The Anti-Thyroid Action of Para-Aminosalicylic Acid

Macgregor, AlastairG.; Somner, A. R.

doi:10.1016/s0140-6736(54)92552-0

Cited by 36 publications

(12 citation statements)

References 19 publications

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“…The mechanism of hypothyroidism due to second-line anti-TB drugs is clear and it is both treatable and reversible (upon discontinuation of the offending drug)[15,16]. Even mild or subclinical hypothyroidism should not be overlooked as it may increase the risk of co-morbidities such as depression[32].…”

Section: Discussionmentioning

confidence: 99%

“…The second-line anti-TB drugs associated with hypothyroidism include ethionamide, prothionamide, and PAS[2,4,14]. These drugs can cause hypothyroidism by inhibiting thyroid hormone synthesis through a mechanism of iodine organification inhibition[15,16]. Clinical hypothyroidism presents with the following symptoms and signs: slowing in both mental and physical activities, dry skin, cold sensitivity, fatigue, muscle cramps, voice changes, and constipation[17].…”

Section: Introductionmentioning

confidence: 99%

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High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India

Andries¹,

Isaakidis²,

Das³

et al. 2013

PLoS ONE

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BackgroundAdverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients.MethodsThis was a prospective, observational cohort study, using routine laboratory data in a Médecins Sans Frontières (MSF) clinic in collaboration with Sewri TB Hospital, Mumbai, India. Hypothyroidism was defined as a thyroid stimulating hormone (TSH) result >10 mIU/L at least once during treatment. Patients having a baseline result and one additional result after 3 months were eligible for enrolment.ResultsBetween October 2006 and March 2013, 116 patients were enrolled, 69 of whom were included. The median (IQR) age was 38 years (34-43) and 61% were male. By March 2013, 37/69 (54%) had hypothyroidism after at least 90 days of treatment. Age, gender, CD4 counts and stavudine-based ART were not associated with the occurrence of hypothyroidism in multivariate models. The co-administration of PAS and ethionamide was found to double the risk of hypothyroidism (RR: 1.93, 95% CI: 1.06-3.54).DiscussionHigh rate of hypothyroidism was recorded in a Mumbai cohort of MDR-TB/HIV co-infected patients on treatment. This is a treatable and reversible AE, however, it may go undiagnosed in the absence of regular monitoring. Care providers should not wait for clinical symptoms, as this risks compromising treatment adherence. Simple, affordable and reliable point-of-care tools for measuring TSH are needed, especially in high MDR-TB burden countries. Our findings suggest the need for TSH screening at baseline, three months, six months, and every six months thereafter for HIV-infected patients on MDR-TB treatment regimens containing PAS and/or ethionamide, until newer, safer and more efficacious MDR-TB regimens become available.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India

Andries¹,

Isaakidis²,

Das³

et al. 2013

PLoS ONE

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“…It was already known that the antituberculous drug, p-aminosalicylic acid, depressed the rate of oxygen consumption in man (MacGregor and Somner, 1954) and it is interesting to note that the 5-aminosalicylic acid possessed a similar depressant property.…”

Section: Discussionmentioning

confidence: 99%

The Relative Potencies of Some Substituted Salicylic Acids as Metabolic Stimulants in the Intact Rat

Andrews

1958

British Journal of Pharmacology and Chemotherapy

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The effects of eighteen substituted benzoic acids on the rate of oxygen consumption have been studied in rats. 2: 3-Dihydroxybenzoic acid, phthalic acid and 6-methylsalicylic acid were, at the doses used, inactive; m-and p-hydroxybenzoic acid, 2:4-, 2:5-, 2:6-, 3:4-, and 3: 5-dihydroxybenzoic acid, o-aminobenzoic acid, salicyluric acid, salicylamide and 5-aminosalicylic acid decreased the rate of oxygen consumption. Only salicylic acid and o-, m-andp-cresotic acid (3-, 4-and 5-methylsalicylic acid respectively) increased the rate of oxygen consumption. Molar potency ratios of the cresotic acids as metabolic stimulants relative to salicylic acid were determined; o-cresotic acid was the most powerful with a ratio of 2.61, m, and p-cresotic acid had values of 1.78 and 1.89 respectively. Two possible explanations of the higher potencies of the cresotic acids were considered. No difference in the primary action of the drug was established by determining the effect on rate of oxygen consumption of a mixture of o-cresotic and salicylic acids. An alternative possibility was that the rates of detoxication and excretion of the cresotic acids differed among themselves and from salicylic acid. No such differences were found.It is well established that sodium salicylate, in moderate dosage, increases the rate of oxygen consumption of experimental animals (Singer, 1901 ;Reid, 1957) and man (Barbour and Devenis, 1919; Cochran, 1952).Meade (1954) found that only salicylic acid, among all the mono-and di-hydroxybenzoic acids, increased the rate of oxygen consumption of rats; m-hydroxybenzoic acid was a depressant and the other acids were inactive. Hall, Tomich, and Woollett (1954) investigated a number of antirheumatic compounds and other substances chemically related to salicylic acid. They found that only salicylic acid and acetylsalicylic acid increased the rate of oxygen consumption of rats or mice; 2:5-and 2: 6-dihydroxybenzoic acid, mand p-hydroxybenzoic acid and salicylamide were inactive.The present work compares eighteen substituted benzoic acids with respect to their ability to stimulate oxygen consumption; the relative potencies of the active compounds are compared and commented upon.The rat was chosen as the most practical experimental animal, the smallest in which changes in oxygen consumption can be easily detected over 1 hr. periods. METHODSOxygen consumption was measured with a closedcircuit manometric method described by Cameron (1958).In the first experiments Wistar albino rats weighing 230 to 290 g. were used. The animals were paired for sex and weight, and in each run one animal received the test solution while the other received an identical volume of normal saline. The drugs were administered by intraperitoneal injection as solutions of the sodium salts at pH 7 to 9; the doses administered were the highest that could be tolerated. Dose/Response Experiments. -The compounds used in these experiments were salicylic acid and o-, m-, and p-cresotic acid (3-, 4-, and 5-methylsalicylic acid respectively). Wistar ...

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“…PAS can cause hypothyroidism by inhibiting iodine organification, a necessary step in thyroid hormone synthesis (8). PAS therapy was initially discontinued after the introduction of rifampin and pyrazinamide.…”

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confidence: 99%

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Parvez

Shin

Jung

et al. 2017

Antimicrob Agents Chemother

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para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (K m values) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 M, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC 50 s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential for in vivo DDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.

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The Anti-Thyroid Action of Para-Aminosalicylic Acid

Cited by 36 publications

References 19 publications

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India

The Relative Potencies of Some Substituted Salicylic Acids as Metabolic Stimulants in the Intact Rat

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

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