Special Issue "Cyclooxygenase(COX) Inhibitors"

Guest Editor
Dr. Tilo Grosser
Department of Pharmacology, Institute for Translational Medicine and Therapeutics, Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
E-Mail: tilo@upenn.edu
Interests: study on the translational therapeutics of benefit and risk of drugs targeting the cyclooxygenase system using cellular systems; model organisms and mechanistic phenotyping studies in humans

Dear Colleagues,

Cyclooxygenase (COX) inhibitors are commonly used to alleviate pain, inflammation and fever. They inhibit the formation of prostanoids, which reduce the threshold to stimulation of peripheral nociceptors, increase the excitability of spinal sensory neurons and stimulate thermo sensitive neurons in the preoptic area of the brain. Low dose aspirin is the preferred antiplatelet regimen for cardiovascular prophylaxis. Perhaps more than 60 million people in the United States consume a COX inhibitor regularly. Over 40 distinct compounds are marketed as almost 1000 brands, formulations, and doses. The major side effects of these drugs are caused by coincident inhibition of cytoprotective and homeostatic prostanoids. Thus, all COX inhibitors may be associated with gastrointestinal complications, including serious bleeds. COX-2 selective compounds have been shown to reduce the incidence of these bleeding events, but are more likely to cause serious cardiovascular events than nonselective drugs. All COX inhibitors have been reported to elevate blood pressure and/or cause salt retention and edema, although they do so to variable degrees amongst individuals, if at all. Evidence from human pharmacology and genetics, genetically manipulated rodents and other animal models and randomized trials indicates that these cardiovascular adverse events are consequent to suppression of COX-2 dependent cardioprotective prostanoids, particularly, prostacyclin.

It has long been appreciated that the response to any COX inhibitor may vary substantially from patient to patient. Can we predict which patients are likely to benefit from treatment with a particular compound and which patients are likely to develop complications, such as heart attack and stroke? Does the cardiovascular risk extend to some or several or all of the older, non-isoform selective COX inhibitors? What are the relative roles of inhibition of COX-1 and COX-2 in therapeutic efficacy and risk? A much more detailed understanding of the biology of the prostanoid biosynthetic-response system, the molecular mechanisms and pharmacoepidemiology of therapeutic benefit and risk of COX inhibitors, their human pharmacology, and genetic and non-genetic factors that cause variability in these drugs is a necessary prerequisite to development of an evidence based paradigm to personalize therapy with COX inhibitors.

This special issue presents an opportunity to create a readily accessible collection of insightful reviews of current knowledge, evolving concepts, provocative ideas and original research articles in these very topics as a resource for students and trainees in our laboratories and for those who are interested in this field.

Sincerely,

Dr. Tilo Grosser
Guest Editor

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• cyclooxygenase-1
• cyclooxygenase-2
• prostaglandins
• prostanoids
• nonsteroidal antiinflammatory drugs

Type of Paper: Review
Title: COX inhibitors and the Newborn Kidney?
Authors: F.G. Smith ¹, A.Wade  ², M.L.Lewis 3, W.Qi 1
Affiliations: ¹ Department of Physiology & Pharmacology/Paediatrics, Faculty of Medicine, University of Calgary, Canada; Email: fsmith@ucalgary.ca
² Department of Paediatrics, Faculty of Medicine, University of Calgary, Canada
³ Department of Medical Science, Faculty of Medicine, University of Calgary, Canada
Abstract: This review will be focussed on the influence of COX inhibitors on the structural development as well as the function of the developing kidney.  In addition, clinical implications of the use of COX inhibitors in pregnancy, and in the newborn infant, will be evaluated, with specific reference to their effects on the kidney.

Type of Paper: Review
Title: Mechanistic and Pharmacological Issues on Aspirin as Anticamcer Agent
Authors: Melania Dovizio, Annalisa Bruno, Stefania Tacconelli and Paola Patrignani *
Affiliation: Department of Neuroscience and Imaging and Center of Excellence on Aging (CeSI), “G. d’Annunzio” University, Chieti, Italy; E-Mail: paola_patrignani@tin.it
Abstract: Recent findings showed that aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. The finding of aspirin benefit at low-doses given once daily, the same than the one used for cardioprevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. In fact, at low-doses given every 24 hours, aspirin is acting by a complete inhibition of cyclooxygenase(COX)-1 in platelets (in the presystemic circulation) while causing a limited and rapidly reversible inhibitory effect on COX-2 expressed in nucleated cells. In fact, aspirin has a short half-life in human circulation (approximately 20 min) and nucleated cells have the ability to resynthesize the acetylated COX-isozymes within a few hours. COX-independent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/β-catenin signaling and the acetylation of extra-COX proteins, have been suggested to  play a role in its chemopreventive effects, but, their relevance remains to be demonstrated in vivo at clinical doses. Colorectal cancer and atherothrombosis may share a common mechanism of disease, i.e. platelet activation in response to epithelial (in tumorigenesis) and endothelial (in tumorigenesis and atherothrombosis) injury.