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CONTRAST IN MEDICAL DISCOVERIES
ATRIAL T WAVE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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ACKNOWLEDGMENT: Suggestions regarding the prepDr. J. M. Evans aration of the manuscript were given and Dr. A. S. Gooch. We are gratefu to Miss Suzanne Earley, R. T., who performed the key role in data organization and processing. Mr. Don Gruver did computer prow-amming. Professor Terrence Ireland provided statistical consultation. The assistance of Miss Anne Lush is also appreciated.
REFERENCES 1 HERING, H.E.: Uber die finalschwankung (Ta Zacke) des Vorhofelektrogramms, Pfluger's Arch. Ges. Physiol., 144: 1, 1912. 2 ZUCKERMANN, R., CABRERA, E., FISHLEDER, B.L., AND
SODI-PALLARES, D.: Electrocardiogram in chronic cor pulmonale, Amer. Heart I., 35:421, 1948. 3 GROSS, D.: The auricular T wave and its correlation to the cardiac rate and to the P wave, Amer. Heart I., 50:24, 1955. 4
WASSERBURGER,
R.H.,
WARD,
V.G.,
CULLEN,
R.E., RAs-
MUSSEN, H.K., AND JUHL, J.H.: The Ta wave of the adult electrocardiogram: an expression of pulmonary emphysema, Amer. Heart J., 54:875, 1957. 5 BURCH, G.E., AND DE PASQUALE, N.P.: The electrocardiographic diagnosis of pulmonary heart disease, Amer. I. Cardiol., 11:622, 1963.
9
6 SNEDECOR, G.W.: Statistical methods, Ames, Iowa: The Iowa State College Press, 1946. 7 BALDWIN, E.DE F., COURNAND, A., AND RICHARDS, D.W. JR. : Pulmonary insufficiency: physiological classification, clinical methods of analysis, standard values in normal subjects, Medicine, 27:243, 1948. 8 GAENSLER, E.A.: Analysis of ventilatory defect by timed vital capacity measurements, Amer. Rev. Tuberc., 64: 265, 1951. 9 WASSERBURGER, R.H., KELLEY, J.R., RAS~IUSSEN, H.K., AND JUHL, J.H.: The electrocardiographic pentalogy of pulmonary emphysema, Circulation, 20:831, 1959. 10 MnLER, R., AND PERELMAN, J.S.: Multiple disturbances of rhythm and conduction and unusual auricular T wave in a case of myocardial infarction, Amer. Heart I., 31: 501, 1946. 11 HELLERSTEIN, H.K.: Atrial infarction with diagnostic electrocardiographic findings, Amer. Heart J., 36:422, 1948. 12 ABRAMSON, D.I., FENICHEL, N.M., AND SHOOKHOFF, C.: A study of electrical activity in the auricles, Arner. Heart J., 15:471, 1938. Reprint requests: Dr. Calatayud, 2150 Pennsylvania Avenue NW, Washington, D. C. 20037
CONTRAST IN MEDICAL DISCOVERIES A report published in 1941 caught the attention of Dr. Jorgen Lehmann, Director of the Central Laboratory of Sahlgrens Hospital of Gothenburg, Sweden. According to this report, benzoic acid and one of its derivatives, salicylic acid (orthoxybenzoic acid) increased the oxygen uptake of the tubercle bacillus. This information prompted Lehmann to suggest attempts at further chemical modification of the compound so as to increase its interference with the oxygen need of this microorganism. The aim of this purposeful search was to find a potent bacteriostatic agent against the tubercle bacillus. Along these lines of investigation, it was found that by adding an amino radical to saUcylic acid in the para position, a compound was produced, paraaminosalicylic acid, PAS, which suppressed the growth of tubercle bacilli in culture. Subsequent experiments revealed that this new chemical retarded the development of tuberculosis in mice and guinea pigs. More recent studies showed that radioactive C carrying PAS penetrated into caseous lung foci in 30 minutes. Clinical trials in March 1943 confirmed the value of PAS as a useful therapeutic agent in pulmonary and extrapulmonary forms of tuberculosis. Today PAS is generally accepted as a very effective drug given as part of a combination treatment, that is as a companion supportive agent to isonicotinic acid hydrazide and streptomycin. The contrasting historic background pertains to isonicotnic acid hydrazide (INH). The latter is a standard drug in the treatment as well as in the prophylaxis of tuberculosis. After its oral administration, adequate blood levels are reached within an hour. Moreover,
DIS. CHEST, VOL. 56, NO.1, JULY 1969
INH is still detectable after 24 hours although it diffuses readily into body tissues and caseous foci. Its poteney is predicated on the fact that it penetrates the waxy coat of the tubercle bacillus more promptly than streptomycin or PAS. INH influences the formation of the waxy capsule of the tubercle bacillus adversely. Futhermore, experimental studies show that this compound interferes with or prevents the formation of fibrous capsule about a tuberculous lesion and facilitates the resorption of the latter. It is a matter of record that INH was first investigated as an antituberculosis agent in 1950. Groups of research workers at large pharmaceutical companies in the United States came across INH as an intermediary product while exploring the antituberculosis properties of a derivative of thiosemicarbazone of isonicotinvl aldehyde. Following thorough laboratory and experimental research work, the first clinical reports on the high specific efficacy of INH were published simultaneously in the DISEASES OF THE CHEST and the AMERICAN REVIEW OF TUBERCULOSIS in April 1952. Forty years elapsed between this historic date and 1912, the year when Meyer and Mally of Prague first described the synthesis and chemical properties of INH in one of the German monthly scientific journals. In those days, the mortality from tuberculosis was over 200 per 100,000 in some of the underdeveloped countries. Thus millions of people died of tuberculosis throughout the world during the subsequent 40 years because INH had not been studied for therapeutic purposes. Andrew L. Banyai, M.D.
br
ACKNOWLEDGMENT: Suggestions regarding the prepDr. J. M. Evans aration of the manuscript were given and Dr. A. S. Gooch. We are gratefu to Miss Suzanne Earley, R. T., who performed the key role in data organization and processing. Mr. Don Gruver did computer prow-amming. Professor Terrence Ireland provided statistical consultation. The assistance of Miss Anne Lush is also appreciated.
REFERENCES 1 HERING, H.E.: Uber die finalschwankung (Ta Zacke) des Vorhofelektrogramms, Pfluger's Arch. Ges. Physiol., 144: 1, 1912. 2 ZUCKERMANN, R., CABRERA, E., FISHLEDER, B.L., AND
SODI-PALLARES, D.: Electrocardiogram in chronic cor pulmonale, Amer. Heart I., 35:421, 1948. 3 GROSS, D.: The auricular T wave and its correlation to the cardiac rate and to the P wave, Amer. Heart I., 50:24, 1955. 4
WASSERBURGER,
R.H.,
WARD,
V.G.,
CULLEN,
R.E., RAs-
MUSSEN, H.K., AND JUHL, J.H.: The Ta wave of the adult electrocardiogram: an expression of pulmonary emphysema, Amer. Heart J., 54:875, 1957. 5 BURCH, G.E., AND DE PASQUALE, N.P.: The electrocardiographic diagnosis of pulmonary heart disease, Amer. I. Cardiol., 11:622, 1963.
9
6 SNEDECOR, G.W.: Statistical methods, Ames, Iowa: The Iowa State College Press, 1946. 7 BALDWIN, E.DE F., COURNAND, A., AND RICHARDS, D.W. JR. : Pulmonary insufficiency: physiological classification, clinical methods of analysis, standard values in normal subjects, Medicine, 27:243, 1948. 8 GAENSLER, E.A.: Analysis of ventilatory defect by timed vital capacity measurements, Amer. Rev. Tuberc., 64: 265, 1951. 9 WASSERBURGER, R.H., KELLEY, J.R., RAS~IUSSEN, H.K., AND JUHL, J.H.: The electrocardiographic pentalogy of pulmonary emphysema, Circulation, 20:831, 1959. 10 MnLER, R., AND PERELMAN, J.S.: Multiple disturbances of rhythm and conduction and unusual auricular T wave in a case of myocardial infarction, Amer. Heart I., 31: 501, 1946. 11 HELLERSTEIN, H.K.: Atrial infarction with diagnostic electrocardiographic findings, Amer. Heart J., 36:422, 1948. 12 ABRAMSON, D.I., FENICHEL, N.M., AND SHOOKHOFF, C.: A study of electrical activity in the auricles, Arner. Heart J., 15:471, 1938. Reprint requests: Dr. Calatayud, 2150 Pennsylvania Avenue NW, Washington, D. C. 20037
CONTRAST IN MEDICAL DISCOVERIES A report published in 1941 caught the attention of Dr. Jorgen Lehmann, Director of the Central Laboratory of Sahlgrens Hospital of Gothenburg, Sweden. According to this report, benzoic acid and one of its derivatives, salicylic acid (orthoxybenzoic acid) increased the oxygen uptake of the tubercle bacillus. This information prompted Lehmann to suggest attempts at further chemical modification of the compound so as to increase its interference with the oxygen need of this microorganism. The aim of this purposeful search was to find a potent bacteriostatic agent against the tubercle bacillus. Along these lines of investigation, it was found that by adding an amino radical to saUcylic acid in the para position, a compound was produced, paraaminosalicylic acid, PAS, which suppressed the growth of tubercle bacilli in culture. Subsequent experiments revealed that this new chemical retarded the development of tuberculosis in mice and guinea pigs. More recent studies showed that radioactive C carrying PAS penetrated into caseous lung foci in 30 minutes. Clinical trials in March 1943 confirmed the value of PAS as a useful therapeutic agent in pulmonary and extrapulmonary forms of tuberculosis. Today PAS is generally accepted as a very effective drug given as part of a combination treatment, that is as a companion supportive agent to isonicotinic acid hydrazide and streptomycin. The contrasting historic background pertains to isonicotnic acid hydrazide (INH). The latter is a standard drug in the treatment as well as in the prophylaxis of tuberculosis. After its oral administration, adequate blood levels are reached within an hour. Moreover,
DIS. CHEST, VOL. 56, NO.1, JULY 1969
INH is still detectable after 24 hours although it diffuses readily into body tissues and caseous foci. Its poteney is predicated on the fact that it penetrates the waxy coat of the tubercle bacillus more promptly than streptomycin or PAS. INH influences the formation of the waxy capsule of the tubercle bacillus adversely. Futhermore, experimental studies show that this compound interferes with or prevents the formation of fibrous capsule about a tuberculous lesion and facilitates the resorption of the latter. It is a matter of record that INH was first investigated as an antituberculosis agent in 1950. Groups of research workers at large pharmaceutical companies in the United States came across INH as an intermediary product while exploring the antituberculosis properties of a derivative of thiosemicarbazone of isonicotinvl aldehyde. Following thorough laboratory and experimental research work, the first clinical reports on the high specific efficacy of INH were published simultaneously in the DISEASES OF THE CHEST and the AMERICAN REVIEW OF TUBERCULOSIS in April 1952. Forty years elapsed between this historic date and 1912, the year when Meyer and Mally of Prague first described the synthesis and chemical properties of INH in one of the German monthly scientific journals. In those days, the mortality from tuberculosis was over 200 per 100,000 in some of the underdeveloped countries. Thus millions of people died of tuberculosis throughout the world during the subsequent 40 years because INH had not been studied for therapeutic purposes. Andrew L. Banyai, M.D.