Nonsteroidal Anti-inflammatory Drugs Cardiovascular Risk Research Articles

Novel anti-cancer effect of 2-arachidonoylglycerol via processing body formation in HCA-7 human colon cancer cells

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been reported to exhibit anticancer effects, including against colorectal cancer (CRC); however, the detailed mechanisms have not been clarified. Herein, we demonstrated that 2-AG suppressed cyclooxygenase-2 (COX-2) expression induced by prostaglandin E2 in human colon cancer HCA-7 cells. The suppression of COX-2 expression by 2-AG was through the acceleration of processing body (P-body) formation followed by COX-2 mRNA degradation. These effects were restored by TAK-715, a specific inhibitor of p38 MAPK. Therefore, the effect of 2-AG on COX-2 may be distinct from conventional non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the function of COX-2, whereas 2-AG suppresses the protein expression of COX-2. Recently, the cardiovascular risks of NSAIDs were reported by the Food and Drug Administration in the United States. Therefore, elucidation of the effect of 2-AG is expected to contribute to the development of an alternative and novel therapeutic option that would have no or fewer risks regarding cardiovascular events.

Kardiovaskulární riziko nesteroidních antirevmatik

Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the most widely used drugs. Results of recent large meta-analyses have shown that the cardiovascular risk of NSAIDs is more serious than originally believed and is not associated exclusively with coxibs; it is also increased when using so called traditional NSAIDs. Data obtained to date show the safest drugs of this class in terms of cardiovascular risk are naproxen and ibuprofen at low doses. The position of naproxen as the safest NSAID has been challenged by some more recent findings. The authors examine some results of meta-analyses and conclusions of regulatory agencies.Key words: cardiovascular risk - coxibs - diclofenac - ibuprofen - naproxen - non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis.

Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379-2·378), placebo (OR: 1·655: 95% CI: 1·029-2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146-4·053), and COXIBs (OR: 1·800, 95% CI: 1·217-2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396-0·857) and (OR: 0·609, 95% CI: 0·375-0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027-2·155) and (OR: 1·933, 95% CI: 1·052-3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410-0·887), (OR: 0·517, 95% CI: 0·287-0·929), and (OR: 0·509, 95% CI: 0·280-0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313-1·981), (OR: 1·572, 95% CI: 1·123-2·201) and (OR: 1·838, 95% CI: 1·323-2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658-0·986) and (OR: 0·557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.

Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage.

Nonsteroidal anti-inflammat ory drugs (NSAIDs) are one of the drug types frequently prescribed for their analgesic, anti-inflammatory, and antithrombotic actions, but carry a risk of major gastroduodenal damage from mild erosive changes to serious ulceration leading to fatal outcomes. From the long history of willow tree bark and its extracts being applied for the relief of pain and fever, the synthesis of acetylsalicylic acid, the development of selective cyclooxygenase2 inhibitors (coxibs), and the identification of a G-protein-coupled receptor for prostaglandin, the popular combination regimen of an NSAID and a proton pump inhibitor was invented, but development was continued for further improvement. With regard to major NSAID adverse effects, gastrointestinal (GI) and cardiovascular (CV) risks still remained as problems to be solved. In this review, it is shown that n-3 polyunsaturated fatty acid (PUFA) based NSAIDs can be an angelus custos, supported with facts that an intake of essential n-3 PUFAs orchestrates concerted protective actions against two notorious side effects of NSAIDs, the aforementioned GI risk and CV risk of NSAIDs. Since pills containing n-3 PUFAs, omega-3-acid ethyl ester capsules (Lovaza, Omarcor), have already been safely prescribed to prevent atherosclerosis through lessening lipid burdening, the introduction of a drug delivery system such as a gastroretentive form of n-3 PUFA based NSAIDs will highlight newer hope for GI safety under the guarantee of reduced CV risk. Because n-3 PUFAs have been proven to attenuate cytotoxicity, inhibit lipid-raft-associated harmful signaling, and relieve oxidative stress relevant to NSAIDs, n-3 PUFA based NSAIDs will be next-generation GI-safe NSAIDs.