4-Aminosalicylic acid

Last updated

4-Aminosalicylic acid
P-Aminosalicylic acid.svg
4-Aminosalicylic acid 3d structure.png
Clinical data
Trade names Paser, Granupas, others
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 50–60%
Metabolism liver
Excretion kidney
Identifiers
  • 4-Amino-2-hydroxybenzoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.557 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H7NO3
Molar mass 153.137 g·mol−1
3D model (JSmol)
Melting point 150.5 °C (302.9 °F)
  • OC(=O)c1ccc(N)cc1O
  • InChI=1S/C7H7NO3/c8-4-1-2-5(7(10)11)6(9)3-4/h1-3,9H,8H2,(H,10,11) Yes check.svgY
  • Key:WUBBRNOQWQTFEX-UHFFFAOYSA-N Yes check.svgY
   (verify)

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. [1] Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. [2] 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. [2] It is typically taken by mouth. [2]

Contents

Common side effects include nausea, abdominal pain, and diarrhea. [2] Other side effects may include liver inflammation and allergic reactions. [2] It is not recommended in people with end stage kidney disease. [2] While there does not appear to be harm with use during pregnancy it has not been well studied in this population. [2] 4-Aminosalicylic acid is believed to work by blocking the ability of bacteria to make folic acid. [2]

4-Aminosalicylic acid was first made in 1902, and came into medical use in 1943. [3] It is on the World Health Organization's List of Essential Medicines. [4]

Medical uses

The main use for 4-aminosalicylic acid is for the treatment of tuberculosis infections. [5] [6]

In the United States, 4-aminosalicylic acid is indicated for the treatment of tuberculosis in combination with other active agents. [6]

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. [5]

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. [7]

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. [8] PAS is always used in combination with other anti-TB drugs.[ citation needed ]

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). [9] PAS was once available in a combination formula with isoniazid called Pasinah [10] or Pycamisan 33. [11]

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. [12] [5]

Inflammatory bowel disease

4-aminosalicylic acid has also been used in the treatment of inflammatory bowel disease (ulcerative colitis and Crohn's disease), [13] 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. [14]

Side effects

Gastrointestinal side-effects (nausea, vomiting, diarrhoea) are common; the delayed-release formulation is meant to help overcome this problem. [15] 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. [16] Thyroid goitre is also a side-effect because aminosalicylic acid inhibits the synthesis of thyroid hormones. [17]

Drug interactions include elevated phenytoin levels. When taken with rifampicin, the levels of rifampicin in the blood fall by about half. [18]

The U.S. Food and Drug Administration (FDA) assigned 4-aminosalicylic acid to pregnancy category C, indicating that it is not known whether it will harm an unborn baby. [19]

Pharmacology

With heat, aminosalicylic acid is decarboxylated to produce CO2 and 3-aminophenol. [20]

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. [21]

Mechanism of action

Some studies have shown that principal antitubercular action of PAS occurs via poisoning of folate metabolism. [22]

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. [23]

History

4-aminosalicylic acid was first synthesized by Seidel and Bittner in 1902. [3] It was rediscovered by the Swedish chemist Jörgen Lehmann upon the report that the tuberculosis bacterium avidly metabolized salicylic acid. [24] Lehmann first tried PAS as an oral TB therapy late in 1944. The first patient made a dramatic recovery. [25] 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, and established the principle of combination therapy for tuberculosis. [8] [3]

Other names

Like many commercially significant compounds, 4-aminosalicylic acid has many names including para-aminosalicylic acid, p-aminosalicylic acid, 4-ASA, and simply P.[ medical citation needed ]

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Dihydrofolate reductase</span> Mammalian protein found in Homo sapiens

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene. It is found in the q14.1 region of chromosome 5.

<span class="mw-page-title-main">Trimethoprim</span> Antibiotic

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken orally.

<span class="mw-page-title-main">Streptomycin</span> Aminoglycoside antibiotic

Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is administered by injection into a vein or muscle.

<span class="mw-page-title-main">Isoniazid</span> Antibiotic for treatment of tuberculosis

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For latent tuberculosis, it is often used alone. It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi. It is usually taken by mouth, but may be used by injection into muscle.

ATC code J04Antimycobacterials is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup J04 is part of the anatomical group J Antiinfectives for systemic use.

<span class="mw-page-title-main">Rifamycin</span> Group of antibiotics

The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Sulfamethoxazole</span> Chemical compound

Sulfamethoxazole is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Escherichia coli and Listeria monocytogenes.

<span class="mw-page-title-main">Sulfasalazine</span> Chemical compound

Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is taken by mouth or can be administered rectally.

<span class="mw-page-title-main">Tuberculosis management</span>

Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB) or simply a treatment plan for TB.

<span class="mw-page-title-main">Pyrazinamide</span> Medication

Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.

<span class="mw-page-title-main">Pyrimethamine</span> Medication

Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.

<span class="mw-page-title-main">Thioacetazone</span> Chemical compound

Thioacetazone, also known as amithiozone (USAN), is an oral antibiotic which is used in the treatment of tuberculosis. It has fallen into almost complete disuse due to toxicity and the introduction of improved anti-tuberculosis drugs like isoniazid. The drug has only weak activity against Mycobacterium tuberculosis and is only useful in preventing resistance to more powerful drugs such as isoniazid and rifampicin. It is never used on its own to treat tuberculosis; it is used in a similar way to ethambutol.

<span class="mw-page-title-main">Ethionamide</span> Chemical compound

Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.

<span class="mw-page-title-main">Dihydropteroate</span> Chemical compound

Dihydropteroate is an important intermediate in folate biosynthesis. It is a pterin created from para-aminobenzoic acid (PABA) by the enzyme dihydropteroate synthase.

<span class="mw-page-title-main">Dihydropteroate synthase</span> Class of enzymes

Dihydropteroate synthase (DHPS) is an enzyme classified under EC 2.5.1.15. It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PABA precursor.

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

References

  1. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 140. hdl: 10665/44053 . ISBN   9789241547659.
  2. 1 2 3 4 5 6 7 8 "Aminosalicylic Acid". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. 1 2 3 Donald PR, Diacon AH (September 2015). "Para-aminosalicylic acid: the return of an old friend". The Lancet. Infectious Diseases. 15 (9): 1091–1099. doi:10.1016/s1473-3099(15)00263-7. PMID   26277036.
  4. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. 1 2 3 "Granupas (previously Para-aminosalicylic acid Lucane)". European Medicines Agency (EMA). 17 September 2018. Retrieved 3 April 2020.
  6. 1 2 "Paser- aminosalicylic acid granule, delayed release". DailyMed. 1 May 2010. Retrieved 3 April 2020.
  7. ↑ Mitchison DA (September 2000). "Role of individual drugs in the chemotherapy of tuberculosis". The International Journal of Tuberculosis and Lung Disease. 4 (9): 796–806. PMID   10985648.
  8. 1 2 Fox W, Ellard GA, Mitchison DA (October 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. 3 (10 Suppl 2): S231–S279. PMID   10529902.
  9. ↑ "Paser". RxList. Archived from the original on 13 September 2008. Retrieved 10 October 2008.
  10. ↑ Smith NP, Ryan TJ, Sanderson KV, Sarkany I (March 1976). "Lichen scrofulosorum. A report of four cases". The British Journal of Dermatology. 94 (3): 319–325. doi:10.1111/j.1365-2133.1976.tb04391.x. PMID   1252363. S2CID   26281951.
  11. ↑ Black JM, Sutherland IB (June 1961). "Two Incidents of Tuberculous Infection by Milk from Attested Herds". British Medical Journal. 1 (5241): 1732–1735. doi:10.1136/bmj.1.5241.1732. PMC   1954350 . PMID   20789163.
  12. ↑ "Paser: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 3 April 2020.
  13. ↑ Daniel F, Seksik P, Cacheux W, Jian R, Marteau P (May 2004). "Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis". Inflammatory Bowel Diseases. 10 (3): 258–260. doi:10.1097/00054725-200405000-00013. PMID   15290921.
  14. ↑ Jiang YM, Mo XA, Du FQ, Fu X, Zhu XY, Gao HY, et al. (June 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. PMC   4180660 . PMID   16766929.
  15. ↑ Das KM, Eastwood MA, McManus JP, Sircus W (September 1973). "Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype". The New England Journal of Medicine. 289 (10): 491–495. doi:10.1056/NEJM197309062891001. PMID   4146729.
  16. ↑ Szeinberg A, Sheba C, Hirshorn N, Bodonyi E (July 1957). "Studies on erthrocytes in cases with past history of favism and drug-induced acute hemolytic anemia". Blood. 12 (7): 603–613. doi: 10.1182/blood.V12.7.603.603 . PMID   13436516.
  17. ↑ Macgregor AG, Somner AR (November 1954). "The anti-thyroid action of para-aminosalicylic acid". Lancet. 267 (6845): 931–936. doi:10.1016/S0140-6736(54)92552-0. PMID   13213079.
  18. ↑ 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): 217–225. doi:10.1007/BF00560384. PMID   4854257. S2CID   24202603.
  19. ↑
  20. ↑ 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.
  21. ↑ Zheng J, Rubin EJ, Bifani P, Mathys V, Lim V, Au M, et al. (August 2013). "para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis". The Journal of Biological Chemistry. 288 (32): 23447–23456. doi: 10.1074/jbc.m113.475798 . PMC   3789992 . PMID   23779105.
  22. ↑ Minato Y, Thiede JM, Kordus SL, McKlveen EJ, Turman BJ, Baughn AD (September 2015). "Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance". Antimicrobial Agents and Chemotherapy. 59 (9): 5097–5106. doi:10.1128/AAC.00647-15. PMC   4538520 . PMID   26033719.
  23. ↑ Zhao F, Wang XD, Erber LN, Luo M, Guo AZ, Yang SS, et al. (1 January 2014). "Binding pocket alterations in dihydrofolate synthase confer resistance to para-aminosalicylic acid in clinical isolates of Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy. 58 (3): 1479–1487. doi:10.1128/aac.01775-13. PMC   3957869 . PMID   24366731.
  24. ↑ Lehmann J (December 1949). "The treatment of tuberculosis in Sweden with para-aminosalicylic acid; a review". Diseases of the Chest. 16 (6): 684–703, illust. doi:10.1378/chest.16.6.684. PMID   15396516.
  25. ↑ Lehmann J (January 1946). "Para-aminosalicylic acid in the treatment of tuberculosis". Lancet. 1 (6384): 15–16. doi:10.1016/s0140-6736(46)91185-3. PMID   21008766.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.