Tidsskr Nor Laegeforen 2006 May 11; 126(10): 1326-7 (Read article online)

Rognstad S, Straand J

BACKGROUND: The withdrawal of rofecoxib (Vioxx) from the global market because of adverse cardiovascular effects affected many patients and created a lot of publicity. MATERIAL AND METHODS: 287 patients from four general practices who had received prescriptions for rofecoxib in 2004 were identified from the medical records of their general practitioner (GP) and mailed a questionnaire addressing their reactions and their expectations of their GP in this respect. RESULTS: 140 out of 287 patients returned the questionnaire. More than half were scared by the media frenzy about the withdrawal. 15% had received information from their GP after the withdrawal, whereas 70% wanted this kind of information. 42% had received prescriptions for rofecoxib, even if the patients could not confirm the presence of the diagnostic criteria. INTERPRETATION: The media frenzy gave rise to concern among patients, who want their GP to be more active in informing them about their use of unsafe medication. Better routines and data tools are needed for GPs to better identify and inform patients when needed.

Tidsskr Nor Laegeforen 2006 May 11; 126(10): 1326-7 (Read article online)

Rognstad S, Straand J

BACKGROUND:. The withdrawal of rofecoxib (Vioxx) from the global market because of adverse cardiovascular effects affected many patients and created a lot of publicity. MATERIAL AND METHODS:. 287 patients from four general practices who had received prescriptions for rofecoxib in 2004 were identified from the medical records of their general practitioner (GP) and mailed a questionnaire addressing their reactions and their expectations of their GP in this respect. RESULTS:. 140 out of 287 patients returned the questionnaire. More than half were scared by the media frenzy about the withdrawal. 15 % had received information from their GP after the withdrawal, whereas 70 % wanted this kind of information. 42 % had received prescriptions for rofecoxib, even if the patients could not confirm the presence of the diagnostic criteria. INTERPRETATION:. The media frenzy gave rise to concern among patients, who want their GP to be more active in informing them about their use of unsafe medication. Better routines and data tools are needed for GPs to better identify and inform patients when needed.

Med Klin (Munich) 2006 Mar 15; 101(3): 191-7 (Read article online)

Sawicki PT, Bender R, Selke GW, Klauber J, Gutschmidt S

BACKGROUND AND PURPOSE: After the recall of rofecoxib (Vioxx), there was repeated national and international discussion on the potential number of patients harmed by causally related cardio- and cerebrovascular events. In individual cases, it cannot be determined whether a myocardial infarction or stroke that occurred during rofecoxib therapy was actually directly caused by this drug. On the basis of the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial and German prescription data provided by the Scientific Institute of the Local Health Care Fund, the authors therefore conservatively estimated the number of patients harmed by rofecoxib in Germany between 2001 and 2004. METHODS: Under simplifying assumptions that, as in the VIGOR study, the risk of rofecoxib or naproxen therapy can be described by a Cox model with exponentially distributed event times, it is possible to calculate the daily risk of cardio- and cerebrovascular events in patients treated with these drugs. The estimated number of patients experiencing cardio- and cerebrovascular events under rofecoxib or naproxen therapy can be calculated by multiplying the daily risks by the defined daily doses prescribed in Germany. The difference between these numbers produces the estimated number of patients harmed by rofecoxib. RESULTS: On the basis of the data pool, a total of 7,092 additional diseased or deceased patients due to rofecoxib therapy were estimated (95% confidence interval: 2,004-15,416). The simplifying assumptions made together with the underreporting of events in the VIGOR trial are more likely to lead to an underestimation than an overestimation of affected patients. When assessing the benefit-harm ratio of rofecoxib, it needs to be considered that its protective gastrointestinal effects were not assessed compared with the optimum long-term therapy. It can be assumed that a comparison of rofecoxib with a combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric mucosal barrier protectors (e. g., misoprostol) would not have shown an advantage in favor of rofecoxib therapy. CONCLUSION: The example of rofecoxib and the relatively high number of patients harmed by it in Germany indicate that, before widely prescribing a new drug, a more thorough assessment of the benefit-harm ratio of the drug is required as well as a stronger consideration of therapeutic alternatives and a timely conduct of meaningful clinical studies. The results of these studies should be promptly communicated in full to physicians and patients.

Cochrane Database Syst Rev 2006; CD004504 (Read article online)

Gagnier J, Vantulder M, Berman B, Bombardier C

BACKGROUND: Low-back pain is a common condition and a substantial economic burden in industrialized societies. A large proportion of patients with chronic low-back pain use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in low-back pain. OBJECTIVES: To determine the effectiveness of herbal medicine for non-specific low-back pain. SEARCH STRATEGY: We searched the following electronic databases: Cochrane Complementary Medicine Field Trials Register (Issue 3, 2005), MEDLINE (1966 to July 2005), EMBASE (1980 to July 2005); checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this very specialized area. SELECTION CRITERIA: We included randomized controlled trials, examining adults (over 18 years of age) suffering from acute, sub-acute or chronic non-specific low-back pain. The interventions were herbal medicines, defined as plants that are used for medicinal purposes in any form. Primary outcome measures were pain and function. DATA COLLECTION AND ANALYSIS: Two authors (JJG & MVT) conducted the database searches. One author contacted content experts and acquired relevant citations. Full references and abstracts of the identified studies were downloaded. A hard copy was retrieved for final inclusion decisions. Methodological quality and clinical relevance were assessed separately by two individuals. Disagreements were resolved by consensus. MAIN RESULTS: Ten trials were included in this review. Two high quality trials examining the effects of Harpagophytum Procumbens (Devil's Claw) found strong evidence that daily doses standardized to 50 mg or 100 mg harpagoside were better than placebo for short-term improvements in pain and rescue medication. Another high quality trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx). Two trials examining the effects of Salix Alba (White Willow Bark) found moderate evidence that daily doses standardized to 120 mg or 240 mg salicin were better than placebo for short-term improvements in pain and rescue medication. An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib. Three low quality trials on Capsicum Frutescens (Cayenne), examining various topical preparations, found moderate evidence that Capsicum Frutescens produced more favourable results than placebo and one trial found equivalence to a homeopathic ointment. AUTHORS' CONCLUSIONS: Harpagophytum Procumbens, Salix Alba and Capsicum Frutescens seem to reduce pain more than placebo. Additional trials testing these herbal medicines against standard treatments are needed. The quality of reporting in these trials was generally poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions.

Bioorg Med Chem Lett 2006 Apr 5; (Read article online)

Caturla F, Amat M, Reinoso RF, Córdoba M, Warrellow G

The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.

Hautarzt 2006 Apr 28; (Read article online)

Hirschfeld G, Sperfeld AD, Kassubek J, Scharffetter-Kochanek K, Sunderkötter C

After the oral administration of the COX 2 inhibitor rofecoxib (Vioxx((R))) as part of an oral provocation test, a 64-year-old woman developed acute anterograde and retrograde amnesia which lasted for several hours. The patient did not show symptoms of anaphylaxis. Neurological examination did not reveal focal symptoms or an epileptic seizure. Diffusion-weighted magnetic resonance imaging only showed a small region of increased signal intensity in the left hippocampus. The patient thus had no anaphylactic drug reaction, but a transient global amnesia (TGA) or amnestic episode. TGA is an acute, reversible, cerebral dysfunctional state which lasts from 1 h up to maximally 24 h and which is associated with anterograde and retrograde amnesia. While about half of the cases appear to occur spontaneously, other cases are preceded by physically or emotionally stressful events. In our patient it may have been the emotional distress caused by the oral provocation testing that has triggered the TGA. When TGA occurs during oral challenge of drugs, we recommend repeating the oral challenge of the tested drug.

Ugeskr Laeger 2006 Mar 27; 168(13): 1343-4 (Read article online)

Calvo N, Iversen E, Munck LK

COX-2 inhibitors and NSAIDs have similar analgesic, anti-inflammatory and severe upper intestinal side effects. Adding to the sparse and casuistic reports, a further five cases of severe lower intestinal illness associated with COX-2 inhibitor ingestion are presented. Diarrhoea due to microscopic colitis was associated with short-time ingestion of refecoxib and celecoxib by two patients. Refecoxib intake for two months was associated with spontaneous perforation of a well-functioning J-pouch in a patient with ulcerative colitis. Intake of celecoxib and etodolac was associated with colonic ulceration and stricture. Side effects related to COX-2 inhibitors are similar to those related to NSAIDs.

Postgrad Med J 2006 Apr; 82(966): 242-5 (Read article online)

Sooriakumaran P

The selective COX-2 inhibitors (coxibs) were originally developed to minimise the adverse effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) while maintaining the same analgesic and anti-inflammatory properties. Many large studies confirmed the improved gastric side effect profile of coxibs compared with non-selective NSAIDs; however, reports of increased cardiovascular morbidity and mortality followed, and the manufacturer Merck was forced to withdraw rofecoxib (Vioxx) from the market. Other coxibs have also either perished or had restrictions placed on their use. However, there seem to be significant differences between coxibs regarding their cardiovascular profiles, and the evidence for a class effect is dubious. In this paper, the current body of knowledge regarding the cardiovascular toxicities of coxibs is reviewed. The take home message for prescribing NSAIDs and those coxibs still on the market seems to be one of caution rather than contraindication, except in patients with significant cardiovascular risk factors.

Inflammopharmacology 2005; 13(4): 419-25 (Read article online)

Halpern GM

In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist.

Harefuah 2005 Dec; 144(12): 848-51, 910 (Read article online)

Hefer E

When scientific researches are being published one should consider carefully the different possible influences which may change the results. These influences may be of two kinds: Non-Causal explanations, and Casual explanations. Researchers may arrive at their results and not have considered all the causative explanations. Occams's Razor is the basic rule by which most reasonable explanations are chosen. A statistical result and an appropriate simple theory to explain it, is not sufficient to prove causative effect. In many cases though, the media and public tend to accept a statistically significant result as if it was a proven cause and effect relation. There are several conditional demands called Bradford Hill criteria of which epidemiological data and results are only one, the more results arrived by using the Bradford Hill criteria, the better chances exist that the examined variable is the cause for the effect. Finally, there is a gap between a proven causal factor for disease or the harmful effects of treatment and a "clear cut" health policy. There are several intermediate powerful influences which are involved in the process of stating a new health policy. These influences include among others, the involvement of decision makers, political influences and civil service professionals. As an example three different issues of a well proven clinical research will be presented. The research of Rofecoxib = "Vioxx" cardiac effects, the research of Hormonal Replacement Treatment health effects on post menopausal women and the last of Health risks presented by mobile phone use. Although the results of those researches were proven to be statistically significant, Health Policy in each case is different and less clear. Health Policy is not based solely on figures and statistical results, but rather on a far wider and more complex influences and judgment.

Biochemistry 2006 Mar 14; 45(10): 3206-18 (Read article online)

Furse KE, Pratt DA, Schneider C, Brash AR, Porter NA, Lybrand TP

The two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed step in prostaglandin biosynthesis and are the targets of the nonsteroidal antiinflammatory drugs aspirin and ibuprofen and the COX-2 selective inhibitors, Celebrex, Vioxx, and Bextra. The enzymes are remarkable in that they catalyze two dioxygenations and two cyclizations of the native substrate, arachidonic acid, with near absolute regio- and stereoselectivity. Several theories have been advanced to explain the nature of enzymatic control over this series of reactions, including suggestions of steric shielding and oxygen channeling. As proposed here, selective radical trapping and spin localization in the substrate-derived pentadienyl radical intermediate can also be envisioned. Herein we describe the results of explicit, 10 ns molecular dynamics simulations of both COX-1 and COX-2 with the substrate-derived pentadienyl radical intermediate bound in the active site. The enzymes' influence on the conformation of the pentadienyl radical was investigated, along with the accessible space above and below the radical plane and the width of several channels to the active site that could function as access routes for molecular oxygen. Additional simulations demonstrated the extent of molecular oxygen mobility within the active site. The results suggest that spin localization is unlikely to play a role in enzymatic control of this reaction. Instead, a combination of oxygen channeling, steric shielding, and selective radical trapping appears to be responsible. This work adds a dynamic perspective to the strong foundation of static structural data available for these enzymes.

Am J Orthod Dentofacial Orthop 2006 Mar; 129(3): 402-6 (Read article online)

de Carlos F, Cobo J, Díaz-Esnal B, Arguelles J, Vijande M, Costales M

INTRODUCTION: The purpose of this study was to compare the effects of a conventional nonsteroidal anti-inflammatory drug, diclofenac (Voltaren [Novartis, Barcelona, Spain]), and a specific cyclooxygenase-2 (COX-2) inhibitor, rofecoxib (Vioxx [MSD, Madrid, Spain]), on the inhibition of dental movement induced with a coil-spring orthodontic apparatus in rats. METHODS: Tooth movement was measured on the lateral cranial teleradiographs of 42 male Wistar rats in 6 experimental groups: (1) 50-g coil spring and 2 rofecoxib injections of 1 mg per kilogram of body weight; (2) similar orthodontic procedure and 2 diclofenac injections of 10 mg per kilogram of body weight; (3) the same orthodontic treatment and 0.9% saline-solution injections; and (4), (5), and (6) 100-g coil appliance and the same pharmacological treatment as 1, 2, and 3, respectively. RESULTS: The difference in tooth movement, measured in the control animals after 10 days of 50 or 100 g of orthodontic force application, was not statistically significant. Reduction in tooth movement in 50-g traction groups reached statistically significant differences; both rofecoxib or diclofenac were effective in inhibiting dental movement. The comparison of the 3 groups treated with 100 g of force also reached statistical significance. Both rofecoxib and diclofenac significantly inhibited dental movement, partially in the case of rofecoxib and totally in the case of diclofenac. Nevertheless, no statistically significant difference was found between the effects of rofecoxib and diclofenac. CONCLUSIONS: There is no substantial advantage in using selective COX-2 inhibitors compared with nonspecific COX inhibitors to avoid interference with tooth movement during orthodontic treatment in rats.

Am J Physiol Heart Circ Physiol 2006 Apr; 290(4): H1337-46 (Read article online)

Fetalvero KM, Shyu M, Nomikos AP, Chiu YF, Wagner RJ, Powell RJ, Hwa J, Martin KA

Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM alpha-actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14-22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via G(s) activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.

BMC Cancer 2006; 6: 27 (Read article online)

Harris RE, Beebe-Donk J, Alshafie GA

BACKGROUND: Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. METHODS: We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003-2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals. RESULTS: Results showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14-0.59), regular aspirin (OR = 0.49, 95% CI = 0.26-0.94), and ibuprofen or naproxen (0.36, 95% CI = 0.18-0.72). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of breast cancer. CONCLUSION: Selective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.

Aust Fam Physician 2005 Nov; 34(11): 945-8 (Read article online)

Wong M, Chowienczyk P, Kirkham B

BACKGROUND: Rofecoxib (Vioxx) was withdrawn from the market because of increased death from cardiovascular (CV) events. Other selective cyclooxygenase-2 (COX-2) inhibitors and traditional nonsteroidal anti-inflammatory drugs (NSAIDs) may share this risk, but to what extent is unclear. OBJECTIVE: This article reviews the available evidence using a PubMed search for increased CV risk with COX-2 inhibitors and NSAIDs, explores possible mechanisms, and makes recommendations for their appropriate use in clinical practice. DISCUSSION: Rofecoxib, celecoxib, and the combination of valdecoxib and parecoxib have been found in prospective trials to increase CV risk. NSAIDs have also been found to be associated with increased CV risk in observational studies, but large randomised controlled trials with adequate follow up are required to further investigate this. Recommendations are to use drugs at lowest dose and for shortest duration possible. In patients with or at high risk for CV disease, COX-2 inhibitors are contraindicated. A traditional NSAID plus proton pump inhibitor may be used, but with caution.

Curr Pharm Des 2006; 12(8): 971-5 (Read article online)

Dogné JM, Hanson J, Supuran C, Pratico D

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".