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Paser (Aminosalicylic Acid) - Description and Clinical Pharmacology

 
 



DESCRIPTION

PASER granules are a delayed release granule preparation of aminosalicylic acid (p-aminosalicylic acid: 4-aminosalicylic acid) for use with other anti-tuberculosis drugs for the treatment of all forms of active tuberculosis due to susceptible strains of tubercle bacilli. The granules are designed for gradual release to avoid high peak levels not useful (and perhaps toxic) with bacteriostatic drugs. Aminosalicylic acid is rapidly degraded in acid media; the protective acid-resistant outer coating is rapidly dissolved in neutral media so a mildly acidic food such as orange, apple or tomato juice, yogurt or apple sauce should be used.

Aminosalicylic acid (p-aminosalicylic acid) is 4-Amino-2-hydroxybenzoic acid. PASER granules are the free base of aminosalicylic acid and do NOT contain sodium or a sugar. The molecular formula is C7H7NO3 with a molecular weight of 153.14. With heat p-aminosalicylic acid is decarboxylated to produce CO2 and m-aminophenol. If the airtight packets are swollen, storage has been improper. DO NOT USE if packets are swollen or the granules have lost their tan color and are dark brown or purple.

The structural formula is:

PASER granules are supplied as off-white tan colored granules with an average diameter of 1.5 mm and an average content of 60% aminosalicylic acid by weight. The acid resistant outer coating will be completely removed by a few minutes at a neutral pH. The inert ingredients are:

colloidal silicon dioxide

dibutyl sebacate

hydroxypropyl methyl cellulose

methacrylic acid copolymer

microcystalline cellulose

talc

The packets contain 4 grams of aminosalicylic acid for oral administration three times a day by sprinkling an apple sauce or yogurt to be eaten without chewing. Suspension in an acidic fruit drink such as orange juice or tomato juice will protect the coating for at least 2 hours. Swirling the juice in the glass will help resuspend the granules if they sink.

CLINICAL PHARMACOLOGY

Mechanism of Action: Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) and/or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.

Characteristics: The two major considerations in the clinical pharmacology of aminosalicylic acid are the prompt production of a toxic inactive metabolite under acid conditions and the short serum half life of one hour for the free drug. Both are discussed below.

After two hours in simulated gastric fluid, 10% of unprotected aminosalicylic acid is decarboxylated to form meta-aminophenol, a known hepatotoxin. The acid-resistant coating of the PASER granules protects against degradation in the stomach. The small granules are designed to escape the usual restriction on gastric emptying of large particles. Under neutral conditions such as are found in the small intestine or in neutral foods, the acid-resistant coating is dissolved within one minute. Care must be taken in the administration of these granules to protect the acid-resistant coating by maintaining the granules in an acidic food during dosage administration. Patients who have neutralized gastric acid with antacids will not need to protect the acid resistant coating with an acidic food since no acid is present to spoil the drug. Antacids may influence the absorption of other medications and are not necessary for PASER consumed with an acidic food.

Because PASER granules are protected by an enteric coating absorption does not commence until they leave the stomach; the soft skeletons of the granules remain and may be seen in the stool.

Absorption and excretion: In a single 4 gram pharmacokinetic study with food in normal volunteers the initial time to a 2 µg/mL serum level of aminosalicylic acid was 2 hours with a range of 45 minutes to 24 hours; the median time to peak was 6 hours with a range of 1.5 to 24 hours; the mean peak level was 20 µg/mL with a range of 9 to 35 µg/mL; a level of 2 µg/mL was maintained for an average of 7.9 hours with a range of 5 to 9; a level of 1 µg/mL was maintained for an average of 8.8 hours with a range of 6 to 11.5 hours. The recommended schedule is 4 grams every 8 hours.

80% of aminosalicylic acid is excreted in the urine, with 50% or more of the dosage excreted in acetylated form. The acetylation process is not genetically determined as is the case for isoniazid. Aminosalicylic acid is excreted by glomerular filtration; although previously reported otherwise, probenecid, a tubular blocking agent, does not enhance plasma concentration. In a 1954 study thyroxine synthesis but not iodide uptake was reported reduced about 40% when the sodium salt (not PASER granules) of aminosalicylic acid was administered one hour before radio-iodine; the sodium salt typically produces a serum level over 120 µg/mL at one hour lasting one hour. Occasional goiter development can be prevented by the administration of thyroxine but not iodide. Penetration into the cerebrospinal fluid occurs only if the meninges are inflamed.

Approximately 50-60% of aminosalicylic acid is protein bound; binding is reported to be reduced 50% in kwashiorkor.

Microbiology: The aminosalicylic acid MIC for M. tuberculosis in 7H11 agar was less than 1.0 µg/mL for nine strains including three multidrug resistant strains, but 4 and 8 µg/mL for two other multidrug resistant strains. The 90% inhibition in 7H12 broth (Bactec) showed little dose response but was interpreted as being less than or equal to 0.12-0.25 µg/mL for eight strains of which three were multi-resistant, 0.50 µg/mL for one resistant strain, questionable for four nonresistant strains and greater than 1 µg/mL for one non-resistant and three resistant strains. Aminosalicylic acid is not active in vitro against M. avium.

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