4-Aminosalicylic acid

{{Short description|Anti-tuberculosis and anti-inflammatory drug}}

{{Infobox drug

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| image = P-Aminosalicylic acid.svg

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| tradename = Paser, Granupas, others

| Drugs.com = {{drugs.com|monograph|aminosalicylic-acid}}

| MedlinePlus =

| DailyMedID = Aminosalicylic acid

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| routes_of_administration = By mouth

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| ATC_prefix = J04

| ATC_suffix = AA01

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| legal_US = Rx-only

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| legal_EU = Rx-only

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| legal_status = Rx-only

| bioavailability =

| protein_bound = 50–60%

| metabolism = liver

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| excretion = kidney

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 65-49-6

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| PubChem = 4649

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| DrugBank = DB00233

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4488

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| UNII = 5B2658E0N2

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| KEGG = D00162

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 27565

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1169

| NIAID_ChemDB = 020064

| PDB_ligand = BHA

| synonyms =

| IUPAC_name = 4-Amino-2-hydroxybenzoic acid

| C=7 | H=7 | N=1 | O=3

| SMILES = OC(=O)c1ccc(N)cc1O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C7H7NO3/c8-4-1-2-5(7(10)11)6(9)3-4/h1-3,9H,8H2,(H,10,11)

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| StdInChIKey = WUBBRNOQWQTFEX-UHFFFAOYSA-N

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| melting_point = 150.5

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4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis.{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free |page=140}} Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

Common side effects include nausea, abdominal pain, and diarrhea. Other side effects may include liver inflammation and allergic reactions. It is not recommended in people with end stage kidney disease. While there does not appear to be harm with use during pregnancy it has not been well studied in this population. 4-Aminosalicylic acid is believed to work by blocking the ability of bacteria to make folic acid.{{cite web|title=Aminosalicylic Acid|url=https://www.drugs.com/monograph/aminosalicylic-acid.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231049/https://www.drugs.com/monograph/aminosalicylic-acid.html|archive-date=20 December 2016}}

4-Aminosalicylic acid was first made in 1902, and came into medical use in 1943.{{cite journal | vauthors = Donald PR, Diacon AH | title = Para-aminosalicylic acid: the return of an old friend | journal = The Lancet. Infectious Diseases | volume = 15 | issue = 9 | pages = 1091–1099 | date = September 2015 | pmid = 26277036 | doi = 10.1016/s1473-3099(15)00263-7 }} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}

Medical uses

The main use for 4-aminosalicylic acid is for the treatment of tuberculosis infections.{{cite web | title=Granupas (previously Para-aminosalicylic acid Lucane) | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/granupas-previously-para-aminosalicylic-acid-lucane | access-date=3 April 2020 | archive-date=15 August 2020 | archive-url=https://web.archive.org/web/20200815111328/https://www.ema.europa.eu/en/medicines/human/EPAR/granupas-previously-para-aminosalicylic-acid-lucane | url-status=live }}{{cite web | title=Paser- aminosalicylic acid granule, delayed release | website=DailyMed | date=1 May 2010 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f2753dc-5f0c-4f49-9335-e519afb69ba6 | access-date=3 April 2020 | archive-date=3 August 2020 | archive-url=https://web.archive.org/web/20200803175339/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f2753dc-5f0c-4f49-9335-e519afb69ba6 | url-status=live }}

In the United States, 4-aminosalicylic acid is indicated for the treatment of tuberculosis in combination with other active agents.

In the European Union, it is used in combination with other medicines to treat adults and children from 28 days of age who have multi-drug resistant tuberculosis when combinations without this medicine cannot be used, either because the disease is resistant to them or because of their side effects.

=Tuberculosis=

Aminosalicylic acid was introduced to clinical use in 1944. 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.{{cite journal | vauthors = Mitchison DA | title = Role of individual drugs in the chemotherapy of tuberculosis | journal = The International Journal of Tuberculosis and Lung Disease | volume = 4 | issue = 9 | pages = 796–806 | date = September 2000 | pmid = 10985648 }}

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. PAS is always used in combination with other anti-TB drugs.{{citation needed|date=August 2022}}

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).{{cite web|title=Paser |publisher=RxList |url=http://www.rxlist.com/cgi/generic/paser.htm |access-date=10 October 2008 |archive-url=https://web.archive.org/web/20080913183444/http://www.rxlist.com/cgi/generic/paser.htm |archive-date=13 September 2008 |url-status=dead }} PAS was once available in a combination formula with isoniazid called Pasinah{{cite journal | vauthors = Smith NP, Ryan TJ, Sanderson KV, Sarkany I | title = Lichen scrofulosorum. A report of four cases | journal = The British Journal of Dermatology | volume = 94 | issue = 3 | pages = 319–325 | date = March 1976 | pmid = 1252363 | doi = 10.1111/j.1365-2133.1976.tb04391.x | s2cid = 26281951 }} or Pycamisan 33.{{cite journal | vauthors = Black JM, Sutherland IB | title = Two Incidents of Tuberculous Infection by Milk from Attested Herds | journal = British Medical Journal | volume = 1 | issue = 5241 | pages = 1732–1735 | date = June 1961 | pmid = 20789163 | pmc = 1954350 | doi = 10.1136/bmj.1.5241.1732 }}

4-Aminosalicylic acid was approved for medical use in the United States in June 1994, and for medical use in the European Union in April 2014.{{cite web | title=Paser: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=074346 | access-date=3 April 2020 | archive-date=15 September 2020 | archive-url=https://web.archive.org/web/20200915060651/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=074346 | url-status=live }}

=Inflammatory bowel disease=

4-Aminosalicylic acid has also been used in the treatment of inflammatory bowel disease (ulcerative colitis and Crohn's disease),{{cite journal | vauthors = Daniel F, Seksik P, Cacheux W, Jian R, Marteau P | title = Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis | journal = Inflammatory Bowel Diseases | volume = 10 | issue = 3 | pages = 258–260 | date = May 2004 | pmid = 15290921 | doi = 10.1097/00054725-200405000-00013 }} but has been superseded by other drugs such as sulfasalazine and mesalazine.

=Others=

4-Aminosalicylic acid 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.{{cite journal | vauthors = Jiang YM, Mo XA, Du FQ, Fu X, Zhu XY, Gao HY, Xie JL, Liao FL, Pira E, Zheng W | title = Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study | journal = Journal of Occupational and Environmental Medicine | volume = 48 | issue = 6 | pages = 644–649 | date = June 2006 | pmid = 16766929 | pmc = 4180660 | doi = 10.1097/01.jom.0000204114.01893.3e }}

Side effects

Gastrointestinal side-effects (nausea, vomiting, diarrhoea) are common; the delayed-release formulation is meant to help overcome this problem.{{cite journal | vauthors = Das KM, Eastwood MA, McManus JP, Sircus W | title = Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype | journal = The New England Journal of Medicine | volume = 289 | issue = 10 | pages = 491–495 | date = September 1973 | pmid = 4146729 | doi = 10.1056/NEJM197309062891001 }} 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.{{cite journal | vauthors = Szeinberg A, Sheba C, Hirshorn N, Bodonyi E | title = Studies on erthrocytes in cases with past history of favism and drug-induced acute hemolytic anemia | journal = Blood | volume = 12 | issue = 7 | pages = 603–613 | date = July 1957 | pmid = 13436516 | doi = 10.1182/blood.V12.7.603.603 | doi-access = free }} Thyroid goitre is also a side-effect because aminosalicylic acid inhibits the synthesis of thyroid hormones.{{cite journal | vauthors = Macgregor AG, Somner AR | title = The anti-thyroid action of para-aminosalicylic acid | journal = Lancet | volume = 267 | issue = 6845 | pages = 931–936 | date = November 1954 | pmid = 13213079 | doi = 10.1016/S0140-6736(54)92552-0 }}

Drug interactions include elevated phenytoin levels. When taken with rifampicin, the levels of rifampicin in the blood fall by about half.{{cite journal | vauthors = Boman G | title = Serum concentration and half-life of rifampicin after simultaneous oral administration of aminosalicylic acid or isoniazid | journal = European Journal of Clinical Pharmacology | volume = 7 | issue = 3 | pages = 217–225 | year = 1974 | pmid = 4854257 | doi = 10.1007/BF00560384 | s2cid = 24202603 }}

It is not known whether it will harm an unborn baby.{{cite web | title=Aminosalicylic acid (Paser) Use During Pregnancy | website=Drugs.com | date=28 February 2020 | url=https://www.drugs.com/pregnancy/aminosalicylic-acid.html | access-date=3 April 2020 | archive-date=15 September 2020 | archive-url=https://web.archive.org/web/20200915062959/https://www.drugs.com/pregnancy/aminosalicylic-acid.html | url-status=live }}

Pharmacology

With heat, 4-aminosalicylic acid is decarboxylated to produce CO₂ and 3-aminophenol.{{cite journal | vauthors = Vetuschi C, Ragno G, Mazzeo P | title = Determination of p-aminosalicylic acid and m-aminophenol by derivative UV-spectrophotometry | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 6 | issue = 4 | pages = 383–391 | year = 1988 | pmid = 16867404 | doi = 10.1016/0731-7085(88)80003-7 }}

=Mode of action=

4-Aminosalicylic acid 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 (Hydroxy-H₂Pte and Hydroxy-H₂PteGlu) antimetabolite, which competes with dihydrofolate at the binding site of dihydrofolate reductase (DHFR). The binding of Hydroxy-H₂PteGlu to dihydrofolate reductase will block the enzymatic activity.{{cite journal | vauthors = Zheng J, Rubin EJ, Bifani P, Mathys V, Lim V, Au M, Jang J, Nam J, Dick T, Walker JR, Pethe K, Camacho LR | title = para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis | journal = The Journal of Biological Chemistry | volume = 288 | issue = 32 | pages = 23447–23456 | date = August 2013 | pmid = 23779105 | pmc = 3789992 | doi = 10.1074/jbc.m113.475798 | doi-access = free }}

= Mechanism of action =

Some studies have shown that principal antitubercular action of PAS occurs via poisoning of folate metabolism.{{cite journal | vauthors = Minato Y, Thiede JM, Kordus SL, McKlveen EJ, Turman BJ, Baughn AD | title = Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance | journal = Antimicrobial Agents and Chemotherapy | volume = 59 | issue = 9 | pages = 5097–5106 | date = September 2015 | pmid = 26033719 | pmc = 4538520 | doi = 10.1128/AAC.00647-15 }}

= Resistance =

It was initially thought that resistance of 4-aminosalicylic acid came from a mutation affecting dihydrofolate reductase (DHFR). However, it was discovered that it was caused by a mutation affecting the dihydrofolate synthesis (DHFS) enzyme activity. The mutations of isoleucine 43, arginine 49, serine 150, phenylalanine 152, glutamate 153, and alanine 183 were found to affect the binding pocket of the dihydrofolate synthase enzyme. This will reduce the ability for hydroxy-H₂Pte to bind to dihydrofolate synthase and preventing 4-aminosalicylic acid from poisoning the folate metabolism.{{cite journal | vauthors = Zhao F, Wang XD, Erber LN, Luo M, Guo AZ, Yang SS, Gu J, Turman BJ, Gao YR, Li DF, Cui ZQ, Zhang ZP, Bi LJ, Baughn AD, Zhang XE, Deng JY | title = Binding pocket alterations in dihydrofolate synthase confer resistance to para-aminosalicylic acid in clinical isolates of Mycobacterium tuberculosis | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 3 | pages = 1479–1487 | date = 1 January 2014 | pmid = 24366731 | pmc = 3957869 | doi = 10.1128/aac.01775-13 }}

History

4-Aminosalicylic acid was first synthesized by Seidel and Bittner in 1902. It was rediscovered by the Swedish chemist Jörgen Lehmann upon the report that the tuberculosis bacterium avidly metabolized salicylic acid.{{cite journal | vauthors = Lehmann J | title = The treatment of tuberculosis in Sweden with para-aminosalicylic acid; a review | journal = Diseases of the Chest | volume = 16 | issue = 6 | pages = 684–703, illust | date = December 1949 | pmid = 15396516 | doi = 10.1378/chest.16.6.684 }} Lehmann first tried PAS as an oral TB therapy late in 1944. The first patient made a dramatic recovery.{{cite journal | vauthors = Lehmann J | title = Para-aminosalicylic acid in the treatment of tuberculosis | journal = Lancet | volume = 1 | issue = 6384 | pages = 15–16 | date = January 1946 | pmid = 21008766 | doi = 10.1016/s0140-6736(46)91185-3 }} The drug proved better than streptomycin, which had nerve toxicity and to which TB could easily develop resistance. In 1948, researchers at Britain's Medical Research Council demonstrated that combined treatment with streptomycin and PAS was superior to either drug alone, and established the principle of combination therapy for tuberculosis.{{cite journal | vauthors = Fox W, Ellard GA, Mitchison DA | title = Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications | journal = The International Journal of Tuberculosis and Lung Disease | volume = 3 | issue = 10 Suppl 2 | pages = S231–S279 | date = October 1999 | pmid = 10529902 }}

Other names

4-Aminosalicylic acid has many names including para-aminosalicylic acid, p-aminosalicylic acid, 4-ASA, and simply P.{{medcn|date=April 2020}}