Mesalazine and Cyclosporine
Mesalazine is also called as Mesalamine or 5-aminosalicylic acid, and its systematic name is 5-amino-2-hydroxybenzoic acid.
Formulation. Usually, mesalazine is administered in the form of modified release (MR) tablet. Different formulations of mesalazine in UK are Asacol, Ipocol, Mezavant, Octasa, Pentasa, and Salofalk. The above mentioned formulations may vary from each other in their indications, dose frequency, tablet strengths, interactions, pharmaceutical, and pharmacological properties. Most of these formations are available as MR preparations. Commonly used mechanism for modified release tablets is their enteric coating. In order to prepare different formulations, Eudragit L and S polymers are commonly used coating polymers. Eudragit L has the ability to dissolve at pH greater than 6, therefore making it easy for the tablet to be dissolved in jejunum, where the pH is from six to seven. On the other hand, Eudragit S has the ability to dissolve at pH greater than 7 making it a better choice for dissolution in the ileum or color, where the pH is more than 7. These polymers can also be combined or they can be used with certain other polymers making it possible to use the drug in different conditions (NHS, medicinesresources.nhs.uk).
Clinical Uses and Indications. Mesalazine is an anti-inflammatory drug that is commonly used for the treatment of ulcerative colitis, a chronic inflammatory bowel disease in mild to moderate cases, and maintenance of remission. It is also used for the treatment of Crohn’s disease. Some formulations such as Octasa MR and Asacol MR can be used for maintenance of remission in Crohn’s ileo-colitis (NHS, medicinesresources.nhs.uk).
Pharmacology. Mesalazine acts on the inflamed lining of the intestine to stop the development of the substances that can result in inflammation (NHS, ouh.nhs.uk). In order to treat acute disease, overall daily dose equal to two or three doses can be considered depending on the formulation. Research shows that oral delayed-release mesalazine given as a single dose or multiple doses has a good safety profile showing well-tolerance as well as efficacy in both maintenance and induction treatment (NHS, medicinesresources.nhs.uk).
In a study, it was reported that systemic exposure to 5-aminosalicylate as determined by urinary excretion data and fecal excretion of 5-aminosalicylate are comparable for all formulations of oral mesalazine and pro-drugs. None of the formulations of the drug are released at pH of 1-2, and most of the formulation showed release of the drug in 30 to 60 minutes at pH 7.2 (NHS, medicinesresources.nhs.uk).
Most commonly encountered side effects of the drug include headache. This is the reason that most of the patients do not show willingness to take the drug. Among the other side effects are nausea, indigestion, watery diarrhea, mild allergic reactions, itchiness, rash, and fever. In rare conditions, the drug can also affect lungs, liver, kidneys, pancreas, and generation of red blood cell in the bone marrow. These effects can also cause bruising, bleeding, fever, sore throat, and malaise. However, due to well-tolerance, about 80% of patients do not experience any side effects (NHS, ouh.nhs.uk).
Precautions. Some of the formulations such as Ipocol MR and Asacol MR may show interaction with lactulose or other similar preparations that can decrease stool pH, thereby preventing the release of mesalazine. However, this interaction need further studies as it is a theoretical interaction. Other mesalazine tablets are found to have no interaction with these substances (NHS, medicinesresources.nhs.uk).
Cyclosporine is also known as Ciclosporin or Cyclosporine A (NHS, southend.nhs.uk). Cyclosporine A and cyclosporine G are two different forms of cyclosporine. Cyclosporine G is a natural analogue of cyclosporine A that has been developed to show immunosuppressive activity similar to that of cyclosporine A but with low renal toxicity (Suki, and Massry 1114).
Formulation. Cyclosporine shows poor solubility in water. Therefore, researchers have developed emulsion and suspension forms of the drug for oral administration as well as injection. Novartis initially introduced it with the name Sandimmune that was found in the form of soft gelatin capsules, oral solution, and intravenous administration. These are non-aqueous compositions. Some of the additives used in the preparation of cyclosporine are cremophor EL, castor oil, and alcohol. A novel formulation of cyclosporine A produces a transparent microemulsion aqueous fluid, simulating the mixed micellar phase obtained after the digestion of lipid particles. This fluid helps in the rapid release of cyclosporine in the gastrointestinal tract and maximum absorption. Microemulsion formulation of cyclosporine is also available for optimal bioavailability and blood concentration. In the present era, microemulsion formulation is under extensive research in Europe as well as in the United States. It is also thought that the microemulsion formulation would replace the oral preparations as well as soft gelatin capsules in the near future (Suki, and Massry 1114).
Pharmacology. Absorption of the drug from the gastrointestinal tract is not complete, i.e. about 30%, and can be erratic. Most of the drug is in bound state in the body. For example, 60% to 70% of the drug is bound to red blood cells, 10% to 20% of the drug is bound to white blood cells, and some of the drug is bound to plasma lipoproteins. The drug binds to tissues outside of the vascular system (Lehne 875).
Therapeutic dose of the drug may change depending on the use, type of formulation, and age of patient undergoing transplantation. Moreover, concomitant disease, and liver and renal function have also to be considered. Therapeutic range of the drug is from 100 ng/ml to 300 ng/ml (NHS, southend.nhs.uk). Drug can result in toxicity in higher doses (Lehne 875). The drug may start showing toxic effects above 400 ng/ml (NHS, southend.nhs.uk). In order to reduce toxicity due to higher drug levels in the blood and organ rejection due to lower drug levels in the body, blood levels of the drug have to be measured periodically (Lehne 875).
Hepatic microsomal enzymes play an important role in the extensive metabolism of the drug. Therefore, the drugs acting on these enzymes can significantly affect cyclosporine levels. Cyclosporine and its metabolites are excreted through the bile. However, negligible amounts appear in the urine (Lehne 875).
Cyclosporine can result in several adverse reactions, and most commonly encountered adverse reactions are infection, nephrotoxicity, tremor, hypertension, and hirsutism. Infection and nephrotoxicity are considered as the most serious adverse effects (Lehne 875).
Clinical Uses and Indications. Cyclosporine is commonly used in the process of organ transplantation (transplant surgery) to stop the problem of rejection by the body, as it is an immunosuppressant drug (NHS, southend.nhs.uk). Cyclosporine is also used as antifungal agent, carcinogenic agent, antirheumatic drug, dermatologic drug, and anti-asthmatic drug (ChEBI, ebi.ac.uk).
Precautions. It has to be considered that sub-therapeutic levels of the drug can result in organ rejection. On the other hand, higher levels can result in renal damage (NHS, southend.nhs.uk).
ChEBI. “CHEBI:4031 - cyclosporin A”. Wellcome Trust Genome Campus, EBI. 04 Aug. 2014. Web. 03 Feb. 2016 <https://www.ebi.ac.uk/chebi/searchId.do?chebiId=4031>
Lehne, R.A. Pharmacology for Nursing Care. Elsevier/Saunders, 2013. Print.
NHS. "Cyclosporin". Southend University Hospital. NHS Foundation Trust., n.d. Web. 03 Feb. 2016 <http://www.southend.nhs.uk/pathology-handbook/test-directory/test-directory-c-index/cyclosporin/>
NHS. "Mesalazine". Oxford Radcliffe Hospitals. NHS Trust., 02 Jul. 2010. Web. 03 Feb. 2016 <http://www.ouh.nhs.uk/patientguide/leaflets/files%5C100722paedmesalazine.pdf>
NHS. "What are the differences between different brands of mesalazine tablets?". NHS healthcare professionals. UK Medicines Information (UKMi)., 01 May. 2014. Web. 03 Feb. 2016 < http://www.medicinesresources.nhs.uk/GetDocument.aspx?pageId=504085>
Suki, W.N., and S.G. Massry. Suki and Massry’s Therapy of Renal Diseases and Related Disorders. Springer US, 2013. Print.