Nonsteroid anti-inflammatory drugs (NSAID) and risk of cardiovascular events. Literature review and clinical implications

Non steroid anti-inflammatory drugs (NSAIDs) are largely used for treatment of acute and chronic pain, even for long periods of time (months or years). While it is known that their use is frequently associated with gastrointestinal damage, including major bleedings from peptic ulcer, the risk of cardiovascular events related to NSAID has received much less attention. However, there is a large body of evidence showing that NSAIDs (both “traditional”, such as diclofenac or indobufen, and selective cyclooxygenase inhibitors, COX-2) are associated with a significant increase of risk of cardiovascular events, both fatal and nonfatal. Consequently, several options have been proposed for the treatment of pain, including the use of analgesic drugs with different mechanisms of action, such as the opiates. Of interest, the Italian Drug Agency (AIFA) published a few years ago a warning (Nota 66) on the careful prescription of NSAIDs in patients with overt heart disease, such as coronary artery disease and heart failure. Aim of this paper is to present the current status of knowledge on the proper use of NSAIDs and other analgesic drugs in the management of acute and chronic pain.

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Interactions between the Cyclooxygenase Metabolic Pathway and the Renin-Angiotensin-Aldosterone Systems: Their Effect on Cardiovascular Risk, from Theory to the Clinical Practice

BioMed Research International ◽

10.1155/2018/7902081 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Jakub Gawrys ◽

Karolina Gawrys ◽

Ewa Szahidewicz-Krupska ◽

Arkadiusz Derkacz ◽

Jakub Mochol ◽

...

Keyword(s):

Cardiovascular Events ◽

Combined Therapy ◽

Cyclooxygenase Inhibitors ◽

Low Doses ◽

Renin Angiotensin ◽

Complication Risk ◽

Inflammatory Drugs ◽

Artery Disease ◽

High Doses

Coronary artery disease (CAD) and stroke are the most common and serious long-term complications of hypertension. Acetylsalicylic acid (ASA) significantly reduces their incidence and cardiovascular mortality. The RAAS activation plays an important role in pathogenesis of CVD, resulting in increased vascular resistance, proliferation of vascular-smooth-muscle-cells, and cardiac hypertrophy. Drugs acting on the renin-angiotensin-aldosterone system (RAAS) are demonstrated to reduce cardiovascular events in population with cardiovascular disease (CVD). The cyclooxygenase inhibitors limit the beneficial effect of RAAS-inhibitors, which in turn may be important in subjects with hypertension, CAD, and congestive heart failure. These observations apply to most of nonsteroidal anti-inflammatory drugs and ASA at high doses. Nevertheless, there is no strong evidence confirming presence of similar effects of cardioprotective ASA doses. The benefit of combined therapy with low-doses of ASA is—in some cases—significantly higher than that of monotherapy. So far, the significance of ASA in optimizing the pharmacotherapy remains not fully established. A better understanding of its influence on the particular CVD should contribute to more precise identification of patients in whom benefits of ASA outweigh the complication risk. This brief review summarizes the data regarding usefulness and safety of the ASA combination with drugs acting directly on the RAAS.

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A concise review on advances in development of small molecule anti-inflammatory therapeutics emphasising AMPK: An emerging target

International Journal of Immunopathology and Pharmacology ◽

10.1177/0394632016673369 ◽

2016 ◽

Vol 29 (4) ◽

pp. 562-571 ◽

Cited By ~ 8

Author(s):

Chethan Gejjalagere Honnappa ◽

Unnikrishnan Mazhuvancherry Kesavan

Keyword(s):

Drug Targets ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Cyclooxygenase Inhibitors ◽

Evolutionarily Conserved ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Acid Pathway ◽

Clinical Trial Results ◽

Amp Activated Protein Kinase

Inflammatory diseases are complex, multi-factorial outcomes of evolutionarily conserved tissue repair processes. For decades, non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors, the primary drugs of choice for the management of inflammatory diseases, addressed individual targets in the arachidonic acid pathway. Unsatisfactory safety and efficacy profiles of the above have necessitated the development of multi-target agents to treat complex inflammatory diseases. Current anti-inflammatory therapies still fall short of clinical needs and the clinical trial results of multi-target therapeutics are anticipated. Additionally, new drug targets are emerging with improved understanding of molecular mechanisms controlling the pathophysiology of inflammation. This review presents an outline of small molecules and drug targets in anti-inflammatory therapeutics with a summary of a newly identified target AMP-activated protein kinase, which constitutes a novel therapeutic pathway in inflammatory pathology.

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Current status of inflammasome blockers as anti-inflammatory drugs

Expert Opinion on Investigational Drugs ◽

10.1517/13543784.2012.690032 ◽

2012 ◽

Vol 21 (7) ◽

pp. 995-1007 ◽

Cited By ~ 47

Author(s):

Gloria López-Castejón ◽

Pablo Pelegrín

Keyword(s):

Current Status ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Non-selective nonsteroidal anti-inflammatory drugs and cardiovascular events: is aldosterone the silent partner in crime?

British Journal of Clinical Pharmacology ◽

10.1111/j.1365-2125.2006.02678.x ◽

2006 ◽

Vol 61 (6) ◽

pp. 738-740 ◽

Cited By ~ 24

Author(s):

Kathleen M. Knights ◽

Arduino A. Mangoni ◽

John O. Miners

Keyword(s):

Cardiovascular Events ◽

Inflammatory Drugs ◽

Anti Inflammatory

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The use of analgesic drugs by South African veterinarians : continuing education

Journal of the South African Veterinary Association ◽

10.4102/jsava.v72i1.613 ◽

2001 ◽

Vol 72 (1) ◽

Cited By ~ 33

Author(s):

K.E. Joubert

Keyword(s):

Chronic Pain ◽

Continuing Education ◽

South African ◽

Specific Drug ◽

Analgesic Drugs ◽

Flunixin Meglumine ◽

Post Operative Pain ◽

Analgesic Agents ◽

Anti Inflammatory ◽

Balanced Anaesthesia

According to a survey, non-steroidal anti-inflammatory agents were the most popular analgesic used in South Africa for management of peri-operative pain, acute post-operative pain and chronic pain. The most popular non-steroidal anti-inflammatory agents are flunixin meglumine and phenylbutazone. The most popular opioid type drug is buprenorphine, followed by morphine. In the peri-operative setting, analgesic agents were not actively administered to 86.3 % of cats and 80.7 % of dogs. Analgesic premedications were frequently administered, e.g. xylazine or ketamine, but no specific drug was administered for post-operative pain. Veterinarians need to critically review their anaesthetic and analgesic practices in order to achieve balanced anaesthesia.

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Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

The Lancet ◽

10.1016/s0140-6736(07)61909-6 ◽

2007 ◽

Vol 370 (9605) ◽

pp. 2138-2151 ◽

Cited By ~ 88

Author(s):

Vibeke Strand

Keyword(s):

Cardiovascular Events ◽

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

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Effects of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs on Biofilms and Planktonic Cells of Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.1.41-47.2004 ◽

2004 ◽

Vol 48 (1) ◽

pp. 41-47 ◽

Cited By ~ 116

Author(s):

Mohammed A. S. Alem ◽

L. Julia Douglas

Keyword(s):

Candida Albicans ◽

Biofilm Formation ◽

Significant Inhibition ◽

Cyclooxygenase Inhibitors ◽

Fungal Colonization ◽

Prostaglandin E ◽

Disk Model ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Biofilm Development

ABSTRACT Prostaglandins are now known to be produced by Candida albicans and may play an important role in fungal colonization. Their synthesis in mammalian cells is decreased by inhibitors of the cyclooxygenase isoenzymes required for prostaglandin formation. In the present study, a catheter disk model system was used to investigate the effects of nonsteroidal anti-inflammatory drugs (all cyclooxygenase inhibitors) on biofilm formation by three strains of C. albicans. Seven of nine drugs tested at a concentration of 1 mM inhibited biofilm formation. Aspirin, etodolac, and diclofenac produced the greatest effects, with aspirin causing up to 95% inhibition. Celecoxib, nimesulide, ibuprofen, and meloxicam also inhibited biofilm formation, but to a lesser extent. Aspirin was active against growing and fully mature (48-h) biofilms; its effect was dose related, and it produced significant inhibition (20 to 80%) at pharmacological concentrations. Simultaneous addition of prostaglandin E2 abolished the inhibitory effect of 25 or 50 μM aspirin. At 1 mM, aspirin reduced the viability of biofilm organisms to 1.9% of that of controls. Surviving cells had a wrinkled appearance, as judged by scanning electron microscopy, and consisted of both yeasts and hyphae. Treatment with other cyclooxygenase inhibitors, such as etodolac, resulted in biofilms that consisted almost entirely of yeast cells. In conventional assays for germ tube formation, these drugs produced significant inhibition, whereas aspirin had little effect. Our findings suggest that cyclooxygenase-dependent synthesis of fungal prostaglandin(s) is important for both biofilm development and morphogenesis in C. albicans and may act as a regulator in these physiological processes. Our results also demonstrate that aspirin possesses potent antibiofilm activity in vitro and could be useful in combined therapy with conventional antifungal agents in the management of some biofilm-associated Candida infections.

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