4-Aminosalicylic acid

The main use for 4-aminosalicylic acid is for the treatment of tuberculosis infections. In the United States, 4-aminosalicylic acid is indicated for the treatment of tuberculosis in combination with other active agents. 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. but has been superseded by other drugs such as sulfasalazine and mesalazine.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. ==Side effects==

Gastrointestinal side-effects (nausea, vomiting, diarrhoea) are common; the delayed-release formulation is meant to help overcome this problem. 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. Thyroid goitre is also a side-effect because aminosalicylic acid inhibits the synthesis of thyroid hormones. Drug interactions include elevated phenytoin levels. When taken with rifampicin, the levels of rifampicin in the blood fall by about half. It is not known whether it will harm an unborn baby. ==Pharmacology==

With heat, 4-aminosalicylic acid is decarboxylated to produce CO2 and 3-aminophenol. 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. Mechanism of action Some studies have shown that principal antitubercular action of PAS occurs via poisoning of folate metabolism. 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. == History ==

4-Aminosalicylic acid was first synthesized by Seidel and Bittner in 1902. Lehmann first tried PAS as an oral TB therapy late in 1944. The first patient made a dramatic recovery. The manner in which Lehmann discovered the TB indication for PAS was salient in the history of drug discovery because it was a rare example in which a person mentally postulated the exact molecule for a drug based on their acquired knowledge of the biochemical behaviour of an analogue of the molecule. 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. ==Other names==

4-Aminosalicylic acid has many names including para-aminosalicylic acid, p-aminosalicylic acid, 4-ASA, and simply P. == References ==