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The introduction of selective COX-2 inhibitors (so-called 'coxibs') has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs 'controversial me-too' saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer's disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed. [ABSTRACT FROM AUTHOR]

The Center for Drug Evaluation and Research (CDER) performs an essential role in public health by ensuring, evaluating, and monitoring the safety and efficacy of drugs before they are sold in the US. Before approving new drug applications, CDER ensures that therapeutic benefits of both prescription and over-the-counter drugs (brand name and generic) provide more health benefits than the potential risks. First passed by Congress in 1992, the Prescription Drug User Fee Act (PDUFA) allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund new drug approvals. The law allowed the FDA to expedite drug approvals, but possibly lowered standards for safety and brought potential conflicts of interest within the FDA and pharmaceutical industry. To examine the conflicts of interest, we conducted a review using the Excerpta Medica database, US National Library of Medicine National Institutes of Health Database (PubMed), Scopus, and Google. Our search yielded Vioxx (rofecoxib) and Exondus-51 (eteplirsen) as examples of consequence when the FDA and pharmaceutical industry are too closely aligned. We further examine how the pharmaceutical industry may indirectly influence the FDA by lobbying to Congress or directly by hiring ex-FDA commissioners. [ABSTRACT FROM AUTHOR]

The introduction of selective COX-2 inhibitors (so-called ‘coxibs’) has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs ‘controversial me-too’ saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer’s disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed.

The context of this paper examines the industry pressures, that led to the Vioxx Recall in 2004. Current information on the pharmaceutical industry, Federal Legislation and FDA has been updated to provide an ethical perspective comparing the past and present landscape of the industry. During the early 2000 's, the pharmaceutical industry is going through difficult times due to the external pressures from society. Some of the factors that have created industry pressures are (1) high cost of pharmaceuticals, (2) medications aren't regulated close enough ensuring they are safe and effective, and (3) consumers lack confidence in pharmaceutical companies, Congress, and governmental agencies. As a result, Congress, pharmaceutical companies, and governmental agencies need to work together as a team to rebuild the confidence of consumers by implementing ethical processes that will drive the pharmaceutical industry in the right direction. By developing, implementing, and evaluation processes to overcome these factors, the pharmaceutical industry can ensure they are doing the right ethical measures to meet the needs of society. [ABSTRACT FROM AUTHOR]

Aims Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Methods and results Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. Conclusion These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA. [ABSTRACT FROM AUTHOR]

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of ‘hidden cardiotoxicity’ is defined as cardiotoxicity of a drug that manifests in the diseased (e.g. ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g. ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.

Background: The schistosome parasite induced granulomatous inflammation in the host following oviposition in the liver.Aim:The present study aimed to evaluate the efficacy of two antiinflammatory drugs; Hostacortin (steroidal) and Vioxx (non-steroidal) in ameliorating the damaging effects of S. mansoni infection in mice. Materials and methods: The anti-inflammatory activity of the two drugs was evaluated at dose levels of 10, 50,100 and 200 mg/kg body weight. Each drug was orally administered to mice infected with 80 S.mansoni cercariae / mouse for 10 consecutive days after 6-weeks of infection. Some biochemical parameters including the hepatic function as enzymatic activity of aminotransaminases; alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and alkaline phosphatase (ALP) in liver as well as serum albumin and liver total protein were determined. In addition, some parasitological parameters as worm burden, liver egg count hepatic granuloma size and relative liver weight were performed to evaluate the possible anti-inflammatory effect of the two anti-inflammatory drugs in ameliorating the severity of the schistosomiasis disease. Results: The results showed that Hosstacortin treatment had no marked effect on the parasite burden and liver egg count. However, it caused a pronounced improvement with a high tendency for normalization in transaminases (ALAT and ASAT) and alkaline phosphatase (ALP) activities in liver tissue homogenate. In addition, serum albumin and liver total protein was observed to attain, to some extent, their normal levels by increasing dose regimens of Hostacortin. Also, a significant reduction in granuloma size by 22.2% and 31.6% was detected for doses of 100 and 200 mg/kg Hostacortin, respectively. On the other hand, Vioxx did not affect the parasite burden and liver egg count while it caused high reduction in the enzymatic activities of ASAT, ALAT and ALP in liver tissue homogenate. Also, a moderate increase in serum albumin and a significant reduction in liver total protein levels were observed in mice treated with Vioxx. In contrast to Hostacortin, Vioxx treatment induced a significant increase in the granuloma size by 29.3% at a dose level of 200 mg/kg. Conclusion: The treatment with Hostacortin was found to ameliorate to some extent the severity of the disease, but Vioxx treatment caused additional hepatotoxicity in the S. mansoni infected mice. [ABSTRACT FROM AUTHOR]

We consider the use of default priors in the Bayes methodology for seeking information concerning the true value of a parameter. By default prior, we mean the mathematical prior as initiated by Bayes [Philos. Trans. R. Soc. Lond. 53 (1763) 370--418] and pursued by Laplace [Theorie Analytique des Probabilities (1812) Courcier], Jeffreys [Theory of Probability (1961) Clarendon Press], Bernardo [J. Roy. Statist. Soc. Ser. B 41 (1979) 113-147] and many more, and then recently viewed as "potentially dangerous" [Science 340 (2013) 1177-1178] and "potentially useful" [Science 341 (2013) 1452]. We do not mean, however, the genuine prior [Science 340 (2013) 1177-1178] that has an empirical reference and would invoke standard frequency modelling. And we do not mean the subjective or opinion prior that an individual might have and would be viewed as specific to that individual. A mathematical prior has no referenced frequency information, but on occasion is known otherwise to lead to repetition properties called confidence. We investigate the presence of such supportive property, and ask can Bayes give reliability for other than the particular parameter weightings chosen for the conditional calculation. Thus, does the methodology have reproducibility? Or is it a leap of faith. For sample-space analysis, recent higher-order likelihood methods with regular models show that third-order accuracy is widely available using profile contours [In Past, Present and Future of Statistical Science (2014) 237- 252 CRC Press], But for parameter-space analysis, accuracy is widely limited to first order. An exception arises with a scalar full parameter and the use of the scalar Jeffreys [J. Roy. Statist. Soc. Ser. B 25 (1963) 318-329]. But for vector full parameter even with a scalar interest parameter, difficulties have long been known [J. Roy. Statist. Soc. Ser. B 35 (1973) 189-233] and with parameter curvature, accuracy beyond first order can be unavailable [Statist. Sci. 26 (2011) 299-316], We show, however, that calculations on the parameter space can give full second-order information for a chosen scalar interest parameter; these calculations, however, require a Jeffreys prior that is used fully restricted to the one-dimensional profile for that interest parameter. Such a prior is effectively data-dependent and parameter-dependent and is focally restricted to the one-dimensional contour; these priors fall outside the usual Bayes approach and yet with substantial calculations can still give less than frequency analysis. We provide simple examples using discrete extensions of Jeffreys prior. These serve as counter-examples to general claims that Bayes can offer accuracy for statistical inference. To obtain this accuracy with Bayes, more effort is required compared to recent likelihood methods, which still remain more accurate. And with vector full parameters, accuracy beyond first order is routinely not available, as a change in parameter curvature causes Bayes and frequentist values to change in opposite direction, yet frequentist has full reproducibility. An alternative is to view default Bayes as an exploratory technique and then ask does it do as it overtly claims? Is it reproducible as understood in contemporary science? The posterior gives a distribution for an interest parameter and, thereby, a quantile for the interest parameter; an oracle could record whether it was left or right of the true value. If the average split in evaluative repetitions is in accord with the nominal level, then the approach is providing accuracy. And if not, then what is up, other than performance specific to the parameter frequencies in the prior. No one has answers although speculative claims abound. [ABSTRACT FROM AUTHOR]

Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditions were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7 Å resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin- dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system. [ABSTRACT FROM AUTHOR]

Abstract: The lack of research on how the 2004 safety-related withdrawal of the drug Vioxx affected consumer drug utilization or outcomes for competitors is a missed opportunity to learn from the largest drug withdrawal event in history. Our study fills this void using state-level repeated cross section data from the Medicaid State Drug Utilization (SDU) database of fee-for-service Medicaid claims for prescription drugs, and individual-level panel data from the Medical Expenditure Panel Survey (MEPS) which is a nationally representative survey that contains information on medication use across two years. We find that the withdrawal of Vioxx had both positive and negative effects for specific substitute drugs in its own class (COX-2s), and that it led to an overall increase in the usage of both its most direct competitor class (NSAIDs) and in a class of older similar therapy (Analgesics). We argue these shifts in drug usage represent what could be viewed as an appropriate response to the events. However, aggregate use of drugs in the COX-2 and related classes declined overall, suggesting that some consumers may have over-reacted to the withdrawal events in ways that lessened the health benefits they could receive from this family of drugs. These findings about medication utilization changes in response to negative information are highly relevant for policy design and for determining thresholds for regulatory interventions. [Copyright &y& Elsevier]

This essay considers the ways in which Merck, a major pharmaceutical company, trained salespeople to communicate with physicians about its controversial pain drug, Vioxx. Between 2000 and 2004, approximately 60,000 people died while taking the drug. In this study, we analyzed 989 pages of internal training materials that show how Merck taught employees to communicate with physicians. Inspired by Craig and Tracy, we reconstruct the (1) guiding philosophies, (2) assumed problems, and (3) skills and techniques inherent in Merck's practical theory of communication. Using Nilsen's perspective on ethics, we argue that Merck taught a communication approach that obscured physicians' ability to make a significant choice and unnecessarily put more patients' lives at risk. The essay underscores the need to make communication ethics a primary rather than a secondary research concern. [ABSTRACT FROM AUTHOR]

Participants in some clinical trials are at risk of being harmed and sometimes are seriously harmed as a result of not being provided with available, relevant risk information. We argue that this situation is unacceptable and that there is a moral duty to disclose all adverse clinical trial results to participants in clinical trials. This duty is grounded in the human right not to be placed at risk of harm without informed consent. We consider objections to disclosure grounded in considerations of commercial interest, and we argue that these concerns are insufficient to override the moral duty to disclose adverse clinical trial results. However, we also develop a proposal that enables commercial interests to be protected, while promoting the duty to disclose adverse clinical trial results. [ABSTRACT FROM AUTHOR]

Abstract: The potential prothrombotic effect of the cyclooxygenase-2 (COX-2) inhibitor Rofecoxib (Vioxx) was investigated using murine thrombosis models. In a jugular vein thrombosis model (photochemically induced injury) in lean wild-type mice, Rofecoxib treatment for 4 weeks induced a mild prothrombotic tendency, as indicated by a shorter occlusion time as compared to placebo (median of 12 min versus 36 min; p<0.05). Thrombus size was somewhat, but not significantly, enhanced after Rofecoxib treatment. In a femoral artery thrombosis model (FeCl3 induced injury) Rofecoxib did not cause an enhanced thrombotic tendency in mice with nutritionally induced or genetically determined (ob/ob) obesity. The occlusion time was comparable for obese wild-type mice with (8.8±0.7 min) or without (7.8±2.1 min) Rofecoxib treatment, as well as for ob/ob mice (8.5±0.7 min versus 6.8±3.0 min). Thus, an enhanced prothrombotic effect of Rofecoxib was detected when using a venous thrombosis model in lean mice, but not when using an arterial thrombosis model in obese mice. [Copyright &y& Elsevier]

The author took Celebrex for seven years, only to find out that it could be associated with heart disease, which I now have, and other possible diseases, too. This article discusses some of my experiences and the possible link between Celebrex and heart disease and other illnesses. It is apparent that while I was helped in various ways, I did not always receive complete, excellent medical advice. [ABSTRACT FROM AUTHOR]

Marketing researchers have proposed various conceptual models of ethical decision-making to better clarify the steps in the decision-making process. However, lacking in the literature is comprehensive empirical validation of these models. This manuscript examines the ethical decision-making model proposed by Ferrell et al. [1989, Journal of Macromarketing 56(Fall), 55–64] in the context of a real-world marketing situation. This model is a comprehensive synthesis of previously developed models in the literature. The events surrounding the withdrawal from the market of the pain reliever Vioxx, manufactured by Merck & Co., are detailed. The analysis provides insights into the decision-making process faced by Merck executives and sheds light onto the real-world applicability of the conceptual model. Furthermore, this study demonstrates how potential modifications to existing models can be developed by their examination in the context of real world events. It is hoped that this analysis, along with future examinations, aids marketing researchers in developing a better understanding of the ethical decision-making process in a business context. [ABSTRACT FROM AUTHOR]

An estimated 27,000-60,000 patients died while taking Merck's drug Vioxx between 2000 and 2004. This essay uses Deetz's treatment of systematically distorted communication and Nilsen's significant choice to analyze Merck's communication about the drug. The company claimed publicly to be forthright about Vioxx's safety. The article shows, however, that Merck systematically distorted communication through neutralization, topical avoidance, and disqualification in ways that thwarted physicians' and patients' abilities to make an informed choice about Vioxx. The analysis shows that Merck employees' consent to economic priorities framed these communication practices as legitimate and rational within the organization. The same practices, however, appeared socially irresponsible to members of the scientific community outside the company. In contrast to Merck's practices, the essay offers more participatory communication applications that uphold companies' moral obligation to their stakeholders. [ABSTRACT FROM AUTHOR]

Elucidation of differences between the active sites of COX-1 and COX-2 allowed the targeted design of the selective COX-2 inhibitors known as coxibs. They were marketed as non-steroidal anti-inflammatory drugs (NSAIDs) that had improved upper gastrointestinal (GI) safety compared with older non-selective NSAIDs such as diclofenac and naproxen. Two GI safety studies conducted with arthritis patients demonstrated that in terms of upper GI safety, celecoxib was not superior to diclofenac (CLASS study) but rofecoxib was superior to naproxen (VIGOR study). However, the VIGOR study revealed also that rofecoxib had increased cardiovascular (CV) risk compared with naproxen. This clinical outcome was supported by the existence of plausible eicosanoid-based biological mechanisms whereby selective COX-2 inhibition could increase CV risk. Nevertheless, the existence of CV risk with rofecoxib was successfully discounted by its pharmaceutical company owner, Merck & Co, with the assistance of specialist opinion leaders and rofecoxib achieved widespread clinical use for 4–5 years. Rofecoxib was withdrawn from the market when several clinical trials in colorectal cancer and post-operative pain revealed increased CV risk with not only rofecoxib, but also coxibs. The commercial success of rofecoxib provides a case-study of failure of the medical journal literature to guide drug usage. Attention to ethical issues may have provided a more useful guide for prescribers. [ABSTRACT FROM AUTHOR]

Since the early 1980s, private, for-profit corporations have become increasingly involved in all aspects of scientific research, especially of biomedical research. In this essay, I argue that there are dangerous epistemic consequences of this trend, which should be more thoroughly examined by social epistemologists. In support of this claim, I discuss a recent episode of pharmaceutical research involving the painkiller Vioxx. I argue that the research on Vioxx was epistemically problematic and that the primary cause of these inadequacies was faulty institutional arrangements. More specifically, the research was organized in such a way as to allow short-term commercial interests to compromise epistemic integrity. Thus, the Vioxx case study, in conjunction with numerous case studies developed elsewhere, provides strong reasons for believing that the privatization of the biomedical sciences is epistemically worrisome, and it suggests that the primary response to this situation should be a social, or organizational, one. What kind of organizational response would be most beneficial? I briefly discuss two prominent social epistemological proposals for how scientific research should be organized - namely those of Philip Kitcher and Helen Longino - and I suggest that they are incapable of dealing with the phenomenon of privatization. I then draw upon the Vioxx episode in order to outline an alternative suggestion for reorganizing certain aspects of pharmaceutical research. [ABSTRACT FROM AUTHOR]

The article discusses ethical concerns regarding the conduct of the pharmaceutical industry in the light of the development and withdrawal of non-steroidal anti-inflammatory drug Vioxx. The growing concerns over the safety and efficacy of Vioxx has forced its manufacturers to withdraw it from the market. The author opines that bioethical aspects in drug manufacturing should be taken into consideration by the drug manufacturers.

On July 14, 2005, opening arguments were given in Ernst v. Merck, the first Vioxx®-related lawsuit to reach a jury. Mark Lanier represented the widow of Robert Ernst, who died in May 2001 at age 59, after taking Vioxx® for 8 months. The coroner's report indicated that Ernst died of an arrhythmia. Lanier pointed out that the Merck Manual of Medical Information states that arrhythmias are associated with heart attacks 90% of the time (Keller, 2005). The trial was held in Angleton, Texas, with the 23rd District Court Judge Ben Hardin presiding. After 5 weeks of testimony, the jury realized not only how early Merck knew of the cardiovascular effects of Vioxx® but how they continued to aggressively market the drug despite these devastating effects. A seven-man, five-woman jury deliberated for 10 1/2 hours over 2 days before returning a verdict for the plaintiff. [ABSTRACT FROM AUTHOR]

Background: A prospective, randomized, double-blinded clinical trial was designed to study the effects of preemptive rofecoxib (Vioxx) analgesia in patients undergoing elective laparoscopic cholecystectomy.Methods: One hundred-twenty patients were enrolled in the study over a 21-month period, and 116 completed the study. One half of the patients received 50 mg rofecoxib preoperatively and the other half, placebo. Both groups were demographically similar. Medical information, patient and nursing assessments, and surgical data were evaluated.Results: A significant reduction in requirements for postoperative narcotic analgesic dosing was noted in the rofecoxib group. In addition, patients receiving rofecoxib reported significantly less nausea and improvement in their activity level when compared with the control group. No complications were encountered with the preoperative use of rofecoxib.Conclusions: We conclude that in patients undergoing laparoscopic cholecystectomy, preoperative administration of rofecoxib in selected patients may facilitate postoperative recovery and decrease postoperative narcotic requirements. [Copyright &y& Elsevier]

Adsorption and reduction of rofecoxib were investigated by cyclic and square-wave voltammetry on a hanging mercury drop electrode in electrolytes of various pH values. The reduction process on hanging mercury drop electrodes gave rise to a single peak within the entire pH range (2.0–11.5). In alkaline solutions, rofecoxib gave a sensitive adsorptive reductive peak; approximately 10 times larger than those obtained by applying a square-wave scan without prior accumulation. Application of the method to the determination of rofecoxib in two pharmaceutical products (Vioxx 12.5 and 25 mg), without sample pretreatment, resulted in acceptable deviation from the stated concentrations. [Copyright &y& Elsevier]

Objective: To compare the incidence of selected spontaneously reported adverse events (AEs) in patients with osteoarthritis (OA) treated with rofecoxib (VIOXX, 12.5 mg qd) or Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid).Methods: Double-blind, parallel-group, 6-week study of patients aged > or = 40 years with a clinical diagnosis of OA treated with rofecoxib or Arthrotec. Primary endpoint: self-reported diarrhea; secondary endpoints: abdominal pain, discontinuations due to AEs, GI AEs and NSAID-type GI AEs (ie., acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea, vomiting).Results: Among 483 patients (80.3% females, mean age 62.1), the rofecoxib group vs the Arthrotec group respectively reported diarrhea 6.2% vs 16.2% (p<0.001); drug-related diarrhea 3.7% vs 16.2% (p<0.001); one or more clinical AEs 52.9% vs 73.0% (p<0.001); GI AEs 28.9% vs 48.5% (p<0.001); NSAID-type GI AEs 18.6% vs 29.9% (p=0.004); discontinuations due to abdominal pain 0.4% vs 3.7% (p<0.05); and discontinuations due to any AE 4.1% vs 9.1% (p=0.029). No significant differences were observed in efficacy.Conclusion: Rofecoxib 12.5 mg qd has improved GI tolerability and similar efficacy compared to Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid). [ABSTRACT FROM AUTHOR]

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of 'hidden cardiotoxicity' is defined as cardiotoxicity of a drug that manifests in the diseased (e.g., ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g., ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs. [ABSTRACT FROM AUTHOR]

As this special themed edition of The Journal of Legal Nurse Consulting on Pain Management went to print, Vioxx (rofecoxib), a nonsteroidal anti-inflammatory drug (NSAID) was withdrawn from the market by its manufacturer, Merck & Co., Inc. On September 30, 2004, Merck announced the withdrawal of Vioxx based on the results of the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial. [ABSTRACT FROM AUTHOR]