Therapeutic Uses of Aspirin

Abstract

Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is used to treat include many different diseases. Lower doses of aspirin have also been indicated to decrease the threat of loss of life from a heart strike, or the risk of stroke in people who are at high risk or who have cardiovascular illness, but not in elderly people who are healthful. Recent research suggests that aspirin may help prevent the development of cancerous tumors, such as those of the stomach, intestines, or even the breast. However, despite the fact that aspirin is considered a “good” medicine for the prevention and treatment of many diseases, doctors recommend that no one should take aspirin without a doctor’s approval, because taking it is not only not safe for all people but it can also interact with other medicines and cause harm. The most useful therapeutic properties of aspirin depend on its inhibition of prostaglandin formation. Along with interference in thromboxane production, aspirin inhibits synthesis of prostaglandins. Under normal background, thromboxane and prostacyclin are in homeostatic equilibrium, with incompatible effects on platelet aggregation and vascular action. In this chapter, therapeutic uses of aspirin will be presented.

1. Introduction

Aspirin is one of the most widely used medicines [1], with some disputes about its real birth date, and it has celebrated its 120th birthday. Chemically, aspirin is called acetylsalicylic acid and is widely used as an analgesic, antipyretic, and anti-inflammatory agent, as well as for treating headache and muscle and joint pain [2].

It is also used long-term in people at high risk for ischemic disease. It is considered to be one of the major drugs that has been discovered [3], and no drug is currently as widely used as aspirin. It is a nonsteroidal anti-inflammatory drug (NSAID) that suppresses normal platelet function. It is used as an analgesic, antipyretic, and anti-inflammatory agent. At low doses, it is also taken as a platelet anticoagulant (antithrombotic). It should not be taken by people who are deficient in the G6PD enzyme or by people under 16 years of age because of the risk of Reye’s syndrome (high fever, headache, sudden death) and with caution by people taking anticoagulation agents. Many people take aspirin to reduce the risk of heart attack. Aspirin helps to prevent thrombosis in the heart or even in the brain; thus, strokes can be avoided. This discovery was made by Dr. Lawrence Craven in approximately 1950 when he noticed unusual bleeding in children who were taking aspirin to treat pain after tonsil surgery. Recent research suggests that aspirin may help prevent the development of cancerous tumors, such as those of the stomach, intestines, or even the breast. However, although aspirin is considered a “good” medicine for the prevention and treatment of many diseases, doctors recommend that no one should take aspirin without a doctor’s approval because taking it is not only unsafe for all people but can also interact with other medicines and cause harm. Women who are pregnant should avoid taking aspirin. Despite these problems, aspirin is still one of the oldest and most widely used drugs in the world [3]. The side effects of aspirin are presented in Figure 1.

Figure 1.

Main side effects of aspirin [4].

2. Effects and uses of aspirin

2.1 Antiplatelet effect of aspirin

The most useful therapeutic properties of aspirin depend on its ability to inhibit prostaglandin formation. Prostaglandins are a large group of biologically active, unsaturated fatty acids with 20 carbon atoms produced during the metabolism of arachidonic acid and through the cyclooxygenase pathway. They are local hormones that are rapidly formed, act on adjacent regions and are subsequently broken down and destroyed by enzymes. The prostaglandins PGD2, PGE2, PGF2a, PGI1, PGI2, prostacyclin, and thromboxane (TXA2) are important mediators of inflammation. Nonsteroidal anti-inflammatory drugs inhibit the production of prostaglandins. Prostaglandins affect a wide number of biological processes, including vasodilation, vascular permeability, bronchospasm, platelet aggregation, dysmenorrhea, inhibition of gastric secretion, and stimulation of nerve receptors of algae during tissue destruction, inhibition of sleep, and maintenance of an open arterial duct. Exogenous administration of PGE2 in the form of a gel is used to soften the cervix before the onset of labor.

The normal endothelium is a stable, strong antithrombotic (thromboresistant) blood flow surface. It exhibits anticoagulant, fibrinolytic, and antiplatelet properties. Prothrombotic and antithrombotic properties. However, whenever the endothelium is activated or disrupted, it rapidly transforms into a prothrombotic surface, which effectively promotes coagulation, inhibits fibrinolysis, and activates platelets. Hemostatic transformation of the vessel wall is caused by mechanical damage or by disruption and activation of vascular cells by factors such as cytokines, cytokine bacterial endotoxins, hypoxia, and various hemodynamic forces. Prostaglandin I2 (PGI2, prostacyclin) is an important endothelial oxygenation product that is synthesized through cyclooxygenase (COX) and prostacyclin synthase from arachidonic acid [5]. Prostacyclin, like nitric oxide (NO), is both a vasodilator and an inhibitor of platelet aggregation (but not platelet adhesion). These actions are achieved through the activation of adenylate cyclase, thereby increasing the levels of cyclin adenosine monophosphate (cAMP) in target cells, which are vascular smooth muscle cells and platelets. The hyperpolarizing endothelial proliferative factor (EDHF) and carbon monoxide, a byproduct of the metabolism of hemoglobin to chlorpromazine by haem oxygenase [6], are also direct factors in vasodilators, which are used by endothelial cells. Endothelial adenosine diphosphate (ADPase) or CD39 [7] is a membrane inhibitor of platelets that may indirectly promote vasodilation by producing adenosine. These properties of the endothelium are compensated by endothelial vasoconstrictor factors, including platelet-activating factor, platelet-activating factor endothelin-1, and thromboxane A2 (TXA2).

2.1.1 Biological inflammation mediators

2.1.1.1 Derived from plasma

• Quinines (bradykinin)

• Complement factors (C3a, C3b, C5a, C5, C6, and C7)

• Fibrin degradation products

• Hageman factor

• Protease inhibitors (α2 macroglobulin and α1 antitrypsin)

• CRP

2.1.1.2 Produced locally in tissues

• Arachidonic acid products (PGE2, PGI2, TxB2, and LTB4)

• Vasodilator amines (histamines)

• Cytokines (interleukins 1 (IL-1) and 2 (IL-2))

• Oxygen and nitric oxide free radicals

• Platelet-activating factor

Cyclooxygenase and lipoxygenase act on arachidonic acid and release prostaglandins (PGE), prostacyclin (PGI2), thromboxane (TxB2), and leukotrienes (LT). These biological products exert a variety of actions, both inflammatory and anti-inflammatory, while some eicosanoids cause severe pain. Thromboxanes are physiologically active compounds found in many organs of the body. They are formed in vivo from prostaglandin endo-peroxides and cause platelet aggregation, arterial constriction, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. They are produced by platelets, which cause blood to clot and blood vessels to constrict. It also encourages the accumulation of platelets. Thromboxane A2 (TXA2) is active but is very unstable and has a half-life of only 30 seconds before it undergoes hydrolysis to form thromboxane B2 (TXB2), which is inactive [8].

COX-1 is an enzyme that occurs in a wide range of cells throughout the whole organism. It maintains the formation of PGs involved in the performance of essential functions (e.g., control of blood flow through individual organs). COX-2 (Figure 2) is synthesized from the beginning (de novo) in anti-inflammatory cells [10], such as neutrophils and mast cells, after exposure to bacterial endotoxins and/or cytokines (e.g., tumor necrosis factor (TNF) and interleukin 1b). The production of PGs at sites of inflammation and/or tissue can cause damage. COX-2 is released in large quantities locally in the area of inflammation or systemically after infection. Originally, it was thought that this was a result of an increase in arachidonic acid. In 1990, however, it was shown that this increase in the formation of prostaglandins was due to an increase in the expression of the enzyme cyclooxygenase [11]. We now know that increased cyclooxygenase is not cyclooxygenase-1 but rather an isomer of cyclooxygenase-2. In the sequence of reactions that produce prostaglandins from arachidonic acid, aspirin inhibits the essential enzyme cyclo-oxygenase.

Figure 2.

The “Cox-2 crystal structure” of cox-2 inhibited by aspirin [9].

The antiplatelet effect of aspirin results from the elimination of COX-1 and COX-2. It causes permanent acetylation of serine at position 530 in COX-1 and at site 516 in COX-2, regulating the connection of arachidonic acid to the catalytic active site of the enzyme. Aspirin has a greater effect on COX-1 than on COX-2, as it is approximately 170 times more effective at inhibiting COX-1 [12]. Additionally, along with interfering with thromboxane production, aspirin also inhibits the synthesis of prostaglandins, most importantly, prostacyclin. In a normal environment, thromboxane and prostacyclin are in homeostatic equilibrium, with incompatible effects on platelet aggregation and vascular action (thromboxane is synthesized within platelets, but prostacyclin is synthesized within endothelial cells) [13].

2.2 Anti-inflammatory uses of aspirin

One of the properties of the immune system is the ability to communicate, coordinate, and move cells to achieve protection against foreign invaders. Communication between immune cells is achieved by means of small protein molecules produced by different types of cells called cytokines. The class of cytokines includes a wide variety of regulatory factors produced by many different types of cells. They are usually secreted by immune cells when they encounter a pathogen, activating other immune cells and thus increasing the immune response. T cells and macrophages are important sources of cytokine production. Cytokines are divided into chemokines, interleukins, and lymphokines based on their function and the cells that secrete them or the target cells on which they act. Examples of inflammatory cytokines are interferon (IFN)-a, tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6, and IL-8 (Figure 3).

Figure 3.

Pathways of inflammation [14].

Aspirin affects the inflammatory pathway by irreversibly inhibiting cyclooxygenase (COX)-1, altering the enzyme activity of COX-2, and decreasing the production of prostaglandins and thromboxane. The above mechanisms are effective in increasing the risk of atherosclerosis and heart disease [15]. Aspirin can lower oxidative stress and defend against oxidative damage. There are useful effects of aspirin in preclinical and clinical studies of mood disorders and schizophrenia. Epidemiological data suggest that high-dose aspirin is associated with a decreased risk of Alzheimer’s disease. COX-2 inhibitors may cause neuroinflammatory reactions, reduce antioxidant resistance, and promote neuronal progression. COX-2 inhibition may also interfere with inflammation decreases the production of prostaglandin E2 (PGE2). Therefore, to understand the clinical efficacy of aspirin in patients with neuropsychiatric disorders such as depression and schizophrenia, it is important to consider how its inhibition of COX-1 affects these patients [15].

2.3 Aspirin in preeclampsia prevention

Preeclampsia (PE) is defined as hypertension during pregnancy (systolic blood pressure >140 mmHg and diastolic >90 mmHg), together with albuminuria (>300 mg of albumin in a 24-hour urine collection or >30 mg/mmol in a random urine sample or more than one cross in a urine stick), with or without abnormal edema. A severe form of preeclampsia can threaten the life of both mothers and children. Approximately 1 in 200 women (0.5%) develop severe preeclampsia during pregnancy. Symptoms tend to become apparent in the latter stages of pregnancy but may appear for the first time even after delivery.

Symptoms of a severe form of preeclampsia include the following:

• Severe headaches that do not subside with simple painkillers

• Vision problems, such as blurred vision or flashes in front of the eyes

• Severe pain just below the ribs

• Burning in the chest that does not go away with antacids

• Rapidly increasing swelling in the face, hands, or feet

• A very strong feeling of sickness.

Preeclampsia affects the development of the placenta, which can prevent normal fetal development. There may also be less fluid around the fetus in the uterine environment. If the placenta is severely damaged, then the fetus will be in a very difficult situation. In some cases, this can even lead to the death of the fetus in the womb. Medical monitoring aims to identify and rescue the most at-risk fetuses and deliver them since the delivery of the fetus, especially the placenta, is the treatment for preeclampsia.

In PE, the creation of thromboxane A2 and prostaglandin I2 is modified by the excessive accumulation of TXA2 metabolites in the maternal systemic circulation. This leads to increased actuation and aggregation of platelets and vasoconstriction, resulting in decreased placental perfusion and oxidative stress. Aspirin acetylates the platelet enzyme COX, altering the synthesis of different prostaglandins, and behaves as an analgesic and anti-inflammatory agent. Aspirin permanently suppresses COX-1 and reversibly suppresses COX-2 to a minor extent. The consequent reticence of the COX-dependent creation of thromboxane A2 prevents platelet aggregation. This result is maintained for the entire platelet lifespan of 8–9 days [16]. Low-dose aspirin decreases fatality and despair in pregnant women at high risk of PE. The FDA has assigned this drug as pregnancy category C, and treatment is relatively safe. Although aspirin can cross the placenta, it is safe at low doses [16, 17].

2.4 Antitumor effect of aspirin

Many studies have established that aspirin can minimize the morbidity and mortality of tumors, including bladder cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, lung cancer, and prostate cancer.

Angiogenesis is a crucial process in the course of tumorigenesis. Cancer cells have the ability to exploit preexisting vessels (coadoption) to initiate the creation of a well-vascularized tumor. The defensive response of the initial vessels to this process is the regression of the vessels, resulting in the formation of an unvascularized tumor. The tumors that will succeed in growing are those that have overcome the process of vascular regression, inducing angiogenesis again. The main factor that induces angiogenesis is hypoxia. Von-Hippel Lindau protein (VHL) plays an important role in regulating HIF-1a gene expression and is increased in hypoxic cancer cells (hypoxia inducible factor), leading to the transcriptional overexpression of several genes, the products of which induce angiogenesis. The most important are vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF). VEGF binds to the receptors VEGFR-1/flt-1 and VEGFR-2/KDR/flk-1, which are located on the surface of existing endothelial cells and promote proliferation, migration, differentiation, and survival. This process is mediated through changes in the expression of integrins (a family of receptors for endothelial cell adhesion to the surrounding layer). Eventually, these immature vessels need to mature, a process through which the action of PDGF on its receptors in pericytes leads to the coating of neoplastic vessels by pericytes [18, 19].

The mode of action of aspirin in cancer prevention has not been established. The anticancer effects of aspirin are proposed to occur through acetylation-mediated inactivation of COX, as COX-2 is upregulated in 80–90% of colorectal cancers [20]. Another study in human intestinal mucosal cells revealed that low-dose aspirin produced acetylation of COX-1 and strongly inhibited PGE2 synthesis to reduce the levels of S6 kinase, which is involved in the blockage of early colorectal carcinogenesis [21].

Salicylic acid, the hydrolyzed outcome of aspirin, is also involved in the chemopreventive effects of aspirin. Salicylic acid was shown to bind to many cellular proteins (salicylic acid binding proteins or SABPs), such as IκB kinase (IKK), a constituent of the NF-κB complex AMP-activated protein kinase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and CDK2, affecting their levels and/or functional activity [22]. Aspirin may also inhibit mammalian target of rapamycin (mTOR), HIF-1α, and VEGF-A signaling related to antiangiogenesis and the development of autophagy at the protein level in murine hepatocarcinomatous and sarcoma models. mTOR is a 282 kPa intracellular serine/threonine kinase that acts as a central regulator of cell proliferation and the cell cycle. When the mTOR biochemical pathway is activated, the risk of cancer may increase [23].

3. Conclusions

Aspirin, or acetylsalicylic acid, is one of the most widely known analgesic and anti-inflammatory drugs. Depending on the dosage used, it can reduce pain, as well as fever, and may also be beneficial in preventing cerebral thrombosis and stroke. Αspirin was launched in 1899, and to date, it is a benchmark analgesic drug with sales exceeding 400,000 tons worldwide. High doses of aspirin are used for its anti-inflammatory effect, while low doses of aspirin are usually used for its antiplatelet effect. The most common side effect of the drug (Figure 3) is the induction of digestive erosion and ulcers. The most serious complication is bleeding from these lesions, especially for bleeding from aspirin-treated patients.

Aspirin exerts both therapeutic and toxic effects on the body’s actions mainly through the inhibition of COX, a key enzyme for the metabolism of arachidonic acid to produce prostaglandins. There are two main forms of COX: (a) COX-1 or basic COX-1, which is continuously produced (such as prostaglandin E2 in the kidneys, prostaglandin E2 in the mouth and kidneys, prostaglandin I2 or prostacyclin in blood vessels, and thromboxane in platelets), and (b) COX-2 or inducible COX-2, the production of which is induced during the inflammatory phase reaction and may induce the production of COX-1-like prostaglandins depending on the inflammatory organ.

The antiplatelet effect of aspirin results in the elimination of COX-1 and COX-2. It causes permanent acetylation of a serine at position 530 in COX-1 and at position 516 in COX-2, regulating the connection of arachidonic acid to the catalytic active site of the enzyme. Aspirin can also lower oxidative stress and protect against oxidative damage. There are advantageous outcomes of aspirin in preclinical and clinical studies on mood derangement and schizophrenia, and epidemiological data suggest that high-dose aspirin is related to a decreased risk of AD. COX-2 inhibitors may cause neuroinflammatory reactions, reduce antioxidant resistance, and provoke neuroprogression. COX-2 inhibition may also interfere with inflammation, decreasing the production of PGE2. Aspirin may also inhibit mTOR, HIF-1α, and VEGF-A signaling related to antiangiogenesis and the development of autophagy at the protein level in murine hepatocarcinomatous and sarcoma models. mTOR is a 282 kPa intracellular serine/threonine kinase that acts as a central regulator of cell proliferation and the cell cycle. When the mTOR biochemical pathway is activated, the risk of cancer may increase [24, 25, 26].

Future prospects related to aspirin could include further research on the possible treatment of new diseases and the study of genetic polymorphisms possibly involved in the drug’s mechanism of action.