4-Aminosalicylic acid

4-Aminosalicylic acid
Systematic (IUPAC) name
4-amino-2-hydroxy-benzoic acid
Clinical data
Trade names Paser
  • C
Oral
Pharmacokinetic data
Protein binding 50–60%
Metabolism Hepatic
Excretion Renal
Identifiers
65-49-6 Yes
J04AA01
PubChem CID 4649
DrugBank DB00233 Yes
ChemSpider 4488 Yes
UNII 5B2658E0N2 Yes
KEGG D00162 Yes
ChEBI CHEBI:27565 Yes
ChEMBL CHEMBL1169 Yes
NIAID ChemDB 020064
Chemical data
Formula C7H7NO3
153.135 g/mol
Physical data
Melting point 150.5 °C (302.9 °F)
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4-aminosalicylic acid, commonly known as PAS, is an antibiotic used to treat tuberculosis.[1] This organic compound has also been use since the 1940s for the treatment of inflammatory bowel diseases (IBDs), where it has shown greater potency in ulcerative colitis and Crohn's disease.[2] It is thought to act via NF-κB (nuclear factor-kappa B) inhibition and free radical scavenging. 5-Aminosalicylic acid, sold under the name mesalazine, is a closely related compound that also has medical uses.

Medical uses

The main use for 4-aminosalicyclic acid is for the treatment of tuberculosis infections.

Tuberculosis

Aminosalicylic acid was introduced to clinical use in 1948. It was the second antibiotic found to be effective in the treatment of tuberculosis, after streptomycin. PAS formed part of the standard treatment for tuberculosis prior to the introduction of rifampicin and pyrazinamide.[3]

Its potency is less than that of the current five first-line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin) for treating tuberculosis and its cost is higher, but it is still useful in the treatment of multidrug-resistant tuberculosis.[1] PAS is always used in combination with other anti-TB drugs.

The dose when treating tuberculosis is 150 mg/kg/day divided into two to four daily doses; the usual adult dose is therefore approximately 2 to 4 grams four times a day. It is sold in the US as "Paser" by Jacobus Pharmaceutical, which comes in the form of 4 g packets of delayed-release granules. The drug should be taken with acid food or drink (orange, apple or tomato juice).[4] PAS was once available in a combination formula with isoniazid called Pasinah[5] or Pycamisan 33.[6]

The European Medicines Agency (EMA) has recommended granting a marketing authorization for PAS in multidrug-resistant tuberculosis in adults and children when other treatments cannot "be devised for reasons of resistance or tolerability."[7]

Inflammatory bowel disease

PAS has also been used in the treatment of inflammatory bowel disease (ulcerative colitis and Crohn's disease),[2] but has been superseded by other drugs such as sulfasalazine and mesalazine.

Others

PAS has been investigated for the use in manganese chelation therapy, and a 17-year follow-up study shows that it might be superior to other chelation protocols such as EDTA.[8]

Pharmacology

With heat, aminosalicylic acid is decarboxylated to produce CO2 and 3-aminophenol.[9]

The U.S. FDA assigned PAS to pregnancy category C, indicating that it is not known whether it will harm an unborn baby.

Side effects

Gastrointestinal side-effects (nausea, vomiting, diarrhoea) are common; the delayed-release formulation is meant to help overcome this problem.[10] It is also a cause of drug-induced hepatitis. Patients with glucose-6-phosphate dehydrogenase deficiency should avoid taking aminosalicylic acid as it causes haemolysis.[11] Thyroid goitre is also a side-effect because aminosalicylic acid inhibits the synthesis of thyroid hormones.[12]

Drug interactions include elevated phenytoin levels. When taken with rifampicin, the levels of rifampicin in the blood fall by about half.[13]

History

PAS was discovered by the Swedish chemist Jörgen Lehmann upon the report that the tuberculosis bacterium avidly metabolized salicylic acid. Lehmann first tried PAS as an oral TB therapy late in 1944. The first patient made a dramatic recovery.[14] The drug proved better than streptomycin, which had nerve toxicity and to which TB could easily develop resistance. In the 1948, researchers at Britain's Medical Research Council demonstrated that combined treatment with streptomycin and PAS was superior to either drug alone.[1]

Other names

Like many commercially significant compounds, PAS has many names including para-aminosalicylic acid, p-aminosalicylic acid, 4-ASA, and simply P.

Mode of action

PAS has been shown to be a pro-drug and it is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity.[15]

External links

References

  1. ↑ 1.0 1.1 1.2 Fox, W.; Ellard, G. A.; Mitchison, D. A. (1999). "Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications". The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 3 (10 Suppl 2): S231–S279. PMID 10529902.
  2. ↑ 2.0 2.1 Daniel F, Seksik P, Cacheux W, Jian R, Marteau P (2004). "Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis". Inflamm Bowel Dis 10 (3): 258–260. doi:10.1097/00054725-200405000-00013. PMID 15290921.
  3. ↑ Mitchison DA (2000). "Role of individual drugs in the chemotherapy of tuberculosis Role of individual drugs in the chemotherapy of tuberculosis". Int J Tuberc Lung Dis 4 (9): 796–806. PMID 10985648.
  4. ↑ "Paser". RxList. Archived from the original on 25 October 2008. Retrieved 2008-10-10.
  5. ↑ Smith NP, Ryan TJ, Sanderson KV, Sarkany I (1976). "Lichen scrofulosorum: A report of four cases". Br J Dermatol 94 (3): 319–325. doi:10.1111/j.1365-2133.1976.tb04391.x. PMID 1252363.
  6. ↑ Black JM; Sutherland, IB (1961). "Two incidents of tuberculous infection by milk from attested herds". Br Med J 1 (5241): 1732–1735. doi:10.1136/bmj.1.5241.1732. PMC 1954350. PMID 20789163.
  7. ↑ Drug Discovery & Development. EMA Recommends Two New Tuberculosis Treatments. November 22, 2013.
  8. ↑ Jiang, Y. M.; Mo, X. A.; Du, F. Q.; Fu, X.; Zhu, X. Y.; Gao, H. Y.; Xie, J. L.; Liao, F. L.; Pira, E.; Zheng, W. (2006). "Effective Treatment of Manganese-Induced Occupational Parkinsonism with p-Aminosalicylic Acid: A Case of 17-Year Follow-Up Study". Journal of Occupational and Environmental Medicine 48 (6): 644–649. doi:10.1097/01.jom.0000204114.01893.3e. PMID 16766929.
  9. ↑ Vetuschi, C.; Ragno, G.; Mazzeo, P. (1988). "Determination of p-aminosalicylic acid and m-aminophenol by derivative UV-spectrophotometry". Journal of pharmaceutical and biomedical analysis 6 (4): 383–391. doi:10.1016/0731-7085(88)80003-7. PMID 16867404.
  10. ↑ Das, K. M.; Eastwood, M. A.; McManus, J. P. A.; Sircus, W. (1973). "Adverse Reactions during Salicylazosulfapyridine Therapy and the Relation with Drug Metabolism and Acetylator Phenotype". New England Journal of Medicine 289 (10): 491–495. doi:10.1056/NEJM197309062891001. PMID 4146729.
  11. ↑ Szeinberg, A.; Sheba, C.; Hirshorn, N.; Bodonyi, E. (1957). "Studies on erthrocytes in cases with past history of favism and drug-induced acute hemolytic anemia". Blood 12 (7): 603–613. PMID 13436516.
  12. ↑ MacGregor, A. G.; Somner, A. R. (1954). "The anti-thyroid action of para-aminosalicylic acid". Lancet 267 (6845): 931–936. PMID 13213079.
  13. ↑ Boman G (1974). "Serum concentration and half-life of rifampicin after simultaneous oral administration of aminosalicylic acid or isoniazid". European journal of clinical pharmacology 7 (3): 217–25. doi:10.1007/BF00560384. PMID 4854257.
  14. ↑ Lehmann, J. (1946). "Para-aminosalicylic acid in the treatment of tuberculosis". Lancet 1 (6384): 15. doi:10.1016/s0140-6736(46)91185-3. PMID 21008766.
  15. ↑ Zheng J, Rubin EJ, Bifani P, Mathys V, Lim V, Au M, Jang J, Nam J, Dick T, Walker JR, Pethe K, Camacho LR. para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem. 288(32):23447-56. http://www.jbc.org/content/288/32/23447.long