NSAIDs 1.1 (0.67, 1.83), rofecoxib 1.29 (0.78, 2.13) and celecoxib 1.47 (0.85, 2.53). CONCLUSIONS We found weak and statistically nonsignificant associations between use of NSAIDs and COX-2 inhibitors and hospitalization with CHF. This low RR is consistent with the results of recently published studies, but not with early studies that found an approximate doubling of risk with use of NSAIDs. The dilution of risk and the significantly lower levels of prescribing for recurrent than for first-time cases of heart failure suggest that prescribing doctors heeded messages that NSAIDs may precipitate CHF in vulnerable individuals, and that they have applied the same message to selective COX-2 inhibitors.