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CARONAMIDE FOR INCREASING PENICILLIN PLASMA CONCENTRATIONS IN MAN FREE

J. WILLIAM CROSSON, M.D.; WILLIAM P. BOGER, M.D.; CHRISTOPHER C. SHAW, M.D.; A. KATHRINE MILLER, Ph.D.
[+] Author Affiliations

The work herein reported was made possible by the cooperation of Garfield C. Duncan, M.D., Director of the Division of Medicine, Pennsylvania Hospital, who granted permission for the study of patients on the medical wards.


Philadelphia


JAMA. 1947;134(18):1528-1532. doi:10.1001/jama.1947.02880350012005
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A new drug, caronamide,1 when given orally to patients receiving penicillin produces a physiologic and reversible inhibition of the excretion of this antibiotic, which results in elevation of the concentration of penicillin in the plasma.

The primary objective of penicillin therapy is the maintenance of therapeutic concentrations of the antibiotic in the body tissues, but there appears to be no general agreement concerning therapeutic concentrations. Nor has it yet been made clear whether the maintenance of a constant level of penicillin plasma concentration is more desirable than the attainment of intermittent and temporary high levels. There does appear to be general agreement, however, that the attainment of high concentrations of penicillin is desirable.

It is difficult to attain elevated concentrations because of the rapidity with which penicillin is absorbed from the site of injection and excreted by the kidneys. Efforts have been made to maintain plasma concentrations of the

REFERENCES

Caronamide is 4'-carboxyphenylmethanesulfonanilide and is prepared by Sharp & Dohme, Inc., Philadelphia.
Meakins, J. C.; Smith, F., and Gold, M. A.:  A Comparative Study of Some Commercial Preparations of Oral Penicillin , Canad. M. A. J. 55:97-101 ( (Aug.) ) 1946;.
Rammelkamp, C. H., and Bradley, S. W.:  Excretion of Penicillin in Man , Proc. Soc. Exper. Biol. & Med. 53:30-32 ( (May) ) 1943;.
Beyer, K. H.; Woodward, R.; Peters, L.; Verwey, W. F., and Mattis, is, P. A.::  The Prolongation of Penicillin Retention in the Body by Means of Para-Aminohippuric Acid , Science 100: 107-108 ( (Aug. 4) ) 1944;.
Beyer, K. H.; Flippin, H.; Verwey, W. F., and Woodward, R.:  The Effect of Para-Aminohippuric Acid on Plasma Concentration of Penicillin in Man , J. A. M. A. 126:1007-1009 ( (Dec. 16) ) 1944;.
Bronfenbrenner, J., and Favour, C. B.:  Increasing and Prolonging Blood Penicillin Concentrations Following Intramuscular Administration . Science 101:673-674 ( (June 29) ) 1945;.
Spaulding, E. H.; Bondi, A., Jr., and Early, E.:  The Effect of Combining Sodium Benzoate with Oral Penicillins , Science 105:210-211 ( (Feb. 21) ) 1947;.
Abraham, E. P.; Chain, E.; Fletcher, C. M.; Gardner, A. D.; Heatley, N. G.; Jennings, M. A., and Florey, H. W.:  Further Observations on Penicillin , Lancet 2: 177-189 ( (Aug. 16) ) 1941;.
Rake, G., and Richardson, A. P.:  Pharmacology of Penicillin , Ann. New York Acad. Sc. 48:143-174 ( (Sept. 27) ) 1946;.
Beyer, K. H.:  New Concept of Competitive Inhibition of the Renal Tubular Excretion of Penicillin , Science 105:94-95 ( (Jan. 24) ) 1947;.
Beyer, K. H.; Verwey, W. F.; Woodward, R.; Peters, L., and Mattis, P. A.:  The Enhancement of the Plasma Concentration of Penicillin in Dogs by the Simultaneous Administration of Para-Aminohippuric Acid , Am. J. M. Sc. 209:608-621 ( (May) ) 1945;.
Beyer, K. H.; Peters, L.; Woodward, R., and Verwey, W. F.:  The Enhancement of the Physiological Economy of Penicillin in Dogs by the Simultaneous Administration of Para-Aminohippuric Acid , J. Pharmacol. & Exper. Therap. 82: 310-323 ( (Dec.) ) 1944;.
Beyer, K. H.; Mattis, P. A.; Patch, E. A., and Russo, H. F.:  Para-Aminohippuric Acid: Its Pharmacodynamic Actions , J. Pharmacol. & Exper. Therap. 84: 136-146 ( (June) ) 1945;.
Loewe, L.; Rosenblatt, P., and Alture-Werber, E.:  A Refractory Case of Subacute Bacterial Endocarditis Due to Veillonella Gazogenes Clinically Arrested by a Combination of Penicillin, Sodium Para-Aminohippurate, and Heparin , Am. Heart J. 32: 327-338 ( (Sept.) ) 1946;.
Avery, N. L., Jr.; Mayer, O. B., and Nelson, R. C.:  Massive Doses of Penicillin in the Treatment of Subacute Bacterial Endocarditis , Ann. Int. Med. 24:900-904 ( (May) ) 1946;.
Mokotoff, R.; Brams, W.; Katz, L. N., and Howell, K. M.:  The Treatment of Bacterial Endocarditis with Penicillin: Results of Seventeen Consecutive Unselected Cases , Am. J. M. Sc. 211:395-416 ( (April) ) 1946;.
Sprague, J. M.; Ziegler, C.; Cragoe, E. J., and Miller, C. S.: 4'-Carboxyphenylmethanesulfonanilide, to be published.
Beyer, K. H.; Miller, A. K.; Russo. H. F.; Patch, E. A., and Verwey, W. F.:  The Inhibitory Effect of Caronamide on the Renal Elimination of Penicillin , Am. J. Physiol. , to be published.
Beyer, K. H.; Russo, H. F.; Patch, E. A., and Tillson, E. A.: Caronamide: Its Pharmacologic Properties, to be published.
Beyer, K. H.; McKinney, S. E.; Tillson, E. A., and Green, C. W.: Caronamide: Its Toxicologic Effects, to be published.
Verwey, W. F., and Miller, A. K.: The Effect of Caronamide upon Penicillin Therapy of Experimental Pneumococcus and Typhoid Infections in Mice, to be published.
All penicillin assays were supervised by one of us (A. K. M.) and were performed by the staff of the Department of Bacteriology, Medical Research Division of Sharp & Dohme, Inc.

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Caronamide is 4'-carboxyphenylmethanesulfonanilide and is prepared by Sharp & Dohme, Inc., Philadelphia.
Meakins, J. C.; Smith, F., and Gold, M. A.:  A Comparative Study of Some Commercial Preparations of Oral Penicillin , Canad. M. A. J. 55:97-101 ( (Aug.) ) 1946;.
Rammelkamp, C. H., and Bradley, S. W.:  Excretion of Penicillin in Man , Proc. Soc. Exper. Biol. & Med. 53:30-32 ( (May) ) 1943;.
Beyer, K. H.; Woodward, R.; Peters, L.; Verwey, W. F., and Mattis, is, P. A.::  The Prolongation of Penicillin Retention in the Body by Means of Para-Aminohippuric Acid , Science 100: 107-108 ( (Aug. 4) ) 1944;.
Beyer, K. H.; Flippin, H.; Verwey, W. F., and Woodward, R.:  The Effect of Para-Aminohippuric Acid on Plasma Concentration of Penicillin in Man , J. A. M. A. 126:1007-1009 ( (Dec. 16) ) 1944;.
Bronfenbrenner, J., and Favour, C. B.:  Increasing and Prolonging Blood Penicillin Concentrations Following Intramuscular Administration . Science 101:673-674 ( (June 29) ) 1945;.
Spaulding, E. H.; Bondi, A., Jr., and Early, E.:  The Effect of Combining Sodium Benzoate with Oral Penicillins , Science 105:210-211 ( (Feb. 21) ) 1947;.
Abraham, E. P.; Chain, E.; Fletcher, C. M.; Gardner, A. D.; Heatley, N. G.; Jennings, M. A., and Florey, H. W.:  Further Observations on Penicillin , Lancet 2: 177-189 ( (Aug. 16) ) 1941;.
Rake, G., and Richardson, A. P.:  Pharmacology of Penicillin , Ann. New York Acad. Sc. 48:143-174 ( (Sept. 27) ) 1946;.
Beyer, K. H.:  New Concept of Competitive Inhibition of the Renal Tubular Excretion of Penicillin , Science 105:94-95 ( (Jan. 24) ) 1947;.
Beyer, K. H.; Verwey, W. F.; Woodward, R.; Peters, L., and Mattis, P. A.:  The Enhancement of the Plasma Concentration of Penicillin in Dogs by the Simultaneous Administration of Para-Aminohippuric Acid , Am. J. M. Sc. 209:608-621 ( (May) ) 1945;.
Beyer, K. H.; Peters, L.; Woodward, R., and Verwey, W. F.:  The Enhancement of the Physiological Economy of Penicillin in Dogs by the Simultaneous Administration of Para-Aminohippuric Acid , J. Pharmacol. & Exper. Therap. 82: 310-323 ( (Dec.) ) 1944;.
Beyer, K. H.; Mattis, P. A.; Patch, E. A., and Russo, H. F.:  Para-Aminohippuric Acid: Its Pharmacodynamic Actions , J. Pharmacol. & Exper. Therap. 84: 136-146 ( (June) ) 1945;.
Loewe, L.; Rosenblatt, P., and Alture-Werber, E.:  A Refractory Case of Subacute Bacterial Endocarditis Due to Veillonella Gazogenes Clinically Arrested by a Combination of Penicillin, Sodium Para-Aminohippurate, and Heparin , Am. Heart J. 32: 327-338 ( (Sept.) ) 1946;.
Avery, N. L., Jr.; Mayer, O. B., and Nelson, R. C.:  Massive Doses of Penicillin in the Treatment of Subacute Bacterial Endocarditis , Ann. Int. Med. 24:900-904 ( (May) ) 1946;.
Mokotoff, R.; Brams, W.; Katz, L. N., and Howell, K. M.:  The Treatment of Bacterial Endocarditis with Penicillin: Results of Seventeen Consecutive Unselected Cases , Am. J. M. Sc. 211:395-416 ( (April) ) 1946;.
Sprague, J. M.; Ziegler, C.; Cragoe, E. J., and Miller, C. S.: 4'-Carboxyphenylmethanesulfonanilide, to be published.
Beyer, K. H.; Miller, A. K.; Russo. H. F.; Patch, E. A., and Verwey, W. F.:  The Inhibitory Effect of Caronamide on the Renal Elimination of Penicillin , Am. J. Physiol. , to be published.
Beyer, K. H.; Russo, H. F.; Patch, E. A., and Tillson, E. A.: Caronamide: Its Pharmacologic Properties, to be published.
Beyer, K. H.; McKinney, S. E.; Tillson, E. A., and Green, C. W.: Caronamide: Its Toxicologic Effects, to be published.
Verwey, W. F., and Miller, A. K.: The Effect of Caronamide upon Penicillin Therapy of Experimental Pneumococcus and Typhoid Infections in Mice, to be published.
All penicillin assays were supervised by one of us (A. K. M.) and were performed by the staff of the Department of Bacteriology, Medical Research Division of Sharp & Dohme, Inc.
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