Isoniazid and para-aminosalicylic acid toxicity in 513 cases: a study including high doses of INH and gastrointestinal intolerance to PAS.

In early 1956 it was demonstrated that the combination of isoniazid (INH) and para-aminosalicylic acid (PAS) provided a superior statistically significant treatment result in far-advanced and large cavitary tuberculous lesions.’ This study made a comparison between INH-PAS, streptomycin (SM) -INH, and SM-PAS (all SM was given intermittently). This year the use of high doses of INH in the treatment of pulmonary tuberculosis was again emphasized.2 Available data indicate that PAS competes with INH in the process of acetylation of both drugs. The combination of both drugs results in a higher serum level of biologically active, free, unacetylated INH.3 Thus, by adding PAS and elevating the dose of INH to 10 or 16 milligrams per kilogram of body weight per day instead of the more usual dose of about 5 milligrams per kilogram per day, an effective serum concentration of “free” INH can be attained. It is suggested that this level be at least 0.8 micrograms per milliliter of serum six hours after one-third of the total daily dose of INH and PAS is given.4 If one accepts that INH and PAS, with more elevated doses of INH, constitute one of the most effective antituberculous chemotherapeutic drug combinations at present, then one must consider the potential effects of drug toxicity or allergy and drug intolerance. There are many reports to document the multitude of allergic or toxic reactions due to PAS.58 However, detailed studies regarding the incidence and cause of gastrointestinal intolerance due to PAS are not readily found. Many generalities can be found regarding the “accepted” high incidence of intolerance to PAS. A quoted example is, “The well known symptoms of nausea, abdominal distress, vomiting, and diarrhea are a common experience.”5 One of us has seen gastrointestinal intolerance to PAS mount as high as 50 per cent on a single tuberculosis ward. It was of interest to note that this rate was reduced to about 15 per cent when the attitude of the ward doctor toward the “inevitable intolerance to PAS” became changed. It is believed that intolerance to PAS is directly related to the purity of the drug, and the attitude of the physician prescribing the drug which induces a iatrogenie intolerance in the patient. At two recent informal “PAS Meetings,#{176} the problems of drug purity were discussed. Para-aminosalicylic acid varying in age from six months to three years was tested and revealed