Prostaglandin antagonist

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A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.

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NSAIDs are perhaps the best-known prostaglandin antagonists; they suppress the signaling function of prostaglandins, which are important mediators of pain, fever, and inflammation responses, by inhibiting the cyclooxygenase enzymes and thereby reducing prostaglandin synthesis. Corticosteroids inhibit phospholipase A2 production by boosting production of lipocortin, an inhibitor protein. Relatively new NSAIDs, known as COX-2 selective inhibitors or coxibs, are used as specific inhibitors of the COX-2 isoform of cyclooxygenase. The development of these drugs allowed the circumvention of the negative gastrointestinal side effects of NSAIDs while still effectively reducing inflammation.

Prostaglandin antagonists may also help with allergies, primarily seasonal allergies or nasal allergies. The prostaglandin D2 (PGD2) receptor is activated when it comes into contact with PGD2 which is released in the presence of allergens. A research study has been conducted to find an antagonist to the PGD2 receptor, DP1, to possibly treat congestion. ONO-4053 is an antagonist that was used on dogs to help with allergic rhinitis caused by PGD2. The study showed that ONO-4053 given either orally or through IV greatly helped increase nasal volume and possibly relieve rhinorrhea by blocking the PGD2 receptor before it can be activated by PGD2. [1]

Similarly, to how PGD2 antagonists can minimizing symptoms caused by allergies, prostaglandin E2 (PGE2) antagonists can also decrease inflammation, swelling, and pain caused by osteoarthritis. A study was made to see the effect of grapiprant, a prostaglandin EP4 receptor antagonist, which uses allosteric inhibition to prevent PGE2 to bind to its receptor as opposed to generally blocking viable receptors such as prostaglandin endoperoxide synthase or cyclooxygenase. Studies have shown that grapiprant can be used to treat pain and inflammation similar to NSAIDs that are prescribed to dogs with osteoarthritis. NSAIDs interfere with the cyclooxygenase and levels of various chemical mediators which may lead to a disruption in the body’s homeostasis. Grapiprant is able to selectively bind to only the EP4 receptor and minimize any adverse reactions that may occur. [2]

Adverse effects

NSAIDs have been shown to increase the risk of myocardial infarction when taken on a chronic basis for at least 18 months. One emerging hypothesis that may explain these cardiovascular effects is that coxibs create an imbalance in circulating TxA2 (thromboxane A2) and PGI2 (prostacyclin) levels. An increase in the ratio of TxA2/PGI2 could lead to increased platelet aggregation and dysregulation of platelet homeostasis. [3]

The GI and renal systems of patients who are treated with NSAIDS for a long period of time may experience unwanted side effects compared to patients who are treated for shorter durations. Studies on NSAIDS have shown that it can cause acute kidney injury by inhibiting prostaglandin production. The decreased levels of prostaglandins increases the risks of interstitial nephritis since there is lower blood flow to the kidneys. However, the risks of NSAIDs induced kidney failure is higher in people with diabetes or cardiovascular disease. [4]

A study on grapiprant showed that it negatively impacted the GI system, but the response was mild enough for the owners to not seek medical attention or removal from the trial. In contrast, prolonged use of NSAIDs has shown to increase the risk of toxicity of multiple organs like the GI tract, kidneys, and liver. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Prostaglandin</span> Group of physiologically active lipid compounds

Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Prostacyclin</span> Chemical compound

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

<span class="mw-page-title-main">Thromboxane</span> Group of lipids

Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.

<span class="mw-page-title-main">Aspirin-exacerbated respiratory disease</span> Chronic inflammatory disease affecting the sinuses and lungs

Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Compared to aspirin tolerant patients, AERD patients' asthma and nasal polyps are generally more severe. Reduction or loss of the ability to smell is extremely common, occurring in more than 90% of people with the disease. AERD most commonly begins in early- to mid-adulthood and has no known cure. While NSAID intolerance is a defining feature of AERD, avoidance of NSAIDs does not affect the onset, development or perennial nature of the disease.

In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins, the thromboxanes, and the prostacyclins. Prostanoids are seen to target NSAIDS which allow for therapeutic potential. Prostanoids are present within areas of the body such as the gastrointestinal tract, urinary tract, respiratory and cardiovascular systems, reproductive tract and vascular system. Prostanoids can even be seen with aid to the water and ion transportation within cells.

Prostaglandin E<sub>2</sub> Chemical compound

Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2,, PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. They are named based on the prostanoid to which they preferentially bind and respond, e.g. the receptor responsive to PGI2 at lower concentrations than any other prostanoid is named the Prostacyclin receptor (IP). One exception to this rule is the receptor for thromboxane A2 (TP) which binds and responds to PGH2 and TXA2 equally well.

Prostaglandin DP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

The prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), is primarily a receptor for prostaglandin D2 (PGD2). The receptor is a member of the prostaglandin receptors belonging to the subfamily A14 of rhodopsin-like receptors. Activation of DP1 by PGD2 or other cognate receptor ligands is associated with a variety of physiological and pathological responses in animal models.

<span class="mw-page-title-main">Cyclooxygenase-2</span> Human enzyme involved in inflammation

Cyclooxygenase-2 (COX-2), also known as Prostaglandin-endoperoxide synthase 2 (HUGO PTGS2), is an enzyme that in humans is encoded by the PTGS2 gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation.

Prostaglandin EP<sub>4</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP4 has been implicated in various physiological and pathological responses in animal models and humans.

Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

Prostaglandin EP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

Prostaglandin EP<sub>3</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin EP3 receptor (EP3, 53kDa), is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

<span class="mw-page-title-main">Mechanism of action of aspirin</span>

Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia, the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs, which are reversible inhibitors; aspirin creates an allosteric change in the structure of the COX enzyme. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria, and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

<span class="mw-page-title-main">Grapiprant</span> NSAID anti-inflammatory veterinary drug

Grapiprant, sold under the brand name Galliprant, is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA's Center for Veterinary Medicine and was categorized as a non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.

References

  1. ↑ Okada, Yutaka; Yamaguchi, Shinsuke; Matsunaga, Yoko; Nambu, Fumio (February 2015). "Effect of ONO-4053, a DP1 (prostaglandin D2 receptor) Antagonist, on Prostaglandin D2-Induced Nasal Congestion". Journal of Allergy and Clinical Immunology. 135 (2): AB219. doi:10.1016/j.jaci.2014.12.1652 – via Elsevier ScienceDirect.
  2. 1 2 Rausch-Derra, L.; Huebner, M.; Wofford, J.; Rhodes, L. (April 13, 2016). "A Prospective, Randomized, Masked, Placebo-Controlled Multisite Clinical Study of Grapiprant, an EP 4 Prostaglandin Receptor Antagonist (PRA), in Dogs with Osteoarthritis". Journal of Veterinary Internal Medicine. 30 (3): 756–763. doi: 10.1111/jvim.13948 . PMC   4913586 . PMID   27075237. S2CID   18880328.
  3. ↑ Cheng, Y.; Austin, S. C.; Rocca, B.; Koller, B. H.; Coffman, T. M.; Grosser, T.; Lawson, J. A.; Fitzgerald, G. A. (2002). "Role of prostacyclin in the cardiovascular response to thromboxane A2". Science. 296 (5567): 539–41. Bibcode:2002Sci...296..539C. doi:10.1126/science.1068711. PMID   11964481. S2CID   11900030.
  4. ↑ Harirforoosh, Sam; Asghar, Waheed; Jamali, Fakhreddin (2013). "Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications". Journal of Pharmacy & Pharmaceutical Sciences. 16 (5): 821–847. doi: 10.18433/J3VW2F . ISSN   1482-1826. PMID   24393558.
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