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The relative bioavailability of commercially available preparations of aminosalicylic acid and its sodium, potassium, and calcium salts is presented. The doses administered were 4 g for aminosalicylic acid and 2.8, 2.6, and 2.6 g for the sodium, potassium, and calcium salts, respectively. Absorption from tablets of the salts was rapid and complete, but absorption of the free acid was only 77% of the dose. Dissolution of the relatively insoluble acid is a rate-limiting factor in absorption. Although the amount of free acid administered and the absolute amount absorbed were higher, the area under the plasma concentration curve of unmetabolized drug was less than for the salts. This is attributed to capacity-limited acetylation of drug, especially during the first pass. The amount of bioavailable drug is dependent on the rate of metabolism and, hence, the rate of absorption.

It was shown that on adding copolymers of methylacrylate and anthranilic, salicylic and para -aminosalicylic acids to triacetylcellulose, a light stabilization of the polymer is achieved which is resistant to aqueous treatments.

Summary Two simple qualitative tests for PAS in the urine are described, together with the results of both tests in 143 urines from 28 hospital patients receiving various standard dosage schedules of the drug. All urines were positive by both methods. The relative sensitivities of the tests were compared by examining two-hourly specimens of urine from 4 patients, who had received a single 5 g. dose of PAS. The greater sensitivity of the ferric chloride method was demonstrated by its ability to detect this drug in the urine for at least eighteen hours after ingestion and when traces of less than 1 mg. per 100 ml. were present. The hypochlorite method might fail to detect PAS in urine passed sixteen hours or more after the single dose and unless 4·5–5 mg. per 100 ml. of the drug were present in the urinary samples. Urines obtained from 100 consecutive out-patients, irrespective of their drug intake, were tested by both methods. Errors due to drugs known to interfere with the specificity of the tests occurred on 5 occasions with the ferric chloride test, and on one occasion with the hypochlorite test. These errors could be eliminated by using both tests. A further 100 urines from out-patients supposed to be on PAS therapy were similarly tested. Owing to the ability of the ferric chloride test to detect the drug taken on the day prior to the urinary examination and the greater likelihood of out-patients having consumed drugs producing ‘false’ positive reactions with this test, it was concluded that the hypochlorite method gave a more reliable indication of whether PAS had been taken on the morning of the patient's attendance at the clinic. An alarmingly high proportion (24 per cent) of the tests indicated that PAS therapy had not been taken on the day of the examination.

Summary From November 1960, a nation-wide tuberculosis case-finding programme was carried out in Western Samoa for 29 months. 113,657 persons were registered. Of the 55,702 children aged 6 months to 14 years, 93·9% had completed tuberculin tests with 1 TU PPD RT23 with Tween 80.4·7% had a transverse diameter of induration of 10 mm. or more. Of 56,060 persons, 15 years and over, 92·9% were x-rayed. 2·7% showed significant pulmonary lesions, suggestive of pulmonary tuberculosis. 0·6% of the total x-rayed showed positive sputum smear or laryngeal swab culture. The results of one year's domiciliary chemotherapy in Savai'i Island showed fairly satisfactory bacteriological and radiographical results. 67% showed radiographic improvement among the 337 x-rayed. Among the 78 with positive bacteriological examinations before treatment 66 (85%) became negative on both smear and culture. The 111 patients not reviewed include 27% of initially sputum-positive cases and 43% of advanced cases. This indicates a great source of danger to the public health and indicates the area for improvement. It is largely due to frequent population movements (10–30% per annum), frequent changes in name, and lack of understanding and even fear of the tuberculosis control programme.

A series of eighteen metal chelates and complexes of some a -amino acids, peptides, isonicotinoyl hydrazide, p -aminosalicylic acid, p -acetylaminobenzal thiosemicarbazone, and biotin were screened for antibacterial activity against ten microorganisms. Quantitative tests were carried out on six of these compounds by a modified serial tube dilution method; these compounds were the copper complex and chelate of PASA, cobalt chelates of INH and methionine, and copper chelates of glycyl-DL-alanine and biotin. Evidence indicated that the complexes of methionine and biotin were more active than the metal ions, but the action of the chelates of the antitubercular agents appeared to depend in part on dissociation of the chelates.

Summary o (1) 7 cases of tuberculous disease undergoing sodium PAS therapy either singly or in combination with other chemotherapeutic agents, who developed psychotic symptoms during the course of treatment are described. (2) The symptoms developed after a minimum period of two weeks but may be delayed until as late as five months. (3) The mental syndrome took the form of a paranoid or schizoid reaction type of toxic psychosis. (4) It is suggested that the cause of the symptom complex is due primarily to a salicylate stimulation of the pituitary. (5) An explanation of the syndrome is postulated based on Selye's suggestion of the general adaptation syndrome. (6) A further concept of the action of sodium PAS in the treatment of pulmonary tuberculosis is postulated.

Slices of liver and kidney from rats and guinea pigs are active in synthesizing peptide-linked products when glutamic acid, glutamine or asparagine is incubated with benzoic acid, phenylacetic acid or aminosalicylic acid. The peptide-linked products can be deterted by paper chromatography.

Summary 1 Acute and chronic toxic doses of p-aminosalicylic acid to mice have been determined by various routes of administration. 2 Prolonged oral and subcutaneous administration to mice produces some pathological effects on the liver and kidney. 3 A method is described for the estimation in blood and urine, and blood levels curves are given in mice and man. 4 Caronamide has no effect on the blood levels in man. 5 It appears to have no hypoprothrombinaemic or antipyretic effect in rabbits. 6 It exerts a protective effect in mice infected with M. tuberculosis H37 Rv, but it is not so effective an antitubercular drug as streptomycin. My grateful thanks are due to my colleagues Mr. A. S. Beach, Mr. J. H. Marvin, Mr. T. R. Middleton and Mr. C. R. B. Williamson for their assistance in this work, and I am indebted to the Directors of British Chemicals and Biologicals Ltd., for permission to publish this paper.

Summary A comparative pilot scale study has been attempted of the value of two analogues of isoniazid, o-hydroxybenzal isonicotinyl hydrazide and glucuronolactone isonicotinyl hydrazide, and isoniazid itself. 55 patients were included and were allotted by random method to one of these groups. All patients also received PAS. There were few toxic reactions. The two analogues, in the doses used, appeared to equal isoniazid in therapeutic effect though we feel some reservations in the case of glucuronolactone isonicotinyl hydrazide.

1. The ester glucuronide of p-aminosalicylic acid was isolated from the urine of rabbits administered with p-aminosalicylic acid. The methyl acetyl derivative of this compound was identified with synthetic methyl (2-acetoxybenzoyl-4-acetamido-2, 3, 4-tri-O-acetyl-β-D-glucopyranosid) uronate. 2. The ester glucuronide of salicylic acid was isolated as methyl (2-acetoxybenzoyl-2, 3, 4-tri-O-acetyl-β-D-glucopyranosid) uronate from the urine of rabbits administered with salicylic acid, and the structure was confirmed with the synthetic compound.

(1954). Lupus of Mucous Membranes Treated with Antibiotics. Acta Oto-Laryngologica: Vol. 43, No. sup118, pp. 173-179.

NOTWITHSTANDING the great strides forward in the treatment of tuberculosis two questions concerning the treatment of the relatively rare tuberculous pericarditis remain to be answered: What is the effectiveness of chemotherapy on the course of the disease, and what are the criteria for supplementing the treatment with pericardiectomy? The purpose of this paper is to attempt to answer these questions through an analysis of 44 cases of treated tuberculous pericarditis culled from the records of the Veterans Administration. Seven to 10 per cent of all type's of pericarditis are caused by the tubercle bacillus, and another 10 per cent are . . .

In a pilot study to observe the rate of development of resistant strains of tubercle bacilli by the use of streptomycin and para-aminosalicylic acid, it appears that development of such strains is delayed. Streptomycin-resistant tubercle bacilli are sensitive to para-aminosalicylic acid in vitro . Strains of tubercle bacilli in three patients appeared to develop resistance to para-aminosalicylic acid. This matter needs further investigation. Fifteen grams of para-aminosalicylic acid per day caused gastro intestinal disturbance with nausea, emesis and diarrhea. Blood levels ranged from 3 to 7 mgm. per cent four hours after PAS administration. Whether certain specific blood level maintenance is required for therapeutic efficacy requires further study. Prothrombin time was not altered by the above dosage.

SummaryIn vitro studies with rat femora and mouse embryonic radii showed a reduced uptake of radioproline into the bone collagen when p-aminosalicylic acid (approximately 10-2 M) and acetylsalicylic acid (aspirin; approximately 10-3 M) were added to the incubation medium. Autoradiographic examination of rat femora from p-amino-salicylate treated animals also indicated reduced H3-proline uptake by the osteoblasts compared to control animals. Electron microscopic examination of metaphyseal bone from p-aminosalicylate treated and control rats showed cytological alteration of the osteoblasts after p-aminosalicylate treatment.

A relatively simple spectrophotometric method is described for the determination of PAS and isoniazid blood levels. The method is based upon the formation of soluble yellow compounds resulting from the addition of vanillin solution to a solution of PAS or isoniazid at a controlled pH. Recoveries of known quantities added to plasma demonstrate that the method is accurate to ±0.9 per cent for PAS and ±0.4 per cent for isoniazid.

Hubbard, Jerry S. (Oklahoma State University, Stillwater), and Norman N. Durham . Competitive relationship between protocatechuic acid and p -aminosalicylic acid for a cellular transport mechanism. J. Bacteriol. 82: 361–369. 1961.—The oxidation of protocatechuic acid by a Flavobacterium is inhibited by p -aminosalicyclic acid regardless of whether the organism is grown on protocatechuic acid or sequentially induced to protocatechuic acid by growth on p -aminobenzoic acid. Depletion of the substrate from the medium by the cell suspension is dependent, within defined limits, on the inhibitor to substrate ratio, and the inhibition can be overcome by addition of excess substrate. However, this competitive effect is not observed in high inhibitor to substrate ratios. p -Aminosalicylic acid did not affect the rate or extent of oxidation, carbon dioxide evolution, or formation of β-ketoadipic acid during degradation of protocatechuic acid by cell extracts. The results suggest that p -aminosalicylic acid antagonizes the oxidation of protocatechuic acid by the cell suspension by competing with the substrate for a specific transport mechanism, thereby regulating the entry and internal accumulation of the substrate. The lack of a competitive effect in high inhibitor to substrate ratios could be interpreted as an indication that the mechanism for accumulating the substrate may consist of more than one active transport system.

Therapeutical out-look : Desolate cases may become curable. Lobectomy for cavitary tuberculosis without, before or after thoracoplasty, as a rule will be superfluous. Giant cavities or, destructive lesions, badly situated with a view to collapse therapy, shrink by preliminary cavernostomy, so that finally the thoracoplasty becomes possible and efficacious. In the usual indication field of thoracoplasty the plasty may be avoidable in a way that some of these cases recover by an accessory phrenic nerve crush plus pneumoperitoneum, and others by cavernostomy alone. Pregnant women with cavitary tuberculosis may recover and have a healthy baby. And even more, considering the epidemic aspect, the public health as well as state economy, the method seems to be of value.

Cupric and ferrous chelates of p -aminosalicylic acid have been isolated and characterized, and their physical and antitubercular properties compared with those of a previously isolated cupric complex. The cupric chelate showed much higher in vivo antitubercular activity in mice than the cupric complex, and was found to be about thirty times more fat-soluble than the cupric complex. The ferrous chelate was not appreciably active against experimental tuberculosis. The effect of these findings in explaining a possible mechanism of the antitubercular activity of p -aminosalicylic acid is discussed.

Summary o (1) The results obtained (i) at the end of a 90-day course of daily streptomycin (1 gramme) and PAS (15 grammes) and (ii) following a twelve months' period after the start of treatment, in 395 unselected patients with various forms of pulmonary tuberculosis, occurring mainly in young soldiers, have been reviewed. (2) The criteria of assessment, classification and response have been described, and the results have been analysed in detail. (3) Following chemotherapy cavity closure was attained in 30 per cent, sputum conversion in 82 per cent, a marked or moderate radiological response in 84 per cent, and a good or moderate clinical improvement took place in 89 per cent. (4) At the end of one year's total treatment after additional therapeutic procedures 87 per cent of all cavities were closed, sputum conversion occurred in 93 per cent, 86 per cent were much or moderately improved, and 70 per cent had been discharged home quiescent after an average of nine months' hospital treatment. (5) Of the various procedures adopted following chemotherapy 84 per cent produced a satisfactory result.

Summary A case of severe hepatic injury due to PAS hypersensitivity is presented. The clinical course and detailed biochemical investigations are described. After complete recovery from the initial liver impairment, a challenge dose of PAS was given. Its effect upon the liver was assessed by the use of multiple enzyme studies on serial blood specimens. Evidence of liver cell damage after a 3 gm. dose of PAS was indicated by significant rises in the activities of serum glutamicpyruvic transaminase, isocitric dehydrogenase, sorbitol dehydrogenase, and adenosine deaminase. It is suggested that the above enzyme determinations might be used as an effective screening test for detecting hepatic complications in a suspected PAS hypersensitivity reaction. The clinical response, however, still remained the primary indication for immediate withdrawal of the drug.

In an acidic aqueous solution, p -aminosalicylic acid decarboxylates on boiling. The amount of carbon dioxide formed can be measured by using the simple distillation method earlier suggested by the authors. Decarboxylation also yields m -aminophenol and on brominating this product, tribromoresorcinol and ammonia are obtained. The quantity of ammonia formed can be measured by distillation, while the bromination reaction makes it possible to carry out a bromatometric measurement.

Summary The development of isoniazid resistance accompanied by radiographic or bacteriological evidence of relapse has been investigated in a series of 12 out-patients prescribed apparently adequate combinations of sodium PAS and isoniazid dispensed in the same cachet. The emergence of drug resistance was believed to be due to irregular ingestion of the cachets. If relapse, for which there is no other satisfactory explanation, occurs during treatment with sodium PAS and isoniazid in adequate dosages, the drugs should be discontinued temperarily until sensitivity results are obtained. Otherwise loss of sensitivity to PAS may also develop, as occurred in 4 of the 12 individuals in this series.

Summary A controlled comparison has been made of streptomycin plus pyrazinamide (46 patients) and streptomycin plus PAS (36 patients) in the retreatment of patients with pulmonary tuberculosis. The patients had either failed to attain bacteriological quiescence on isoniazid alone or had relapsed bacteriologically after attaining quiescence; all were excreting strains of tubercle bacilli resistant to isoniazid but sensitive to streptomycin and PAS at the start of the trial. The disease status at 1 year was assessed in 41 patients on pyrazinamide and 24 on PAS, and of these, 29 (71%) and 12 (50%), respectively, had bacteriologically quiescent disease. Seven patients (2 on pyrazinamide, 5 on PAS) had their treatment terminated for toxicity, 1 due to a pyrazinamide polyarthritis, 2 on account of hypersensitivity to PAS, and 4 (1 on pyrazinamide, 3 on PAS) because of streptomycin toxicity. Nine patients (2 on pyrazinamide, 7 on PAS) became unco-operative and stopped treatment, and 2 patients (on pyrazinamide) died, 1 of a non-tuberculous condition. Thus, streptomycin plus pyrazinamide was slightly more effective therapeutically than streptomycin plus PAS and was not more toxic or less acceptable to the patients.

The presence of a large excess of p-aminosalicylic acid prevents the direct application of Vierordt’s spectrophotometric method to the determination of isoniazid in tablets. The method can, however, be applied after the bulk of the p-aminosalicylic acid has been removed with ether. The extinction of the aqueous phase containing all the isoniazid and some of the p-aminosalicylic acid is then determined at two wavelengths and the concentration of isoniazid calculated therefrom.

Summary A case of drug-induced jaundice (paraaminosalicylic acid and possibly isonicotinic acid hydrazide) was investigated with immunochemical and immunocytochemical studies. The serum of the patient had complement fixing type autoantibodies against normal liver tissue. The autoantibodies appeared in 2 groups: one type moved in α 1 -globulins and reacted with the cytoplasm of the parenchymal cells; the other type was found in the γ-globulins and reacted with the cytoplasm of the bile duct cells.

1. The use of antibiotics in the treatment of tuberculosis should follow the same basic requirements as the use of antibiotics against any other bacterial disease. An adequate period of treatment with the three drugs lies between six months and one year. 2. Three drug therapy of tuberculosis (streptomycin, PAS and isoniazid) offers a slightly higher conversion rate in the first six month period than previously reported, with the additional advantage of having no change in bacterial sensitivity until after the six month period. 3. All toxic reactions to the three drugs occur during the first 50 days of treatment except for nephritis which may appear later, and it occurred in three out of four patients who had dihydrostreptomycin after a dermatitis medicamentosa from streptomycin. 4. Resectional surgery four to six months after starting chemotherapy is advisable and safe on the three drug routine. 5. Marked restriction of activity is not necessary during hospitalization and full activity does not cause reactivation after discharge. 6. This program of three drugs with early surgery is as effective in extra-pulmonary disease as in pulmonary, and there are no racial differences in regard to response. 7. This program has received splendid patient cooperation. 8. It has left no chronic tuberculosis.

1) Experience with para-aminosalicylic acid (PAS) is evaluated in 30 patients five of whom received only this drug, 12 concurrently with streptomycin and 13 after streptomycin had been discontinued. 2) The daily dose was 9 gms. in four divided doses. The total dose averaged 683.4 gms.; the smallest being 297 gms. and the largest 1288 gms. 3) PAS is not as effective as streptomycin. Best results are obtained when it is used in conjunction with the latter. Forty per cent of the patients improved who received only PAS, 72.7 per cent when it was utilized in conjunction with streptomycin and 61.6 per cent when it followed the use of streptomycin. 4) Criteria for improvement included changes in clinical picture, serial roentgenograms of the chest, blood counts and sedimentation rates. 5) Toxic effects were judged by frequent liver function tests and hemograms. Transient nausea and one case of transient leukopenia and granulocytopenia were the only toxic effects observed.

Summary An investigation has been undertaken to determine the level of bacterial resistance to streptomycin, PAS and isoniazid in cases of previously untreated pulmonary tuberculosis in Ashanti. Of 343 positive cultures tested, 53 (15.4 per cent) showed some degree of resistance to either streptomycin, PAS or isoniazid. Resistance to a single drug was most common; resistance to two or three drugs was found in 32 per cent of all resistant cultures. Isoniazid resistance was most common, but was almost equalled by streptomycin resistance. A rise of 10 per cent was demonstrated in under one year. A comparison is made between the resistance figures in Ashanti and those published for the United Kingdom, Madras and East Africa. Reasons for the differences are postulated. Suggestions are given on how current practice in West Africa might be modified to alleviate the problem.

Summary1. Administration of PAS to rats over a 2-week period produced goiter associated with diminished I131 uptake by the thyroid gland. 2. No effect on the pituitary-adrenal axis was observed. 3. Elevation of liver glycogen concentration was noted in all PAS-treated animals.