Tolerance of Phenyl Para-Aminosalicylate, A Comparative Study

Tolerance of Phenyl Para-Aminosalicylate, A Comparative Study* Y. VUE, H. TSAI, M.D. Oak Terrace, Minnesota

SUMNER S. COHEN, M.D., F.C.C.P., WEN

M.D., F.C.C.P.,

AND SHIH

S

IN CE THE DISCOVERY BY LEHMANN

J

• •

of the tuberculostatic properties of para-aminosalicylic acid (PAS) and its usefulness in conjunction with streptomycin and isoniazid to prevent or delay the development of resistant strains, PAS has become indispensable in the chemotherapy of tuberculosis. But long-term oral administration of PAS entails such pronounced gastrointestinal disturbance that extended treatment often becomes difficult, sometimes impossible.t" In a previous study' we reported on a comparison of the frequency and severity of gastrointestinal symptoms associated with administration of the potassium, calcium, and sodium salts of PAS, and with an anionic exchange resin complex of PAS.** At that time, we concluded that the resin complex PAS was the besttolerated preparation, causing fewer and less severe symptoms than did the other preparations. Since then, a new PAS preparation, the phenyl ester of p-aminosalicylie acidt, which is reported to produce less side reactions while providing full therapeutic response:" has been made available. A preliminary study which we conducted" tended to confirm these findings, This paper summarizes a 28-month clinical *From the Medical Department, Glen Lake State Sanatorium. **Rezipas®, supplied through the courtesy of the Squibb Institute for Medical Research, New Brunswick, N. J. The potassium PAS was furnished through the courtesy of Eli Lilly and Company, Indianapolis, Ind. tSupplied as Pheny-PAS-Tebamin by the Medical Department of The Purdue Frederick Company, New York, N.Y. iThis series of studies was supported in part by research grants from the Medical Departments of The Purdue Frederick Company of New York, N.Y., the Squibb Institute for Medical Research, New Brunswick, N.]., and Eli Lilly and Company, Indianapolis, Ind.

379

study to evaluate tolerance of the new preparation in comparison with other forms of PAS under study at this institution.t METHODS AND MATERIALS

Phenyl p-aminosalicylate is a white crystalline substance with a solubility of 0.7 mg./I00 ml. in water and 12 mg./I00 mI. in serum, and the composition C13HIIN03' One g. provides the equivalent of 0.67 g. of PAS. Administered orally, it is hydrolyzed after absorption from the gastrointestinal tract, to release PAS. In the tolerance studies, phenyl PAS was administered three times daily in the form of a micronized, chocolate-flavored powder suspended in milk and served as an adjunct to each meal. Each dose consisted of one level tablespoon (4 g.) of the powder, providing 2.68 g. of PAS. The resin complex PAS was administered orally in doses of 6 g. four times daily, each dose providing 3 g. of PAS. The potassium, calcium, and sodium salts of PAS were administered orally four times daily in doses of three g. providing respectively, 2.01, 2.16, and 2.64 g. of PAS per dose. Most of the patients received daily doses of 4 to 5 mg. per kg. of body weight of isoniazid in conjunction with the PAS preparations. A total of 530 patients with minimal, moderately advanced, and far advanced pulmonary tuberculosis were involved in this study, of whom 119 were given phenyl PAS in the period from June 5, 1958, when the first patient was placed on that regimen, until August 25, 1960, when the study was completed. The patients were selected at random in the assignment of the type of PAS to be administered, but not all the forms of PAS were concurrently under study at one time. Under this method of

Diseues of

COHEN, VUE AND TSAI

the Chest

TABU I-A COIiPARlSON OF TBB NUIIBOJ PBRCENTAOEJ AND TyPES 01' SYMPTOIIS FOR ALL PATIENTS hCBIVlNO VAlUOU8 FORIIS OF PAS Percent Type of Symptoms No. With No. of With Symptoms Symptoms Type of PAS Mild Per cent Moderate Percent Severe Per cent Patients 119 36.97 21 17.65 19 Phenyl PAS 4415.97 4 3.36 Resin 49.31 54 36.99 17 Complex PAS 146 72 11.64 .68 1 98 54 55.10 Sodium PAS 28 28.57 19 19.39 7 7.14 38 Calcium PAS 101 63 62.38 37.62 18 17.82 7 6.93 21.43 76.19 Acid PAS 42 20 32 47.62 9 3 7.14 Potauium PAS .53 79.2415 28.30 47.17 25 3.77 42 2

selection, 146 were treated with the anionic exchange resin complex of PAS, 98 with sodium PAS, 101 with calcium PAS, 42 with acid PAS, and 53 with potassium PAS. Of the 119 patients on phenyl PAS, 21 were observed for one full year, 86 were followed through until they were discharged, for from one to 11 months. Five were removed from the study when intolerance to phenyl PAS developed. Seven others were removed through death or other causes, all unrelated to the chemotherapy. Twenty-nine of the 119 patients on phenyl PAS had received other fonns of PAS before being placed on this regimen, and of these, 26 had experienced difficulty in tolerating the previous type of PAS. For the most part, all the patients in the study were seen once a week or more by one of the staff physicians assigned to the study. Serum levels for the various types of PAS were determined in fresh blood samples taken one to four hours after administration of the morning dose of PAS. All the blood samples were assayed by the Marshall modification of the Bratton-Marshall test." In classifying the severity of side effects of the various forms of PAS, the following criteria were used: mild: transient symptoms; moderate: partially incapacitating symptoms, requiring the temporary discontinuance and/or reduction of PAS dosage; severe: symptoms preventing the patient from taking food and/or medications, necessitating permanent discontinuance of the PAS.

RESULTS

Tolerance: Table 1 summarizes the observations regarding tolerance made in this study. It will be noted that only 44 (36.97 per cent) of 119 patients taking phenyl PAS showed any untoward symptoms. This figure is significantly lower than the next higher one on the scale, which shows 72 (49.31 per cent) patients with symptoms out of 146 patients taking resin complex PAS. Of the 44 patients on phenyl PAS who showed side reactions, 21 had mild symptoms, 19 moderate, and four severe symptoms. Detailed data on these symptoms are shown in Table 2. Nausea was the most frequent complaint, with 24 (20.1 7 per cent) of the 119 patients on phenyl PAS reporting this symptom, and was followed in point of frequency by gastrointestinal discomfort, with 13 (10.92 per cent) and the same number reporting diarrhea. 2-SYMPTOIIS RBPOaTED Poa 119 PATlBNT8 RECEIVINO PHENYL PAS (Number of Patients Showing Symptoms: 44)

TABLE

No. With Symptoms 24 9 13

Nauaea Vomiting Diarrhea Anorexia Gas Pain Burning Gastrointestinal

Discomfort S.U.G.I.*

8

5 4 3

13 6t

Severity of Symptoms Mild Moderate Severe 12 11 1 441 6 6 1

6

2

0

4

0

0

8 3

4 3

1 0

302

300

*Symptoms unrelated to the gutrointestinalaystem. patients with dermatologic aysmp~ one with vertigo.

t Five

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TOLERANCE OF PHENYL PAS

TABLE 3-RESULTS OF CHANGE TO PHENYL PAS WITH 26 PATIENTS WHO EXPElUENCED DIFFICULTY IN TOLERATING OTHER FORMS OF PAS No Improve- Improvement ment with with Phenyl Phenyl PAS Previous PAS PAS No. 10· 11 Acid PAS It 4 1 Sodium PAS 5 4 o 4 Calcium PAS Resin Complex PAS 5 4 1 Potassium PAS 1 1 0 Totals 26 23 3 ·One patient intolerant to calcium PAS and resin complex PAS as well as to acid PAS. One patient intolerant also of sodium PAS. tOne patient showed moderate symptoms on 10dium, acid, and phenyl PAS.

Of the 29 patients who had received one or more other forms of PAS before being placed on phenyl PAS, 23 showed improvement in tolerance, three showed no improvement, and three showed no untoward symptoms on either form. The results for the 26 patients who had shown intolerance before being changed to phenyl PAS are shown in Table 3. Five cases of intolerance to phenyl PAS were encountered. In one case there were numerous episodes of nausea and vomiting, with complaints of excessive gas. This patient was also unable to tolerate either calcium PAS or resin complex PAS. In a second case phenyl PAS was discontinued after two days because of severe diarrhea and some gastrointestinal discomfort. In

the third case, gas, burning, and gastrointestinal discomfort were reported. This patient was changed to resin complex PAS, and on this regimen only mild, occasional gas and discomfort were reported. In a fourth instance of side reactions, diarrhea, anorexia, and severe nausea and vomiting were reported. A change to sodium PAS did not relieve these conditions, and a reduced dosage of calcium PAS was substituted, which the patient was able to tolerate well. The fifth patient showed nausea and discomfort on acid PAS and sodium PAS. When changed to phenyl PAS, the symptoms increased, and although they were classified as moderate, their frequency and persistence necessitated discontinuance of the medication. Absorption: A total of 201 determinations of PAS blood serum levels, at one, two, three, and four hours after the morning ingestion of 4 g. of phenyl p-aminosalicylate, were made on 99 of the 119 patients receiving this medication. Average levels at these hours were, respectively, 1.73, 1.55, 1.16, and 0.19 mg. per 100 ml. These levels are low in comparison with those obtained after ingestion of the other forms of PAS studied, which we have reported previously.' There was no indication, however, that the levels obtained with phenyl PAS were not adequate for therapeutic response. The serum levels were in nearly all cases consistent, and an analysis of 27 cases initially treated with phenyl PAS in this study showed clinical

TABLE 4--RESULTS FOLLOWING PHENYL PAS THERAPY Bacteriologic Change:

2 Months

4 Months

Cases Negative At· 6 Months 8 Months

10 Months

12 Months

Minimal Cases 2/2 2/2 1/1 2/2 Mod. Advanced Cases 23/25 24/25 22/22 19/19 13/13 2/2 Far Advanced Cases 7/10 7/10 7/10 5/7 3/4 2/3 Moderate and Pronounced Improvement on Roentgenologic Examinationt Minimal Cases 2/2 2/2 2/2 Mod. Advanced Cases 13/24 20/24 18/20 12/14 8/10 Far Advanced Cases 8/9 8/9 8/8 7/8 4/5 2/2 ·Cases followed for full time of residence. t35 cases followed for full time of residence (24 cases) or until the time of resection (11 cases).

Diseases of the Chest

COHEN, YUE AND TSAI results (Table 4) from the points of view of both bacteriologic change and roentgenologic examination, that compared favorably with those previously reported by us in studies of other types of PAS. SUMMARY AND CONCLUSIONS 1. Observation of the effects of treatment with the phenyl ester of p-aminosalicylic acid of 119 patients with pulmonary tuberculosis was conducted for periods ranging from one to 12 months. Comparisons of tolerance were made with sodium, potassium, and calcium p-aminosalicylates, resin complex of p-aminosalicylic acid, and p-aminosalicylic acid. A total of 530 patients was included in the comparative study. 2. Phenyl p-aminosalicylate was unusually well tolerated; only 36.97 per cent of the patients under this treatment developed symptoms of any type, and of these symptoms better than 90 per cent were mild or moderate. In this study, the PAS form second in degree of tolerance was the resin complex PAS, with 49.31 per cent of patients showing untoward symptoms. 3. While serum blood levels of PAS recorded for 99 of the 119 patients receiving phenyl PAS were somewhat lower than those obtained with the other types of PAS studied, the results, determined clinically and by roentgenologic examination, compare favorably with those obtained with other forms of PAS and reported previously. RESUMEN y CoNCLUSIONES

1. La observaci6n de los efectos del tratamienfenllico del acido paraminosalidto con el ~ster lico en 119 enfermos con tuberculosis pulmonar se condujo por perlodos de I a 12 meses. Las comparaciones de la tolerancia se hicieron con el sodio, potasio, calcio p-arninosalicilatos, resinas complejas del acido paraminosalidlico y acido paraminosalidlico. Un total de 530 enfermos se incluy6 en este estudio comparativo. 2. EI fenil paraminosalicilato fue inusitadamente bien tolerado; s610 36.97 por ciento de los enfermos bajo este tratamiento desarrollaron sintom as de cualquier tipo, y de estos sintornas menos del 90 por ciento fueron moderados, 0 muy ligeros. En este estudio, la mejor tolerancia fue a la resina del PAS, con 49.31 por ciento de

enfermos mostrando efectos indeseables. 3. Si bien el 99 por ciento de los 119 enfermos que recibieron fenil PAS fueron mas bajos que los obtenidos con otros tipos de PAS estudiados, los resultados, determinados cUnicamente y por examen radiol6gico, se comparan favorablemente con los obtenidos con otras formas de PAS que ya se han relatado antes. RESUME

1. L'observation des effets du traitement par l'ester phenyl de I'acide para-aminosalicylique fut conduite chez 119 malades atteints de tuberculose pulmonaire pendant des periodes allant de un a douze mois. La comparaison des tolerances fut faite avec les para-aminosalicylates de sodium, de potassium, de calcium, Ie complexe r~ine de l'acide p-aminosalicylique, et l'acide p-aminosalicylique. Un total de 530 malades fut compris dans I'etude comparative. 2. Le p-arninosalycilate phenyl fut de fac;on 36,97% seulement des inattendue bein tol~r~: mala des sous ce traitement montrerent des symptomes de caracteres variables, et parmi ces symptomes, plus de 90% furent faibles ou moderes. Dans cette ~tude, la frome de P.A.S. la mieux tol~r~e ensuite fut Ie complexe resine du P.A.S., avec lequel 49,31 % de malades montrerent des signes de toxicite, ~ Tandis que les taux de P.A.S. dans Ie serum sanguin enregistres pour 99 sur les 119 malades recevant du P.A.S. phenyl se montrerent quelque peu plus bas que ceux obtenus avec les autres les r~sultats, d~termin~s types de P.A.S. ~tudi~s, cliniquement et par l'examen radiologique, se com parent favorablement a ceux obtenus avec d'autres formes de P.A.S. et anterieurement rapportes, ZUSAMMENFASSUNG

1. Es wurden Beobachtungen angestellt iiber die wirkung der Behandlung mit den PhenylEster der p-Aminosalicylsaure an 119 Patienten mit Lungentuberkulose wahrend Zeitabschnitten zwischen ein und 12 Monaten. Vergleiche hinsichtlich der Vertraglichkeit wurden mit Natrium, Kalium, Calzium p-Aminosalicylaten, dem ResinKomplex der p-Aminosylicylsliure und p-Aminosalicylsaure untemommen. Insgesamt wurden 530 Patienten vergleichend beobachtet, 2. Das Phenyl p-Aminosalicylat wurde ungewohnlich gut vertragen; nur 36, 97% der Kranken, die diese Behandlung hatten, zeigten Symptome irgendwelcher Art, und von diesen Symptomen waren mehr als 90% leicht oder rnassig schwer. Bei dieser Untersuchung war diejenige PAS-Form, die an zweiter Stelle hinsichtlich der Vertraglichkelt stand, die Resin-Komplex PAS mit 49,31 % Patienten,die unerwiinschte Wirkungen zeigten.

Volume 42, No. 4 October 1962

TOLERANCE OF PHENYL PAS

3. Wahrend die Serumblutspiegel von PAS, die von 99 der 119 Patienten gewonnen wurden, unter Behandlung mit Phenyl-PAS etwas niedri-. ger lagen als diejenigen, die bei anderen der untersuchten PAS-Typen zu erzielen waren, stimmen die klinisch und durch rontgenologische U ntersuchung ermittelten Ergebnisse in sehr giinstiger Weise iiberein mit denjenigen, die mit anderen PAS-Formen und aufgrund friiherer Berich te erzieIt wurden. REFERENCES LEHMANN, J.: "Para-aminosalicylic Acid in Treatment of Tuberculosis: Preliminary Communication," Lancet 1: 15, 1946. 2 LEHMANN, J.: "Chemotherapy of Tuberculosis: The Bacteriostatic Action of PAS and Closely Related Compounds upon the Tubercle Bacillus, Together with Animal Experiments and -Clinical Trials with PAS," Suensk, Lakartidn., 43: 2029, 1946. 3 BooER, W. P., GALLAGHER, M. E., AND PITTO, F. W.: "Effect of a New Benzoic Acid Derivative on Penicillin and P-aminosalicylic Acid Levels," t. Philadelphia Gen. H osp., 1: 51, 1950. 4 BOGER, W. P., AND PITTS, F. W.: "An evaluation of Certain Dosage Forms of Para-aminosa-

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licylic Acid (PAS)," Am. Rev. Tuberc., 62: 610, 1950. MADIGAN, D. G.: "Para-aminosalicylic Acid in Tuberculosis," Lancet, 1: 239, 1950. DONNERBURG, R. L., BROWNING, R. H., AND ATWELL, R. J.: "Studies of Conjugated PAS and Ascorbic Acid and Other Forms of Paraaminosalicylic Acid: I. Patient Tolerance," Am. Rev. Tuberc., 76:877, 1957. COHEN, S. S., YUE, W. Y., AND TSAI, S. H.: "Comparison of Toleration, Absorption, and Clinical Efficacy of Several Para-aminosalicylic Acid Preparations in Three Hundred Tuberculous Patients," Am. Rev. Tuberc., 78: 89~, 1958. MEYER, H. C.: "Phenyl P-aminosalicylic Acid," in: Antibiotics Annual, 1957-1958, Medical Encyclopedia, Inc., New York. TORNING, K., JENSEN, K. A., AND KIAER, I.: "Clinical Studies on Tebamin," Acta. Tuberc. Scandinau., 87: 100, 1958. COHEN, S. S., YUE, W. Y., AND TSAI, S. H.: "Comparison of Toleration and Absorption of Phenyl P-aminosalicylate with Several P-aminosalicylic Acid Preparations," Antibiotics Annual, 1958-1959, Medical Encylopedia, Inc. MARSHALL, E. K., JR.: "Determination of Para-aminosalicylic Acid in Blood," Proc. Soc. Exper. Bioi. and Med., 68:471, 1948.

FUNCTION OF MUSCULATURE OF ESOPHAGUS AND STOMACH In two series of animal experiments, selective excisions were perfonned of the muscular layers of the lower esophagus and the cardiac portion of the stomach. From the resulting changes of reflux esophagitis In the esophageal mucosa, the obllque portion of the Inner muscular layer of the stomach which loops around the insertion of the esophagus appeared to be the most Important part of the

sphincteric apparatus which prevents the reflux of gastric juice Into the esophagus. Preservation of this muscle In operations such as the Heller myotomy would seem Indicated to avoid postoperative reflux esophagitis. T.: "The Function of the Musculature of the Esophagus and Stomach in the Esophagogastric Sphincter Mechanism, Surg., Gyner. and Obst», 114:293, 1962.

GAHAGAN,

tt

CONTROVERSIAL ASPECTS OF INTRALOBAR SEQUESTRATION OF LUNG visceral pleural layer. The lesion is sequestered from the pulmonary arterial circulation. The lesion being thus separated and yet In most cases draining through a normal pulmonary vein suggests the primary fault to be In the fetal pulmonary arterial supply. Inasmuch as the lesion In all cases consists of normal lung elements, In an abnormal and disorderly arrangement It could accurately be described as a hamartoma, but only If a separate pleural invagination does not exlst,

At operation, a plane of cleavage cannot be found In true Intralobar sequestration. Although the lesion may appear by palpation to be well circumscribed, an attempt at separation by any form of wedge excision Is not a satisfactory surgical method. In all his cases, the lesion was found enclosed by the normal visceral pleura of the adjacent lower lobe. This Is a strong reason for rejecting sequestration or separation during development as a basis for the origin of the disease. The pulmonary artery never supplles the diseased portion of the lung. This fact clearly has a different significance If the lesion and the normal lung are separated by an Invaginated

SMITH, R. A.: "Some Controversial Aspects of Intralobar Sequestration of the Lung;" SlIrg. G,ner. anti Obst., 114:57, 1962.