Can Chemotherapy Be Extended to Include the Intracellular Disease Agents?

Mudd, Stuart

doi:10.1128/jb.49.6.527-537.1945

Cited by 11 publications

(4 citation statements)

References 37 publications

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“…In vivo the environment is much more complex than in simple laboratory media. For further information and references to the literature, seeSevag et al (1945) andMudd (1945).Thiamine antagonists. Thiamine may be inactivated by an enzyme, thiaminase, which is found in fish viscera(Sealock et al, 1943) and probably occurs in other organisms.…”

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Physiology of the fungi [by] Virgil Greene Lilly [and] Horace L. Barnett.

Lilly¹

1951

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PHYSIOLOGY OF THE FUNGI previous knowledge. Organization and interpretation of facts are equally as important as the experimentation which reveals them.The fungi as a group are highly responsive to their environment and are thus excellent test organisms for inquiring into the secrets of nature.Nature always answers correctly the questions we ask, and, in this sense, no experiment is a failure, although we may fail to ask the question we intended, or we may misunderstand the answer given. Infinite care is required to frame a question so that a definite answer may be obtained. By observing fungi in nature we are limited to questions asked by nature.Commonly, the environmental and nutritional factors are so complex that the influence of a single variable cannot be evaluated. By controlling the conditions under which a fungus is placed in the laboratory it is possible to ask questions of great precision. Indeed, the number and scope of the questions which we may ask fungi are limited only by the present-day techniques and the curiosity of the investigator.Since most of our knowledge of the physiology of the fungi has been gained from laboratory investigations, the experimental approach will be emphasized in the discussions which follow. However, this choice is not meant to minimize the importance of and need for critical observations in nature.By emphasizing the results of careful laboratory research, we are better able in the following chapters to present the facts necessary for an understanding of the vital principles of fungus physiology, and also to show that these principles, theories, and hypotheses are founded upon experimental evidence. FUNGUS PHYSIOLOGY IN RELATION TO OTHER SCIENCESPhysiology is that branch of science which deals with the life processes or the activities of organisms. The activities of the whole organism or of any of its parts may be hmited by its form or structure. Both the activity and the form of an individual are determined to a great extent by its genetic constitution and are modified by the environment to which the organism is exposed. Physiology, therefore, is not an independent subject.An understanding of physiological principles is based, in part, upon facts and theories from many other fields of science, such as chemistry, physics, anatomy, cytology, bacteriology, and genetics. Many of the physiological principles which have been established for one group of organisms apply equally well to other groups. The vitamins essential to the normal growth of the fungi are the same as those required by man, animals, and the higher plants. The general functions of these vitamins appear to be the same in all organisms. The difference in the vitamin requirements seems to lie in the different abilities of these groups of organisms (or individuals within the group) to synthesize these necessary compounds. As Schopfer (1943) has pointed out, the The life processes of the fungi involve numerous chemical transformations.Living organisms make and use special organic catalysts, enzymes, which control ...

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Physiology of the fungi [by] Virgil Greene Lilly [and] Horace L. Barnett.

Lilly¹

1951

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“…This primary drug fixation concept has been elaborated by Clark (1933), King and Strangeways (1942), and by Mudd (1945). Mudd (1945) stressed the common p-aminophenyl structural basis of a number of biologically active compounds such as sulphonamides, antipyretics, local anaesthetic esters of p-aminobenzoic acid and organometallic antiprotozoal agents; to these may be added the antitubercular drug p-aminosalicylic acid (Youmans, Raleigh, and Youmans, 1947) which is also trypanocidal (Pick, 1950), and p-aminobenzenephosphonic acid which is antibacterial (Bauer, 1941;Kanitkar and Bhide, 1947;Thayer, Magnuson and Gravatt, 1953). The diversity of active substances with the above general configuration implies the existence of a common and widely-distributed cellular reaction site of complementary structure.…”

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Drug Resistance in Trypanosomes; Selective Interference With Trypanocidal Action

Williamson

1959

British Journal of Pharmacology and Chemotherapy

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Selective reversal of the trypanocidal action of carboxylated arsenicals by p-aminobenzoic acid and of melaminyl arsenicals and diamidines by melamine has been demonstrated in vivo and in vitro. The structural specificity of these reversal phenomena is high, and suggests preferential adsorption of the antagonist during a reversible primary drug fixation stage. Thiols antagonize neutral, carboxylated and melaminyl aromatic arsenicals equally, but not diamidines; p-aminobenzoic acid antagonism is specific for carboxylated arsenicals, and melamine antagonizes only the melaminyl arsenicals and the diamidines. These reversals reflect the pattern of crossresistance behaviour and suggest that cellular structures associated with a reversible stereospecific drug adsorption phase are modified during the development of resistance.

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“…A given concentration of streptomycin would therefore destroy all but a small number of bacteria completely resistant to it and the small concentrations of the added drug or drugs would independently inhibit the small number of surviving bacteria. If, however, a drug can significantly modify cellular metabolism though not inhibit cell division, then it is possible that two drugs acting on a single cell may together effect complete inhibition or killing when each alone could not (Mudd, 1945). One would then have in addition to the independent action, which must occur, this combined action on a single cell.…”

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confidence: 99%

The Correlation between the Inhibition of Drug Resistance and Synergism in Streptomycin and Penicillin

Klein

Kimmelman

1947

J Bacteriol

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The problem of drug resistance has become an important limiting factor in the therapeutic efficiency of streptomycin (Buggs et al., 1946; Finland et al., 1946; Bondi et al., 1946). We have previously shown in the case of streptomycin that of 13 strains tested all had the ability to throw off, spontaneously, variants resistant to streptomycin (Klein and Kimmelman, 1946; Klein, 1947). The destruction by streptomycin of the mass of susceptible bacteria and the multiplication of the fe.w highly resistant variants was indicated to be a mechanism for the development of streptomycin resistance. Alexander and Leidy (1947), working with Hemophilus influertae, have recently obtained similar results. Clinically, the inhibition of the rapid development of streptomycin resistance may then require the destruction of a relatively small number of resistant bacteria, which might be effected by the addition of a low concentration of another drug. In the present work we have therefore studied the combined action of streptomycin, penicillin, and sulfadiazine in vitro and determined the relationship between the synergistic action of the compounds and the inhibition of the development of streptomycin resistance. MATERIALS AND METHODS Staphylococcus aureus, susceptible to streptomycin, penicillin, and sulfadiazine, was used as the test organism. A casein hydrolyzate medium (Strauss, Dingle, and Finland, 1941) containing 0.5 per cent glucose provided a clear mediumwhich was convenient in the determination of growth rates turbidimetrically in the Klett-Summerson photoelectric colorimeter. The presence of the glucose resulted in a drop in pH after 24 hours that did reduce the streptomycin activity (Geiger, Green, and Waksman, 1946). However, this did not interfere with the interpretation of the results on the combined drug action. The tests for drug activity were performed as follows: Six ml of the casein hydrolyzate medium, containing the various drugs singly or in combination, were added to the Klett-Summerson tubes, and a standaxd inoculum of 0.1 ml of a 20-to 24-hour culture, diluted to give a reading of 50 on the Klett-Summmerson colorimeter (approximately 15,000,000 bacteria), was seeded into each of the tubes. This large inoculum provided a rapid initial growth, which permitted the taking of turbidity readings a.t 6 hours, in addition to the 12-, 24-, and 48hour readings. In preliminary assays it was found that the 24-hour growth This investigation has been aided by a grant from the Josiah Macy, Jr., Foundation.

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Can Chemotherapy Be Extended to Include the Intracellular Disease Agents?

Cited by 11 publications

References 37 publications

Physiology of the fungi [by] Virgil Greene Lilly [and] Horace L. Barnett.

Physiology of the fungi [by] Virgil Greene Lilly [and] Horace L. Barnett.

Drug Resistance in Trypanosomes; Selective Interference With Trypanocidal Action

The Correlation between the Inhibition of Drug Resistance and Synergism in Streptomycin and Penicillin

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