Introduction

Conventional pharmacotherapies used in inflammatory bowel diseases (IBD) aims to induce and kept the remission of clinical events and the prevention of new episodes, thus highlighting the use of 5-aminosalicylic acid (5-ASA) [1,2] , main pharmacotherapy for mild/moderate stages of IBD, in addition to being considered a safe and effective drug. [1]

Physicochemical characteristics

The main physicochemical parameters of 5-ASA were presented in Table 1. 5-aminosalicylic acid has stability in solution depends on factors such as pH, temperature, and light exposure. In biological samples, the 5-aminosalicylic acid show instability at
20℃ and acid pH, unlike its metabolite N-acetyl-5-aminosalicylic acid (N-acetyl-5-ASA) that remain stable under the above conditions, highlighting the role of the amino group in the degradation of 5-ASA. Studies show that 5-aminosalicylic acid degrades under conditions that promote oxidation, it was observed that the molecule undergoes an autoxidation mechanism. [3,4]

Pharmacokinetics characteristics

After oral administration, 5-aminosalicylic acid is rapidly absorbed in the first portion of the small bowel, resulting in approximately 30% bioavailability of 5-aminosalicylic acid. When administered rectally, 5-aminosalicylic acid is affected by rectal pH, its absorption can vary between 10 and 20%. The drug has a strong plasma protein binding of 80%, reaching maximum plasma concentration in approximately 3.48 hours. The half-life will vary according to the delivery system, taking from 1.4 to 6 hours and its excretion can occur in the urine or feces, being eliminated in its unchanged or metabolized form. The absorbed 5-aminosalicylic acid is almost completely metabolized in the gastrointestinal tract and liver. The product of metabolism is called N-acetyl-5-ASA. It is an active metabolite, reaching maximum plasma concentration in approximately 3.74 hours, 5 to 10 hours of half-life, and undergoing renal excretion. [5]

Mechanisms of action

Numerous studies classify the mechanism of action of 5-aminosalicylic acid as partially defined (Figure 1). It is argued that the drug has a predominantly local anti-inflammatory action on the intestinal mucosa, by inhibition of lipooxygenase and cyclooxygenase, consequently, the production of leukotrienesand prostaglandins is reduced. It is also reported that the drug acts as a free radicals scavenger, molecules in evidencein inflammatory bowel disease patients.[5] Other mechanisms have been reported, relating the inhibition of the production of inflammatory cytokines as an effect of 5-ASA. The drug can interfere with the action ofnuclear factor kappa B, responsible for the transcription of  pro-inflammatory cytokines. 5-Aminosalicylic acid is also able to inhibit the cellular functions of lymphocytes, macrophages, and natural killer cells, cells present in the inflammation process, thus obtaining the ability to remove reactive oxygenmetabolites.[5]

Maternal and paternal 5-aminosalicylic acid use- safe in conception and pregnancy [6]

Studies on the maternal use of 5-aminosalicylic acid have shown it has low risk during pregnancy, but these have often been small and uncontrolled. N?rg?rd et al aimed to evaluate the safety of maternal and paternal 5-ASAs with a nationwide cohort study. Medications included mesalazine, sulfasalazine, olsalazine and balsalazide.[7] Paternal use was defined as 5-aminosalicylic acid use within 3 months prior to conception; maternal use was defined as 5-ASA use 30?days before conception or during pregnancy. The study used nationwide Danish health registries and included births between 1995 and 2015. Both 5-ASA-exposed and -unexposed patients with ulcerative colitis or Crohn's disease were included. The primary outcomes were rates of preterm birth, small for gestational age (SGA), low Apgar score or major congenital abnormalities (CAs).

The study included 2168 children fathered by men on 5-aminosalicylic acid (majority mesalazine, 94%) and 7732 children fathered by men not on 5-ASA. There were 3618 children with and 7128 without maternal exposure to 5-aminosalicylic acid (majority mesalazine, 92%). Overall, there was no statistically significant increase in OR/HR for preterm labour, SGA, low Apgar score or CA in children exposed to 5-aminosalicylic acid by maternal or paternal use. When evaluating 5-aminosalicylic acid subtypes, paternal pre-conception use of balsalazide by patients with UC had an adjusted HR of 7.22 for CA; however, there were only four CAs, making this result difficult to interpret.

This is the first controlled study to evaluate the safety of paternal pre-conception use of 5-ASAs, and the largest study of maternal use of 5-ASAs during pregnancy. The study is very important given its size, true cohort nature, and the use of national health registries to validate 5-aminosalicylic acid use and assess fetal outcomes. They have conclusive evidence for our patients that 5-aminosalicylic acid medications are safe in pregnancy.

References

[1] Moura, R. M.; Hartmann, R. M.; Licks, F.; Schemitt, E. G.; Colares, J. R.; do Couto Soares, M.; Fillmann, L. S.; Fillmann, H. S.; Marroni, N. P. Antioxidant Effect of Mesalazine in the Experimental Colitis Model Induced by Acetic Acid. J. Coloproctol. 2016, 36, 139–148. DOI: 10.1016/j.jcol.2016.03.003.

[2] Popova, M.; Trendafilova, I.; Zgureva, D.; Kalvachev, Y.; Boycheva, S.; Novak Tusar, N.; Szegedi, A. Polymer-Coated Mesoporous Silica Nanoparticles for Controlled Release of the Prodrug Sulfasalazine. J. Drug Deliv. Sci. Technol. 2018, 44, 415–420. DOI:10.1016/j.jddst.2018.01.020.

[3] Palsmeier, R. K.; Radzik, D. M.; Lunte, C. E. Investigation of the Degradation Mechanism of 5-Aminosalicylic Acid in Aqueous Solution. Pharmaceut. Res. 1992, 09, 933–938. DOI: 10.1023/A:1015813302412.

[4] Jensen, J.; Cornett, C.; Olsen, C. E.; Tj?rnelund, J.; Hansen, S. H. Identification of Major Degradation Products of 5- Aminosalicylic Acid Formed in Aqueous Solutions and in Pharmaceuticals. Int. J. Pharm. 1992, 88, 177–187. DOI: 10. 1016/0378-5173(92)90315-S.

[5] Tavares Junior, A. G., de Araújo, J. T. C., Meneguin, A. B., & Chorilli, M. Characteristics, Properties and Analytical/Bioanalytical Methods of 5-Aminosalicylic Acid: A Review. Critical reviews in analytical chemistry, 2022, 52(5), 1000–1014. https://doi.org/10.1080/10408347.2020.1848516.

[6] Bennett, A., & Horst, S. (2022). Editorial: maternal and paternal 5-aminosalicylic acid use-safe in conception and pregnancy. Alimentary pharmacology & therapeutics, 56(9), 1419–1420. https://doi.org/10.1111/apt.17205.

[7] N?rg?rd, B. M., Friedman, S., Kjeldsen, J., & Nielsen, J. (2022). The safety of paternal and maternal use of 5-aminosalicylic acid during conception and pregnancy: a nationwide cohort study. Alimentary pharmacology & therapeutics, 56(9), 1349–1360. https://doi.org/10.1111/apt.17189.