Una historia de perjuicio, desperdicio y engaño: cómo la gran industria farmacéutica ha socavado la fe pública en los datos de sus ensayos clínicos y qué podemos hacer al respecto / A tale of harm, waste and deception: how big pharma has undermined public faith in trial data disclosure and what we can do about it

El artículo aborda el tema de los datos relacionados con los estudios de intervención en seres humanos conducidos por la industria farmacéutica y cómo la falta de datos, o bien la distorsión de éstos, puede determinar un impacto sobre la toma de decisiones en clínica y en las revisiones sistemáticas. Se comentan los casos de rosiglitazona (Avandia™, GlaxoSmithKline), rofecoxib (Vioxx™, Merck) y de oseltamivir (Tamiflu™, Roche), como ejemplos de perjuicio (morbilidad y mortalidad mayor en quienes han usado los fármacos), de desperdicio (mayor gasto de los gobiernos en programas de control de problemas de salud pública que no tenían base en evidencia) y de engaño (no reporte de eventos adversos por parte de los encargados de los estudios). Las consecuencias de esta conducta sobre la producción científica son múltiples. Principalmente se produce una reducción y distorsión de la base de evidencia para fundamentar las decisiones clínicas, lo que también incluye el sesgo de publicación. Se recogen varias soluciones planteadas en la literatura internacional como el registro de los ensayos clínicos antes de su realización, el uso de directrices para mejorar la calidad de los reportes, fomentar la publicación de todos los resultados de investigación y la autonomía de la academia e investigadores. El registro de los ensayos clínicos no ha sido eficaz en prevenir la opacidad que rodea la experimentación fase III de los ensayos de intervención financiados por la industria. Deben hacerse cargo de este problema los editores de las revistas biomédicas, las autoridades sanitarias encargadas de dar la aprobación a los fármacos antes de su comercialización, los comités de ética que autorizan la ejecución de ensayos en sus establecimientos, los investigadores y académicos y las organizaciones de pacientes. La industria farmacéutica está llamada a responder a estas propuestas que fomentan la transparencia...

The article addresses the issue of data stemming from interventional studies in humans conducted by the pharmaceutical industry and how lack of data, or data distortion, can impact on clinical decision making and systematic reviews. The cases of rosiglitazone (Avandia ™, GlaxoSmithKline), rofecoxib (Vioxx ™, Merck), and oseltamivir (Tamiflu ™, Roche), are discussed as examples of harm (morbidity and mortality were higher in the treatment groups), waste (government spending in public health programs was not based on evidence), and deception (non-reporting of adverse events in fase III trials). The consequences of this behavior on scientific production are manifold. Most importantly, evidence that is used to inform clinical decisions is reduced and distorted, which also includes publication bias. The article mentions several solutions that have appeared in international literature, such as registration of clinical trials prior to implementation, the use of guidelines to improve the quality of reports, encouraging the publication of all research results and safeguarding autonomy of academy and investigators. Registration of clinical trials has not been effective in preventing the opacity surrounding phase III intervention trials funded by industry. Editors of biomedical journals, health authorities in charge of approving drugs before marketing, ethics committees that authorize the conduct of trials in their facilities, researchers, academics and patient organizations, are all major stakeholders. The pharmaceutical industry is called upon to respond to these proposals that promote transparency. If they do so, public trust in research conducted by them may be recovered.

Sorbitan ester niosomes for topical delivery of rofecoxib.

The aim of the present investigation is to encapsulate rofecoxib in niosomes and incorporate the prepared niosomes into dermal gel base for sustained therapeutic action. Niosomes were prepared by lipid film hydration technique and were analyzed for size, entrapment efficiency and drug retention capacity. Niosomal vesicles were then incorporated into blank carbopol gel to form niosomal gel. The in vitro permeation study across pig skin was performed using Keshary-Chien glass diffusion cell. The size and entrapment efficiency of the niosomal vesicles increased with gradual increase in HLB value of nonionic surfactants used. Maximum drug entrapment was observed with Span 20 with HLB value of 8.6 and drug leakage from vesicles was less at refrigerated condition than at the room temperature. Higher proportion of cholesterol made the niosomal formulation more stable with high drug retention properties. The niosomal gel showed a prolong drug release behavior compared to plain drug gel. Differential scanning calorimetric study of drug loaded gel and pig skin after permeation study confirmed inertness of carbopol gel base toward rofecoxib and absence of drug metabolism in the skin during permeation study, respectively. The niosomal formulations were successfully prepared by lipid film hydration technique using cholesterol and Span as nonionic surfactant. Presence of cholesterol made niosomes more stable with high drug entrapment efficiency and retention properties. The lower flux value of niosomal gel as compared to plain drug gel across pig skin assured the prolong drug release behavior with sustained action.

Selective cyclooxygenase-2 inhibition protects against myocardial damage in experimental acute ischemia

BACKGROUND: Acute myocardial infarction is associated with tissue inflammation. Early coronary reperfusion clearly improves the outcome but may help propagate the inflammatory response and enhance tissue damage. Cyclooxygenase-2 is an enzyme that catalyzes the initial step in the formation of inflammatory prostaglandins from arachidonic acid. Cyclooxygenase-2 levels are increased when ischemic cardiac events occur. The overall function of COX-2 in the inflammatory process generated by myocardial ischemic damage has not yet been elucidated. GOAL: The objective of this study was to determine whether a selective cyclooxygenase-2 inhibitor (rofecoxib) could alter the evolution of acute myocardial infarction after reperfusion. METHODS AND RESULTS: This study was performed with 48 mongrel dogs divided into two groups: controls and those treated with the drug. All animals were prepared for left anterior descending coronary artery occlusion. The dogs then underwent 180 minutes of coronary occlusion, followed by 30 minutes of reperfusion. Blood samples were collected from the venous sinus immediately before coronary occlusion and after 30 minutes of reperfusion for measurements of CPK-MB, CPK-MBm and troponin I. During the experiment we observed the mean blood pressure, heart rate and coronary flow. The coronary flow and heart rate did not change, but in the control group, there was blood pressure instability, in addition to maximal levels of CPK-MB post-infarction. The same results were observed for CPK-MBm and troponin I. CONCLUSION: In a canine model of myocardial ischemia-reperfusion, selective inhibition of Cyclooxygenase-2 with rofecoxib was not associated with early detrimental effects on the hemodynamic profile or the gross extent of infarction; in fact, it may be beneficial by limiting cell necrosis.

Acute toxicity of cyclooxygenase-2 inhibitor rofecoxib as a radiosensitizer for concurrent chemoradiation in the treatment of uterine cervical cancer / 부인종양

OBJECTIVE: To evaluate the acute toxicity of rofecoxib during concurrent use with cisplatin-based chemoradiotherapy (CCRT) in patients with cervical cancer. METHODS: We evaluated 67 FIGO stage IB2-IVA cervical cancer patients treated with CCRT between June 2002 and July 2004. The study group included patients who received rofecoxib (N=30) and the control group included patients who received CCRT only (N=37). The patients' medical records were retrospectively reviewed for patient characteristics, toxicity related to CCRT and treatment results. RESULTS: There were no significant differences in toxicity between the two groups. The most common acute grade 3/4 toxicity was neutropenia (13.3% in the study group and 21.6% in the control group). Grade 3/4 late toxicity was observed in 2 (6.6%) patients in the study group and 3 (8.1%) in the control group. There was no treatment-related deaths in either group. Six (20.0%) patients in the study group had treatment failure. In the control group, 6 (16.2%) patients experienced treatment failure. Progression-free and overall survival was 55.8+/-4.2 and 59.0+/-2.8 months, respectively, in the study group, and 69.7+/-4.3 and 71.6+/-3.6 months, respectively, in the control group. There were no differences in progression-free and overall survival between the 2 groups. CONCLUSION: Our data indicate that rofecoxib, at a dose of 25 mg twice daily, has acceptable acute toxicity as a radiosensitizer during CCRT. Although rofecoxib was not efficacious as a radiosensitizer in the present study, the benefit of rofecoxib as a radiosensitizer should be further evaluated in a prospective study.

Cyclooxygenase-2 Inhibitors and Cardivascular Risk / 한양의대학술지

Serious concerns about the cardiovascular safety of rofecoxib had been present since the VIOXX(R) Gastrointestinal Outcomes Research (VIGOR) study first suggested that the drug may increase the risk of myocardial infarction. Subsequent data from major observational studies further implicated the association of rofecoxib with arterial thromboembolic disease. In September 2004, rofecoxib was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on VIOXX (APPROVe) study, which indicated an increase risk of myocardial infarction and stroke among subjects randomized to rofecoxib. In December 2004, the results of the Adenoma Prevention with Celecoxib (APC) study demonstrated a dose-related increase in the risk of cardiovascular events among patients randomized to celecoxib when compared with placebo. Two other large prospective prevention studies of celecoxib, the Prevention of Spontaneous Adenomatous Polyps (Pre SAP) trial and the Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) did not show any sign of increased cardiovascular risk. None of the reported randomized trials studying any COX-2 selective imhibitor, thus far, has been specifically designed to examine cardiovascular outcomes. Hence, no cardiovascular hypotheses have yet been formally tested. Long-term and adequately powered prospective randomized clinical trials in relevant patient populations with clinically appropriate pre-specified cardiovascular end-points, ideally comparing COX-2 selective inhibitors with traditional NSAIDs, are required. Until these trials are completed, careful risk:benefit analysis of any putative increase in cardiovascular risk versus known gastrointestinal benefit for individual agents needs to be undertaken.

Effect of Rofecoxib on Pain and Hemorrhage after Tonsillectomy / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Nonsteroidal anti-inflammatory durgs (NSAIDs) are now widely accepted analgesics for posttonsillectomy patients, but their ability to inhibit platelet cyclooxygenase (COX) may be associated with a risk of increased bleeding after tonsillectomy. Rofecoxib, the recently introduced selective COX-2 inhibitor, may have advantages for analgesics in tonsillectomy in that they produce minimal effects on platelet aggregation. But the analgesic efficacy of rofecoxib in tonsillectomy has not been made known yet. The aim of our randomized prospective study was to compare the analgesic efficacy of rofecoxib, the selective COX-2 inhibitor, and ibuprofen, the classic NSAID, for the posttonsillectomy pain management. We also evaluated the influence of both drugs on the posttonsillectomy bleeding. SUBJECTS AND METHOD: Thirty-eight adult patients undergoing tonsillectomy were randomly divided into either ibuprofen or rofecoxib group. Patients received either oral ibuprofen (600 mg, three times a day) or oral rofecoxib (25 mg, twice a day). Patients recorded pain levels twice daily for 7 days using a visual analogue scale. Posttonsillectomy hemorrhage was recorded in each groups. RESULTS: Pain scores for the 7 days were not significantly different between two groups, but the rofecoxib group reported less pain. Rofecoxib group felt more satisfactorily about early control of postoperative pain. There was no significant difference in the incidence of postoperative hemorrhage between two groups. CONCLUSION: Rofecoxib is as effective as ibuprofen for postoperative pain control in adult tonsillectomy, which might be beneficial for avoiding the adverse effects of NSAIDs.

Study on analgesic effect of rofecoxib on patients with advanced carcinoma / 重庆医科大学学报

Objective:To study the analgesic effect of rofecoxib on patients with advanced carcinoma.Methods:In a randomized clinical trial,108 pathologically diagnosed cancer patients were treated with rofecoxib(dose 25～50mg/d) and the pain relief was observed among all the patients.Results:Rofecoxib was effective in control of cancer related pain in an oral dose of 25～50mg/day with a total effective rate of 84.26%.The main adverse reactions such as drowsiness,dizziness,nausea,vomiting,discomfort in stomach and constipation were slight.Conclusion:Rofecoxib is effective for relieving cancer related pain with sustained duration and slight in adverse reaction and convenient for administration.

Effect of rofecoxib on expressions of VEGF and inducible NOS in human gastric carcinoma tissues established in nude mice by orthotopic transplantation / 第三军医大学学报

Objective To evaluate the inhibitory effect of rofecoxib in human gastric carcinoma tissues established in nude mice by orthotopic transplantation through the expressions of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Methods After the models of human gastric carcinoma in nude mice by orthotopic transplantation were established, rofecoxib was administered intragastrically. The expressions of VEGF and iNOS were evaluated in the local tumors by Envision immunohistochemical method. Results The expression of VEGF protein in isotonic saline group, rofecoxib group and combination group were 81.25%, 61.25%, and 35.00% respectively.There was significant difference between rofecoxib group and isotonic saline group, and so was rofecoxib group and combination group (P

The Preemptive Analgesic Effects of Rofecoxib after Spinal Fusion Surgery / 대한마취과학회지

BACKGROUND: The administration of nonsteroidal antiinflammatory drugs (NSAIDs) can significantly affect spinal fusion for the multimodal management of postoperative pain. Moreover, cyclooxygenase-2 (COX-2) inhibitors may offer an alternative to conventional NSAIDs in the management of pain after spine stabilization surgery. This study was designed to determine the analgesic efficacy of different doses of rofecoxib. METHODS: We evaluated 60 inpatients undergoing one level spinal fusion surgery by a single surgeon. All patients received patient-controlled analgesia (PCA) morphine. Patients were divided into four groups. Preoperatively, they were given oral rofecoxib (25 mg, 50 mg, 75 mg), or oral placebo. Outcome measures included visual analogue scale (VAS) scores and 24 h morphine consumption at seven time periods during the first 24 h postoperatively. RESULTS: The total dose of morphine was significantly larger in the control and the 25 mg rofecoxib groups than in the other two groups. Morphine consumption was similar in groups receiving 50 mg or 75 mg of rofecoxib. No significant differences in pain scores were observed between the four groups. CONCLUSIONS: The effective doses of rofecoxib for significant analgesia are 50 mg and 75 mg after spinal fusion surgery.

Two Cases of Paroxysmal Hemicrania with Response to Rofecoxib

Paroxysmal hemicrania (PH) has been recently defined as an uncommon primary headache. PH is characterized by frequent attacks of severe unilateral pain associated with autonomic symptoms. The attack frequency usually ranges from 5 to 40 attacks per day. PH is characterized by its absolute responsiveness to indomethacin. However, indomethacin is not often well tolerated because of its gastric side effects. We report two patients with PH who could not tolerate indomethacin due to its severe gastric side effects but dramatically responded to rofecoxib.

Analysis of withdrawal of rofecoxib-cyclooxygenase-2 specific inhibitor / 中国临床药理学与治疗学

Rofecoxib, a COX-2 specific inhibitor, is approved for treatment of osteoarthritis, acute pain and primary dysmenorrhea. On September 30, 2004, Merck announced the voluntary worldwide withdrawal of rofecoxib (Vioxx). This paper reviewed the pharmacological actions of the COX-2 specific inhibitors and the characterization, premarket study, clinical application and side-effects of rofecoxib and analyzed the withdrawal of rofecoxib.

Influence of rofecoxib, a high selective cox-2 inhibitor,on articular cartilage of rats / 中国临床药理学与治疗学

AIM: To observe the influence of rofecoxib, a non steroidal anti inflammatory drug, administrated for a long term on the knee joints cartilage of rats. METHODS: An experimental model of osteoarthritis of left knee in the early stage was induced by cutting achilles tendon in rats, the right knee providing a control. The rats of one group were given rofecoxib orally, and the rats in another group were given saline as a control. After 100 days, the histopathology, ultrastructure, and histochemistry changes on the knee joints cartilage were monitored. RESULTS and CONCLUSION: Rofecoxib, administrated for 100 days, had no harmful influence on chondrocyte and collagen, and could increase proteoglycan of cartilage in some degree in rats.

Apoptosis of the neurocytes and the expression of Bcl-2 and Bax proteins after focal cerebral ischemia-reperfusion injury in rats and the effects of Rofecoxib / 中国药理学通报

Aim To observe the infarct size, apoptosis of the neurocytes,the expressions of Bcl-2 and Bax pro-teins after focal cerebral ischemia-reperfusion injury (CIRI) in the brain tissue of rats and the protective effects of rofecoxib.Methods The model of local CIRI was induced by reversible middle cerebral artery occlusion (MCAO) with inserting a thread through internal carotid artery,2 h occlusion followed by 24 h reperfusion.Rofecoxib was administrated (ig) at the reperfusion initiation. Using TTC staining technique to measure the infarct size of brain,TUNEL technique to examine apoptosis of the neurocytes,immunohistochemical method to examine the expression level of Bcl-2 and Bax proteins in brain tissue.Results After focal CIRI,the infarct focus of brain was showed,both apoptosis rate of the neurocytes and Bax protein expression were significantly increased and the ratio of Bcl-2 to Bax was significantly reduced.With the use of both 1.12 and 2.24 mg?kg -1 doses of rofecoxib,the brain infarct size was dramatically reduced. With the use of 2.24 mg?kg -1 dose of rofecoxib,both apoptosis rate of the neurocytes and Bax protein expression were significantly decreased,both Bcl-2 protein expression and the ratio of Bcl-2 to Bax were significantly higher than that in the group Model.Conclusion The highly selective COX-2 inhibitor rofecoxib may increase Bcl-2 protein expression and decrease Bax protein expression then increase the ratio of Bcl-2 to Bax and so reduce the neurocytes apoptosis in brain tissue thus significantly improve the brain injury after CIRI.