Inflammatory Bowel Disease (IBD) extends into two major chronic idiopathic conditions, Ulcerative Colitis (UC) and Crohns Disease. Ulcerative Colitis occurs due to the bowels being under constant inflammation. This is caused by the inflammatory changed occurring within the sub-epithelial connective tissue[1]. UC is characterised by superficial mucosal ulcerations patients experience symptoms such as bloody stools, severe abdominal pain, tenesmus, fatigue and anaemia[1]. Medications that assist with Ulcerative Colitis symptoms are prescribed depending on the severity and extent of the disease to maintain remission[2]. Common first point of call in terms of treatment for Ulcerative Colitis begins by assessing the severity of the condition, commonly the first point of call is prescribing corticosteroids, with a positive response the steroids are tapered and 5-Aminosalicylates (5-ASA) are introduced[3]. If 5-ASAs and oral steroids have no effect hospitalisation of the patient is required to receive intravenous corticosteroids, with the outcome aim of remission thus resulting in the patient being able to become an outpatient. As an outpatient typically the treatment would then be converted to an oral steroid on a tapered dosage in conjunction with 5-ASAs[4]. Overall if medication does not satisfy the patients need and the severity cannot be maintained a proctocolectomy may need to occur as it is the removal of both the colon and rectum[5].

As there is no current cure for Ulcerative Colitis the maintenance of remission is highly favoured as constant inflammation can increase the risks of cancer and a proctocolectomy procedure as it would decrease the risk of developing colon cancer[1].

The most common form of treatment for patients diagnosed with Ulcerative Colitis are 5-ASAs. 5-ASAs are also known as Mesalazines or Mesalamines, they are Aminosalicylates that are used to treat IBD as they are an anti-inflammatory drug. 5-ASA is pluripotent with numerous anti-inflammatory properties including inhibition of cyclooxygenase and lipoxygenase[4].

The chronic inflammation on the superficial mucosa is caused by the increased levels of prostaglandins found within the mucosa of the endothelium in patients with UC[6]. Linoleic acids are an essential fatty acid that are the dietary precursor of prostaglandins[7]. Linoleic acid is then desaturated and elongated to form arachidonic acid. Arachidonic acid is the immediate precursor of the main prostaglandins in humans[8]. Arachidonic acid is then incorporated into membrane-bound phospholipids, it is released by Phospholipase A1 in response to different signals[9].  Prostaglandin H2 synthesis occurs via an oxidative cyclisation reaction from arachidonic acid to prostaglandin H2 the reaction is catalysed by prostaglandin endoperoxidase (PGH) synthase[9]. PGH synthase enzyme isoenzymes cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). COX-1 is made in most tissues and is needed for maintenance of healthy gastric tissue, renal homeostasis and platelet aggregation. COX-2 is inducible in a limited amount of tissues in response to products of activated immune and inflammatory cells[10]. The increase in prostaglandin synthesis due to initiation of COX-2 facilitates the pain, heat, redness and swelling of inflammation, and the fever of infection[11]. Hence why pharmaceutical treatment of 5-ASAs resulting in inhibition of COX can provide relief for symptoms of inflammation and pain[2].

The COX pathway is one of the main mechanisms of action for 5-ASAs to follow when being used to treat UC[12]. The COX pathway works by attending sites where increased levels of prostaglandin and inflammation are found[13]. Non-steroidal anti-inflammatory agents found in 5-ASAs inhibit the COX pathway[14]. Inhibition works where high levels of prostaglandin are present[4]. 5-ASAs also inhibit production of thromboxane (TXA) as it is a potent vasoconstrictor that increases the adhesion to the endothelium and aggregation of platelets[15]. Increased prostaglandin production is also associated with inhibition of TXA inhibitor synthesis, as the increase causes the removal of substrates for TXA synthesis[15]. 5-ASA and inhibitors are equally effective anti-inflammatory agents, suggesting that the anti-inflammatory properties may function via the inhibition of TXA production[16].

5-ASAs can be taken either orally or rectally, suppositories and enema formulations deliver 5-ASAs directly to the rectum, as the delivery permits high dose therapy at the area of need and avoids systemic exposure[4]. Oral forms such as Salofalk Granules consist of 5-ASA covered by a pH sensitive coating[12]. This way the granules can be slowly released in the colon. Most patients diagnosed with UC can maintain remission using oral once-daily 5-ASAs doses at 1.6-3.0g per day[4]. As topical benefits of 5-ASA in distal UC it is proposed that a combination of oral and topical therapies is most efficacious in patients with active UC, as the therapy has been superior to oral therapy alone[4].

The physicians intention for remission management is towards reducing steroid dependency and utilising 5-ASA use in patients with IBD[17]. Reducing steroid dependency is crucial due to the detrimental side effects[2]. As steroids inhibit the phospholipases synthesising into arachidonic acid, subsequently inhibition of critical maintenance of healthy gastric tissue, renal homeostasis and platelet aggregation cannot occur. 5-ASAs are preferred as they inhibit further down the pathway as a COX-2 inhibitor. Inhibiting the COX-2 pathway results in the unstable peroxides being supressed and no longer being able to produce unrestrained inflammatory responses in UC. Limitations in inhibiting the COX-2 pathway are restricting renal function and regulatory mechanisms of blood pressure as they are highly regulatory in response to alterations in intravascular volume[10, 18].

Appropriate medical treatment can substantially improve quality of life and reduce (IBD) related morbidity, including steroid dependency, hospital admissions and the lifetime risk of surgery [19]. Several new drugs have been introduced into clinical IBD therapy in the current times that have assisted to reduce corticosteroid use and to strengthen response and remission rates[12]. As UC is classified as an idiopathic disease, constant research and new findings may alter the pathway’s we inhibit and may result in finding the primary cause. With the introduction of additional approved drugs in the future, it will be of crucial importance to identify biomarkers to predict and monitor therapeutical success to facilitate customised therapy in IBD[12, 20].

References:

1. Rubin, D.T., et al., Ulcerative Colitis Remission Status After Induction With Mesalazine Predicts Maintenance Outcomes: the MOMENTUM Trial. Journal of Crohn’s and Colitis, 2016. 10(8): p. 925-933.

2. Kokkinidis, D.G., et al., Emerging treatments for ulcerative colitis: a systematic review. Scandinavian Journal of Gastroenterology, 2017. 52(9): p. 923-931.

3. Gionchetti, P., et al., Use of corticosteroids and immunosuppressive drugs in inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease. Digestive and Liver Disease, 2016. 49(6): p. 604-617.

4. Hanauer, S.B., Oral or Topical 5-ASA in Ulcerative Colitis. Digestive Diseases (Basel, Switzerland), 2016. 34(1-2): p. 122-124.

5. Engel, T., et al., Re-phrasing the question: A simple tool for evaluation of adherence to therapy in patients with inflammatory bowel disease. United European Gastroenterology Journal, 2017. 5(6): p. 880-886.

6. Ren, P.-w., et al., Kangfuxinye Enema Combined with Mesalamine for Ulcerative Colitis: A Systematic Review and GRADE Approach. Evidence-based Complementary and Alternative Medicine : eCAM, 2017. 2017: p. 6019530.

7. Owczarek, D., et al., Diet and nutritional factors in inflammatory bowel diseases. World Journal of Gastroenterology, 2016. 22(3): p. 895-905.

8. Biasi, F., et al., Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets. Antioxidants & Redox Signaling, 2013. 19(14): p. 1711-1747.

9. Wang, D. and R.N. DuBois, Pro-inflammatory prostaglandins and progression of colorectal cancer. Cancer letters, 2008. 267(2): p. 197-203.

10. Harris, R.C., COX-2 and the Kidney. Journal of Cardiovascular Pharmacology, 2006. 47.

11. Rogers, K.V., et al., Know Your Variability: Challenges in Mechanistic Modeling of Inflammatory Response in Inflammatory Bowel Disease (IBD). Clinical and Translational Science, 2016: p. n/a-n/a.

12. Neurath, M.F., Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol, 2017. 14(5): p. 269-278.

13. Yin, J., et al., COX-2 mediates PM2.5-induced apoptosis and inflammation in vascular endothelial cells. American Journal of Translational Research, 2017. 9(9): p. 3967-3976.

14. Zhao, X., et al., Efficacy and Safety of Beclomethasone Dipropionate versus 5-Aminosalicylic Acid in the Treatment of Ulcerative Colitis: A Systematic Review and Meta-Analysis. PLoS ONE, 2016. 11(8): p. e0160500.

15. Michalak, A., P. Mosińska, and J. Fichna, Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer. Frontiers in Pharmacology, 2016. 7: p. 459.

16. Saber, M.M., et al., Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines. BMC Cancer, 2016. 16: p. 1-12.

17. Dandin, Ö., et al., The Efficacy of Probiotic (Lactobacillus rhamnosus GG) and 5-ASA (Aminosalicylic Acid) in the Treatment of Experimental Radiation Proctitis in Rats. The Indian Journal of Surgery, 2015. 77(Suppl 2): p. 563-569.

18. Abegunde, A.T., B.H. Muhammad, and T. Ali, Preventive health measures in inflammatory bowel disease. World Journal of Gastroenterology, 2016. 22(34): p. 7625-7644.

19. Chhaya, V., et al., Steroid dependency and trends in prescribing for inflammatory bowel disease – a 20-year national population-based study. Alimentary Pharmacology & Therapeutics, 2016. 44(5): p. 482-494.

20. Mortensen, J.H., et al., Ulcerative colitis, Crohn’s disease, and irritable bowel syndrome have different profiles of extracellular matrix turnover, which also reflects disease activity in Crohn’s disease. PLOS ONE, 2017. 12(10): p. e0185855.