Christopher Lines

Bio: Christopher Lines is an academic researcher from Merck & Co.. The author has contributed to research in topics: Placebo & Migraine. The author has an hindex of 39, co-authored 111 publications receiving 7973 citations. Previous affiliations of Christopher Lines include York University.

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial

Abstract: background Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. methods A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. results A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. conclusions Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk.

Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine.

Abstract: Objective: To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine. Methods: Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses. Results: Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant ( P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose. Conclusions: The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.

Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study.

Abstract: Background: Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer’s disease (AD) and may be mediated via the cyclo-oxygenase–2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase–2, in slowing the progression of dementia in patients with established AD. Methods: A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician’s Interview Based Impression of Change with caregiver input (CIBIC+). Results: Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = −0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE -e4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures. Conclusion: The failure of selective cyclo-oxygenase–2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase–2 does not play a significant role in the pathogenesis of the disorder.

Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant

Abstract: Objective: To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia. Methods: We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep. Results: Suvorexant showed significant ( p values Conclusions: The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia. Classification of evidence: This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

Inflammation, Atherosclerosis, and Coronary Artery Disease

Abstract: ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world. 1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.

Neuroinflammation in Alzheimer's disease

Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.

Abstract: 99mTc : technetium-99m 201TI : thallium 201 ABCB1 : ATP-binding cassette sub-family B member 1 ABI : ankle-brachial index ACC : American College of Cardiology ACCF : American College of Cardiology Foundation ACCOMPLISH : Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension ACE : angiotensin converting enzyme ACIP : Asymptomatic Cardiac Ischaemia Pilot ACS : acute coronary syndrome ADA : American Diabetes Association ADP : adenosine diphosphate AHA : American Heart Association ARB : angiotensin II receptor antagonist ART : Arterial Revascularization Trial ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASSERT : Asymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial AV : atrioventricular BARI 2D : Bypass Angioplasty Revascularization Investigation 2 Diabetes BEAUTIFUL : Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction BIMA : bilateral internal mammary artery BMI : body mass index BMS : bare metal stent BNP : B-type natriuretic peptide BP : blood pressure b.p.m. : beats per minute CABG : coronary artery bypass graft CAD : coronary artery disease CAPRIE : Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events CASS : Coronary Artery Surgery Study CCB : calcium channel blocker CCS : Canadian Cardiovascular Society CFR : coronary flow reserve CHARISMA : Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance CI : confidence interval CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease Epidemiology Collaboration CMR : cardiac magnetic resonance CORONARY : The CABG Off or On Pump Revascularization Study COURAGE : Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation COX-1 : cyclooxygenase-1 COX-2 : cyclooxygenase-2 CPG : Committee for Practice Guidelines CT : computed tomography CTA : computed tomography angiography CV : cardiovascular CVD : cardiovascular disease CXR : chest X-ray CYP2C19*2 : cytochrome P450 2C19 CYP3A : cytochrome P3A CYP3A4 : cytochrome P450 3A4 CYP450 : cytochrome P450 DANAMI : Danish trial in Acute Myocardial Infarction DAPT : dual antiplatelet therapy DBP : diastolic blood pressure DECOPI : Desobstruction Coronaire en Post-Infarctus DES : drug-eluting stents DHP : dihydropyridine DSE : dobutamine stress echocardiography EACTS : European Association for Cardiothoracic Surgery EECP : enhanced external counterpulsation EMA : European Medicines Agency EASD : European Association for the Study of Diabetes ECG : electrocardiogram Echo : echocardiogram ED : erectile dysfunction EF : ejection fraction ESC : European Society of Cardiology EXCEL : Evaluation of XIENCE PRIME or XIENCE V vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization FAME : Fractional Flow Reserve vs. Angiography for Multivessel Evaluation FDA : Food & Drug Administration (USA) FFR : fractional flow reserve FREEDOM : Design of the Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease GFR : glomerular filtration rate HbA1c : glycated haemoglobin HDL : high density lipoprotein HDL-C : high density lipoprotein cholesterol HR : hazard ratio HRT : hormone replacement therapy hs-CRP : high-sensitivity C-reactive protein HU : Hounsfield units ICA : invasive coronary angiography IMA : internal mammary artery IONA : Impact Of Nicorandil in Angina ISCHEMIA : International Study of Comparative Health Effectiveness with Medical and Invasive Approaches IVUS : intravascular ultrasound JSAP : Japanese Stable Angina Pectoris KATP : ATP-sensitive potassium channels LAD : left anterior descending LBBB : left bundle branch block LIMA : Left internal mammary artery LDL : low density lipoprotein LDL-C : low density lipoprotein cholesterol LM : left main LMS : left main stem LV : left ventricular LVEF : left ventricular ejection fraction LVH : left ventricular hypertrophy MACE : major adverse cardiac events MASS : Medical, Angioplasty, or Surgery Study MDRD : Modification of Diet in Renal Disease MERLIN : Metabolic Efficiency with Ranolazine for Less Ischaemia in Non-ST-Elevation Acute Coronary Syndromes MERLIN-TIMI 36 : Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes: Thrombolysis In Myocardial Infarction MET : metabolic equivalents MI : myocardial infarction MICRO-HOPE : Microalbuminuria, cardiovascular and renal sub-study of the Heart Outcomes Prevention Evaluation study MPI : myocardial perfusion imaging MRI : magnetic resonance imaging NO : nitric oxide NSAIDs : non-steroidal anti-inflammatory drugs NSTE-ACS : non-ST-elevation acute coronary syndrome NYHA : New York Heart Association OAT : Occluded Artery Trial OCT : optical coherence tomography OMT : optimal medical therapy PAR-1 : protease activated receptor type 1 PCI : percutaneous coronary intervention PDE5 : phosphodiesterase type 5 PES : paclitaxel-eluting stents PET : positron emission tomography PRECOMBAT : Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease PTP : pre-test probability PUFA : polyunsaturated fatty acid PVD : peripheral vascular disease QoL : quality of life RBBB : right bundle branch block REACH : Reduction of Atherothrombosis for Continued Health RITA-2 : Second Randomized Intervention Treatment of Angina ROOBY : Veterans Affairs Randomized On/Off Bypass SAPT : single antiplatelet therapy SBP : systolic blood pressure SCAD : stable coronary artery disease SCORE : Systematic Coronary Risk Evaluation SCS : spinal cord stimulation SES : sirolimus-eluting stents SIMA : single internal mammary artery SPECT : single photon emission computed tomography STICH : Surgical Treatment for Ischaemic Heart Failure SWISSI II : Swiss Interventional Study on Silent Ischaemia Type II SYNTAX : SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery TC : total cholesterol TENS : transcutaneous electrical neural stimulation TERISA : Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina TIME : Trial of Invasive vs. Medical therapy TIMI : Thrombolysis In Myocardial Infarction TMR : transmyocardial laser revascularization TOAT : The Open Artery Trial WOEST : What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing Guidelines summarize and evaluate all evidence available, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well …

NF-kappaB: linking inflammation and immunity to cancer development and progression.

Abstract: There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.