ASPIRIN: the best NSAID

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ASPIRIN: HISTORY & USES

http://www.aspirin-foundation.com/what/index.htm

http://www.aspirin-foundation.com/what/index.htm AND wikipedia

 

The first reference to aspirin was by a 5th century BC Greek physician who rote of a bitter powder that came from the bark of the willow tree, and it eased pains and reduced fever.  The medicinal part of the plant is the inner bark of the tree. The active extract of the bark is called salicin after the Latin name for the white willow tree. It was isolated in crystalline form in 1828 by Henri Leroux, a French pharmacist. Raffaele Piria, an Italian chemist was able to convert it to salicylic acid. Salicylic acid was isolated from the herb called meadowsweet by German researchers in 1839. While it was somewhat effective, it also caused digestive problems when consumed in high doses.

A French chemist, Charles Frederic Gerhardt, first prepared acetylsalicylic acid in 1853 (named aspirin in 1899). This preparation of aspirin was one of many reactions Gerhardt conducted for his paper on anhydrides and he did nothing further with it. Six years later in 1859, von Gilm created the substance again.  In 1897, a chemist at Friedrich Bayer and Co. began investigating acetylsalicylic acid as a less-irritating replacement for the commonly used salicylate medicines.  By 1899 Bayer was marketing it world wide.  obtained acetylsalicylic acid and claimed to discover aspirin. Regardless of that, aspirin was finally manufactured and put on the market to help those in pain or with fever.

CLINICAL USES

Aspirin, an NSAID, (Non Steroidal Anti-Inflammatory Drug) has 5 medicinal uses:  antipyretic (reduce fever), analgesic (pain), anti-inflammatory (swelling), anti-platelet (reduce blood clotting), inhibit the synthesis of prothrombin, and promote apoptosis (cell death).  The two common side effects are gastrointestinal distress (stomach bleeding and ulcers) and tinnitus (high frequency hum) at higher doses.

ANTIPYRETIC         

Fever is part of the immune response to pathogens.  Aspirin reduces the immune response, and thus moderately reduces fever. 

ANALGESIC

Inflammation is sufficient cause pain.  Thus aspirin can produce a modest reduction in pain.  Since in most instances pain becomes less over time, this results in a belief by many of aspirin being an effective analgesic.  Aspirin and other NSAIDs do not interact with neural pain receptors.    

ANTI-PLATELET

Aspirin and all other COX inhibitors reduce clotting, and thereby promote increased bleeding when injured.  Blood clot, a thrombus, is the final product of the blood coagulation step in homeostasis.  It is achieved via the aggregation of platelets and other clotting factors to form a platelet plug.   A thrombosis is a clot in an intact blood vessel, and is thus pathological.   A thrombus in a large blood vessel will decrease blood flow through that vessel. In a small blood vessel, blood flow may be completely cut-off resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is an emolus.  Some conditions elevate the risk of thrombi developing including atrial fibrillation, atherosclorsis, myocardial infraction (heart attack caused by a blood clot), physical trauma, and extended periods of inactivity.  Women are at an increased risk of a thrombi in a vein, and this risk increases moderately with the taking of estrogen.  Aspirin signficantly reduces the risk of thrombus.[i]  Thrombus in a coronary vessel results in over 60% of all heart attacks.  For this reason, those at significant risk of MI are advised to take aspirin or a pricy alternative. 

                        Thrombin is a coagulation protein that is part of the platelet formation.  It works by converting the soluble fibrinogen into strands of insoluble fibrin, as well as catalyzing many other coagulation-related reactions.  Aspirin inhibits prothrombin synthesis.  Platelet effect is variable.  One study of 2,930 patients found 28% to be resistant to its platelet effect. 

CELL APOPTOSIS  

Aspirin alone has been found to lower the risk of at least 9 common cancers over 20%, and as high as 70%.  A dose-dependent reduction in cell viability was observed in colorectal cancer cells treated with aspirin.   The reduction in cell viability was accompanied by an increase in cell death due to apoptosis through an active process induced by aspirin.  It operates through NF-kB (nuclear factor-kappa B). Other attribute it to an inhibition of the COX-2 enzymes (Cancer Research 58, 4997-5001, November 15, 1998).   It is found in all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.  NF-kB plays a key role in regulating the immune response to infection[ii].    It was found that prolonged treatment with aspirin induced a dose-dependent reduction in cytoplasmic I B levels that correlated with the reduction in the number of viable cells.  This and related results suggest that the degradation is associated with aspirin-induced cell death.  This effect is limited to certain tissues:  it had no effect in embryonic kidney or lung adenocarcinoma cells.  This effect upon apoptosis varies with cell line[iii].

 



[i]   The drug industry promotes the use of heparin and warfarin which are more expensive, have more serious side effects, and are less effective than aspirin. 

[ii] NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die. In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy

[iii] This is because mutations leading to cancer effect various pathways and to varying degrees.  No two cancers have the same set of mutated genes, and their mutations on any gene will also vary.  

SIDE EFFECTS

The most serious is gastrointestinal bleeding, which is not a result of the NSAID’s effect upon clotting (a deceptive way COX-2 inhibitors such as VIOXX were marketed), but rather as an irritant effecting the mucous membrane which protects the stomach.  That only a small percentage have this problem suggests that presence of Helicobacter pylori, the bacterial cause of ulcers, plays a role.  Given this it is prudent to take a coated NSAID.[i]  Moreover, all the NSAID irritate the mucous membrane, and to date no proper heads-up studies comparing aspirin with other NSAIDS have been performed. 

Tinnitus sound is associated with high doses of NSAIDS for prolonged periods of time.  Its severity and duration vary, though usually it ends once the medication is removed.  Tinnitus is associated with other NSAIDS besides aspirin, and is common without a drug vector.[ii] 

 

All NSAIDs, but for aspirin, accelerate the formation of atherosclerosis by blocking the process which reduces the rate of plaque formation.  Simply put, most plaque formation is the result of a white-cell initiated response to certain reactive blood-borne chemicals such as carbon monoxide.  The termination of this response is affected by COX-2 inhibitors, with the exception of aspirin.[iii]

            Metabolism:

                  With doses less than 250 mg the elimination half-life is 2-4.5 hours.  In larger doses (more than 4 grams), due to poor solubility, the half-life is 15-30 hours.  

MECHANISM 

NSAIDs chief mechanism is through the reduction of the cyclooxygenase (COX-1 & COX-2 and structural variants thereof) enzymes which are responsible for the formation of prostanoids, including prostaglandins, prostacyclin, and thromboxane.  This inhibition of COX-1 & COX­-2 can provide relief from inflammation and pain.  The COX enzymes convert arachidonic acid to prostaglandin H2, the precursor of the series-2 prostanoids.  COX-1 is a constitutive enzyme, being found in most mammalian cells; and COX-2 is an induced enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation.  Selective inhibitions by NSAIDs of the COX family of enzymes produce moderate variation upon the effects of this family of drugs. 

                        Thromboxane is a member of the family of lipids knows as eicosanoids.  Thromboxane is named for its role in clot formation (thrombosis).  It is produced in platelets from endoperoxides by the COX enzyme from arachidonic acid.  Its action is by binding to thromboxane receptors.  Thromboxane is a vasoconstrictor and a potent hypertensive agent that facilitates platelet aggregation (blood clotting) by both stimulating activation of new platelets as well as increasing platelet aggregation.  Vasoconstriction at the site of a wound also reduces bleeding. 

            Inflammation is a complex biological response to vascular tissues to harmful stimuli such as pathogens, damaged cells, or irritants.  It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.  This healing response when prolonged and uncheck can lead to a host of conditions including hay fever, atherosclerosis, and rheumatoid arthritis.  It is the reason why chronic infections are statistically associated with atherosclerosis and myocardial infraction (MI).  

          Unfortunately, the COX inhibitors (but for aspirin) also inhibit the mechanism that limits plaque formation.  In a long-term study terminated in December of 2004, Celebrex (a Cox-2 inhibitor) was compared to naproxen as to their ability to reduce the risk of Alzheimer’s disease, the VIGOR study.  Two years into the study it was found that those taking Celebrex had twice the risk of MI, and those on naproxen had a 50% greater risk.  These findings can be extended to most, if not all of the NSAIDs but for Aspirin.  A 2005 article published by the American Heart Association (http://circ.ahajournals.org/cgi/content/full/112/5/759) describes the mechanism for the accelerated plaque formation and who aspirin because of the production of 6-Los does not:

 

Inhibition of COX-2 also has as a theoretical side effect an increase in the flux of arachidonate through the LO pathways, which may be especially important in the setting of inflammation in the atheromatous plaque. The 12-,15-, and 5-LOs all have key roles in inflammation, and the role of each in atherosclerosis has been examined. Although 12-LO and 15-LO appear to contribute to LDL oxidation, the data supporting the proatherogenic role of these enzymes are inconsistent.  Data suggest that 15-LO products may be anti-inflammatory.  Furthermore, work from Serhan’s group shows that acetylation of COX-2 by low-dose aspirin leads to its biosynthesis of 15R-hydroxyeicosatetraenoic acid.  This intermediate is then converted by transcellular metabolism to the antiinflammatory lipoxin 15-epi-lipoxin A4 in leukocytes.

      Mehrabian and colleagues have demonstrated convincingly that 5-LO is a critical determinant of atherogenesis in mouse models of the disease, even in the setting of profound hypercholesterolemia. The inflammatory eicosanoids derived from increased 5-LO expression in plaque–leukotriene B4 and the cysteinyl-leukotrienes–are active in the atherothrombotic vasculature, having been shown to promote inflammatory cell activation, cell proliferation, and vasoconstriction. In human subjects, Dwyer and colleagues showed that a promoter haplotype comprising 4 linked polymorphisms in the 5-LO activating peptide (an accessory protein that facilitates presentation of substrate arachidonate to 5-LO) confers an approximately 2-fold increased risk of myocardial infarction (MI) and stroke in an Icelandic population. Thus, the potential importance of shifting the flux of arachidonate through the LO pathway by inhibiting COX activity bears consideration as we attempt to dissect the vascular consequences of coxib use.  

 

Whatever, the exact pathway, a large body of evidence shows that the long-term taking of aspirin does not accelerate atherosclerosis—unlike the other NSAIDs.

 

For long article on mechanism go to http://www.fasebj.org/content/15/7/1273.full 



[i] Perspective studies of coated and uncoated aspirin are flawed because those with gastrointestinal distress are more likely to take a coated aspirin.  The drug industry has, for financial reasons, has used deceptively clinical research to show the superiority of products.  The result thereof has been in the last century over a million premature deaths.  All NSAIDs, but for aspirin, accelerate atherosclerosis.      

 

[ii] Tinnitus is very widespread in industrialized countries.  It is frequently associated with prolonged exposure to unnatural levels of noise.  In a 1953 study of 80 tinnitus-free university students who were placed in an anechoic chamber, 93% reported hearing a buzzing, pulsing, or whistling sound.

[iii] At http://healthfully.org/aspirin/id16.html.  COX-2 inhibitors promote the inflammation response and thereby accelerate atheromatous plaque deposits.  The 12-,15-, and 6-Los all have key roles in inflammation and atherosclerosis by contributing to LDL and VLDL oxidation.  It appears that 15-LO is anti-inflammatory, and aspirin leads to its synthesis.  Thus unlike others NSAIDs aspirin reduces rather than increases the product of athreomatous plaque.