A Rational Approach to Research in Chemotherapy

Fildes, Paul

doi:10.1016/s0140-6736(00)72741-3

Cited by 214 publications

(45 citation statements)

References 4 publications

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“…The present observations which concern the inhibition of the action of sulfonamides on bacteria by p-aminobenzoic acid are consistent with Fildes' hypothesis (8), which considers substances of this type as " essential metabolites " that are displaced at some stage of bacterial growth by adequate concentrations of sulfonamides. West and Coburn's (4) observations likewise fit into this theory.…”

Section: Discussionsupporting

confidence: 91%

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Observations on the Inhibition of Sulfonamide Action by Para-Aminobenzoic Acid

Strauss¹,

Lowell²,

Finland³

1941

J. Clin. Invest.

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Considerable interest has been aroused recently in the investigation of substances which inhibit the action of the sulfonamide drugs. Lockwood (1) showed that peptones inhibit the action of sulfanilamide on streptococci. Stamp (2) isolated certain fractions of streptococci, and Green (3) isolated fractions of brucella, which have similar activity with respect to the corresponding organisms. West and Coburn (4) showed that under certain conditions coenzymes inhibit the action of sulfapyridine on staphylococci. MacLeod (5) found that the action of sulfapyridine on the colon bacillus in a synthetic medium can be nullified by extracts of certain animal tissues. Woods (6) extracted fractions of yeast which were capable of overcoming the bacteriostatic action of sulfanilamide on streptococci and on colon bacilli. From an analysis of the properties of the active extracts he was led to test a series of known chemical compounds and found that para-aminobenzoic acid had marked inhibitory properties in vitro. Selbie (7) supplemented this work by demonstrating that mice infected with streptococci could not be saved by sulfanilamide if para-aminobenzoic acid were administered at the same time. The reports of the two last named authors and the discussion of their work by Fildes (8) led us to undertake studies of some of the properties of para-aminobenzoic acid in vitro and in human subjects. In this paper are reported the results of observations on the following aspects of these studies: (1) the quantitative relationship between the bacteriostatic effect of sulfonamides on the pneumococcus and the inhibition of this effect by para-aminobenzoic acid; (2) the stages of the action of sulfapyridine on the pneumococcus during which inhibition by para-aminobenzoic acid is effective; (3) a consideration of the absorption and excretion of para-aminobenzoic acid and its chemical determination in blood and urine; (4) a comparison of the activity of the urine of human subjects following ingestion of para-aminobenzoic acid with the activity of this drug when added in vitro to normal urine (the bacteriostatic effect of sulfathiazole on the colon bacillus was utilized for this purpose); (5) a study of the effect of oral administration of para-aminobenzoic acid on the bactericidal power of the blood of subjects receiving sulfonamides; and (6) the effect of paraaminobenzoic acid on rashes and fever due to sulfonamide toxicity.Quantitative relationship between the concentration of sulfonamides and the inhibitory concentration of para-aminobenzoic acid The results are charted in Figure 1. Within the range studied there was a roughly linear relationship between the concentrations of sul-1 Chemical grade, obtained from Eastman Kodak Company.

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Section: Discussionsupporting

confidence: 91%

“…per cent of p-aminobenzoic acid was added to a second tube. In like manner, equal amounts of this drug were added at 4, 8,12,16,20 and 24 hours to the remaining tubes in succession. One tube, containing neither sulfapyridine nor p-aminobenzoic acid, and another, containing 10 mgm.…”

mentioning

confidence: 99%

Observations on the Inhibition of Sulfonamide Action by Para-Aminobenzoic Acid

Strauss¹,

Lowell²,

Finland³

1941

J. Clin. Invest.

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show abstract

“…The existence of metabolic competition between structurally analagous compounds has been demonstrated by the growth inhibiting properties of unnatural metabolites in bacteria and mammalian cells (65)(66)(67). Bacteria may become dependent on such compounds as streptomycin that initially suppress growth (68).…”

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma. Iii. Effect of Urethane Therapy on Plasma Cell Growth, Abnormal Serum Protein Components and Bence Jones Proteinuria 1

Rundles¹,

Dillon²,

Dillon³

1950

J. Clin. Invest.

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“…5), noting that drugs such as arsphenamine and sulfonamides had been introduced into therapeutics empirically, decided to take a more rational approach toward synthesizing and testing new pharmacological agents. Bovet based his strategy on the principles inherent in the antimetabolite theory of Woods and Fildes (Fildes, 1940;Woods, 1940). This theory explained the bacteriostatic action of sulfa drugs by virtue of their ability to competitively antagonize the normal cellular utilization of p-aminobenzoic acid, a metabolite with a chemical structure very similar to that of the sulfonamides.…”

Section: Daniel Bovet: Synthetic Compounds That Inhibit the Actionmentioning

confidence: 99%

A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics

Rubin

2007

Pharmacol Rev

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A Rational Approach to Research in Chemotherapy

Cited by 214 publications

References 4 publications

Observations on the Inhibition of Sulfonamide Action by Para-Aminobenzoic Acid

Observations on the Inhibition of Sulfonamide Action by Para-Aminobenzoic Acid

Multiple Myeloma. Iii. Effect of Urethane Therapy on Plasma Cell Growth, Abnormal Serum Protein Components and Bence Jones Proteinuria 1

A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics

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