Anti-inflammatory

**Anti-inflammatory** (or **antiinflammatory**) is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

## Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate pain by counteracting the cyclooxygenase (COX) enzyme. On its own, COX enzyme synthesizes prostaglandins, creating inflammation. In whole, the NSAIDs prevent the prostaglandins from ever being synthesized, reducing or eliminating the pain.

Some common examples of NSAIDs are aspirin, ibuprofen, and naproxen. The newer specific COX-inhibitors are not classified together with the traditional NSAIDs even though they presumably share the same mode of action.

On the other hand, there are analgesics that are commonly associated with anti-inflammatory drugs but that have no anti-inflammatory effects. An example is paracetamol (known as acetaminophen or Tylenol in the U.S). As opposed to NSAIDs, which reduce pain and inflammation by inhibiting COX enzymes, paracetamol has - as early as 2006 - been shown to block the reuptake of endocannabinoids, which only reduces pain, likely explaining why it has minimal effect on inflammation; paracetamol is sometimes combined with an NSAID (in place of an opioid) in clinical practice to enhance the pain relief of the NSAID while still receiving the injury/disease modulating effect of NSAID-induced inflammation reduction (which is not received from opioid/paracetamol combinations).

### Side effects

Long-term use of NSAIDs can cause gastric erosions, which can become stomach ulcers and in extreme cases can cause severe haemorrhage, resulting in death. The risk of death as a result of GI bleeding caused by the use of NSAIDs is 1 in 12,000 for adults aged 16–45. The risk increases almost twentyfold for those over 75. Other dangers of NSAIDs are exacerbating asthma and causing kidney damage. Apart from aspirin, prescription and over-the-counter NSAIDs also increase the risk of heart attack and stroke.

### Antileukotrienes

Main articles: Antileukotriene
Antileukotrines are anti-inflammatory agents which function as leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists (cysteinyl leukotriene receptors) and consequently oppose the function of these inflammatory mediators. Although they are not used for analgesic benefits, they are widely utilized in the treatment of diseases related to inflammation of the lungs such as asthma and COPD as well as sinus inflammation in allergic rhinitis. They are also being investigated for use in diseases and injuries involving inflammation of the brain (ex. Parkinsons disease).

### Immune selective anti-inflammatory derivatives (ImSAIDs)

ImSAIDs are a class of peptides being developed by IMULAN BioTherapeutics, LLC, which were discovered to have diverse biological properties, including anti-inflammatory properties. ImSAIDs work by altering the activation and migration of inflammatory cells, which are immune cells responsible for amplifying the inflammatory response. The ImSAIDs represent a new category of anti-inflammatory and are unrelated to steroid hormones or nonsteroidal anti-inflammatories.

The ImSAIDs were discovered by scientists evaluating biological properties of the submandibular gland and saliva. Early work in this area demonstrated that the submandibular gland released a host of factors that regulate systemic inflammatory responses and modulate systemic immune and inflammatory reactions. It is now well accepted that the immune, nervous, and endocrine systems communicate and interact to control and modulate inflammation and tissue repair. One of the neuroendocrine pathways, when activated, results in the release of immune-regulating peptides from the submandibular gland upon neuronal stimulation from sympathetic nerves. This pathway or communication is referred to as the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, a regulatory system that plays a role in the systemic control of inflammation.

Early work in identifying factors that played a role in the CST-SMG axis lead to the discovery of a seven amino acid peptide, called the submandibular gland peptide-T. SGP-T was demonstrated to have biological activity and thermoregulatory properties related to endotoxin exposure. SGP-T, an isolate of the submandibular gland, demonstrated its immunoregulatory properties and potential role in modulating the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, and subsequently was shown to play an important role in the control of inflammation.

One SGP-T derivative is a three-amino acid sequence shown to be a potent anti-inflammatory molecule with systemic effects. This three-amino acid peptide is phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) have become the foundation for the ImSAID category. Cellular Effects of feG: The cellular effects of the ImSAIDs are characterized in a number of publications. feG and related peptides are known to modulate leukocyte (white blood cells) activity by influencing cell surface receptors to inhibit excessive activation and tissue infiltration.

One lead ImSAID, the tripeptide FEG (Phe-Glu-Gly) and its D-isomer feG are known to alter leukocyte adhesion involving actions on αMβ2 integrin, and inhibit the binding of CD16b (FCyRIII) antibody to human neutrophils. feG has also been shown to decrease circulating neutrophil and eosinophil accumulation, decrease intracellular oxidative activity, and reduce the expression of CD49d after antigen exposure.

## Bioactive compounds

Many bioactive compounds showed anti-inflammatory activities on albino rat. More recently plumericin from the Amazonian plant *Himatanthus sucuuba* has been described as a potent anti-inflammatory agent *in vitro* and *in vivo*.

## Long-term effects

Anti-inflammatory treatment trials for existing Alzheimer's disease have typically shown little to no effect on halting or reversing the disease. Research and clinical trials continue. Two studies from 2012 and 2013 found regular use of aspirin for over ten years is associated with an increase in the risk of macular degeneration.

## Ice treatment

Applying ice, or even cool water, to a tissue injury has an anti-inflammatory effect and is often suggested as an injury treatment and pain management technique for athletes. One common approach is rest, ice, compression and elevation. Cool temperatures inhibit local blood circulation, which reduces swelling in the injured tissue.

## Health supplements

In addition to medical drugs, some herbs and health supplements may have anti-inflammatory qualities: bromelain from pineapples (*Ananas comosus*). Cannabichromene, a cannabinoid, also has anti-inflammatory effect. Honokiol from *Magnolia* inhibits platelet aggregation, and works as an inverse agonist at the CB2 receptor. Black seed (*Nigella sativa*) has shown anti-inflammatory effect due to its high thymoquinone content. St. John's wort's chief constituent, hyperforin, has been found to be a potent COX-1 and 5-LO inhibitor, with anti-inflammatory effect several fold that of aspirin.

Coal tar has been used for centuries for its anti-inflammatory and analgesic effects. Oral administration for central effects is now rare as coal tar also contains a range of dangerous and carcinogenic compounds, and does not allow for the administration of standardized doses, although some doctors readily utilize coal tar preparations for topical administration (ex. Denorex, Psoriasin) in the treatment of skin conditions such as eczema and atopic dermatitis. Many modern analgesics and anti-inflammatory agents (ex. paracetamol, and its previously used predecessor phenacetin) are derived from compounds which were originally discovered during studies to elucidate the chemicals responsible for the tars reputed health benefits.

## Anti-inflammatory foods

Suggested diets to reduce inflammation include those rich in vegetables and low in simple carbohydrates, and fats such as saturated fats and trans fats. Anti-inflammatory foods include most colorful fruits and vegetables, oily fish (which contain higher levels of omega-3 fatty acids), nuts, seeds, and certain spices, such as ginger, garlic and cayenne. Extra-virgin olive oil contains the chemical oleocanthal that acts similarly to ibuprofen. Those following an anti-inflammatory diet will avoid refined oils and sugars, and show a preference for anti-inflammatory foods in their meal choices.

Omega-3 fatty acids have been shown to disrupt inflammation cell signaling pathways by binding to the GPR120 receptor. This benefit however can be inhibited or even reversed if the ratio of Omega-6/Omega-3 is too high as Omega-6 serves as a precursor to inflammatory chemicals (prostaglandin and leukotriene eicosanoids) in the body. A high proportion of omega-6 to omega-3 fat in the diet shifts the physiological state in the tissues toward the pathogenesis of many diseases: prothrombotic, proinflammatory and proconstrictive. Omega-6 competes with Omega-3 for the same rate limiting factor which is required for the health-benefits of Omega-3, directly reducing the action of Omega-3 in addition to pharmacologically counteracting Omega-3 benefits through its own action as a pro-inflammatory agent.

### Measurement of dietary inflammation

The Dietary Inflammatory Index (DII) is a score (number) that describes the potential of diet to modulate systemic inflammation within the body. The creation of the DII is attributed to scientists led by James R. Hébert at the Statewide South Carolina Cancer Prevention and Control Program in the University of South Carolina.

## Exercise

Developing research has demonstrated that many of the benefits of exercise are mediated through the role of skeletal muscle as an endocrine organ. That is, contracting muscles release multiple substances known as myokines which promote the growth of new tissue, tissue repair, and various anti-inflammatory functions, which in turn reduce the risk of developing various inflammatory diseases.

## Interactions with NSAIDs

Patients on NSAIDs should seek to avoid excessive consumption of Omega-6 containing foods. Although many such foods contain the anti-inflammatory Omega-3 as well, low doses of Omega-6 interfere with Omega-3's ability to reduce inflammation, while higher doses are capable of completely inhibiting the effects of most currently-used anti-inflammatory agents (cyclooxygenase 1 inhibitors, cyclooxygenase 2 inhibitors, and antileukotrienes).

The concomitant use of NSAIDs with alcohol and/or tobacco products significantly increases the already elevated risk of peptic ulcers during NSAID therapy.

NSAID painkillers may interfere with and reduce the efficacy of SSRI antidepressants through inhibiting TNFα and IFNγ, both of which are cytokine derivatives.