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half may be given daily ad libitum without ill effect. The lethal single dose is approximately 40 times the antisepsis-producing dose.
Man. Obviously the lethal dose of any drug for man must be computed from values obtained experimentally in animals. As the experiments already described fix the lethal dose for dogs and rabbits at 20 mgm. per kilogram, we have as the lethal dose for a man of 70 kgm. 1.4 grams., if we make the probable assumption that the toxicity for man is the same as for the other animals. Moreover as dogs withstand daily doses of 10 mgm. per kilogram over a long period without any evidence of injury, it follows that a man should safely tolerate 0.7 gram daily. When it is considered that the antisepsis-producing dose for man may be as low as 10 mgm., and is certainly not more than 20 mgm., it is seen that it should be theoretically possible to administer an antisepsis-producing dose even as often as once every hour, thus certainly keeping the urine constantly antiseptic, and still remain well within a limit that has been shown to be entirely harmless to dogs.
The synthetic compound chlor-mercury fluorescein is excreted by the kidney after intravenous injection as rapidly as is phenolsulphonphthalein. Nearly all of the dye is excreted by the normal kidney a short time after injection but this excretion is accompanied by a cleavage in the organism into fluorescein and some form of mercury combination. The percentage of the fluorescein excreted is large as estimated colorimetrically but only a small part of the total injected mercury appears in the urine within twenty-four hours. The lack of toxic effects either immediate or cumulative after large and repeated doses makes it probable that the mercury may find its exit in the feces.
In either acid or alkaline urine (in vitro) chlor-mercury fluorescein will inhibit the development of the colon bacillus or the staphylococcus aureus in a dilution at least as great as 1-10,000. It is more efficient in acid than in alkaline urine.
The intravenous administration of minute doses (5 to 10 mgm.) to rabbit, dog or man will cause the secretion of antiseptic urine for a definite period of time. The size of the antisepsis producing dose is not proportional to body weight and is approximately the same for the three animals.
The antisepsis producing dose is well within the toxic limit. The single lethal dose for rabbits and dogs is approximately 20 mgm. per kilogram of body weight. Half this dose however (10 mgm. per kilogram) may be given daily to dogs without any ill effects. One dog received a total of more than 2 grams. Five milligrams per kilogram may be given daily to rabbits for an indefinite period. The computed lethal single dose for man is about 140 times the antisepsis producing dose.
No clinical value is yet claimed for this drug, but we believe that it is worthy of a clinical investigation. This has already been begun and will be reported upon in due time. The work reported has however accomplished a definite purpose from an experimental point of view: it has shown that minute doses of a drug possessing the necessary localizing tendency may cause an animal to secrete urine that is definitely antiseptic; and it has shown the possibilities offered in this field by synthetic chemistry.
The authors wish to express their thanks to Dr. A. H. Clark, of the Department of Pathology, Johns Hopkins Medical School, for his kindness in examining the microscopic sections reported upon in this paper.
Davis, E. G.: Urinary antisepsis—A study of the antiseptic properties and renal excretion of compounds related to phenolsulphonphthalein: Preliminary report. Jour. A. M. A., 1918, lxx, 581.
Davis, E. G., And White, E. C.: Urinary antisepsis—Further studies of the antiseptic properties and renal excretion of compounds related to phenolsulphonphthalein. Jour. Urol., 1918, 11, 107.
Hahn And Kostenbader: Toxikologische u. Therapeutische Untersuchung Uber Quecksilberhaltige Farbstoffe. Zeit. fur Chemotherapie (Original abhandlungen), 1912, ii, 71.
Klaqes And Schreiber : Chemotherapy and toxicology of mercury compounds. 17th Intern. Cong. Med. (1913), Section of Therapeutics, 65-71.
Lomholt And Christiansen: BeBtimmung kleiner Mengen Quecksilber in or
ganischen Substanzen. Biochem. Zeit., 1913, lv, 216. Clark, W. M., And Lubs, H. A.: Colorimetric determination of hydrogen ion
concentration. Jour. Bacteriology, 1917, ii, 1. Shoiil, A. T., And Jannet, J. H.: Growth of Bacillus coli in urine at varying
hydrogen ion concentrations. Jour. Urol., 1917, i, 211. Henderson, L. J., And Palmer, W. W.: Intensity of urinary acidity in normal
and pathological conditions. Jour. Bio.. Chem., 1913, xiii, 393. Davis, E. G.. And Hain, R. F.: Urinary antisepsis—The antiseptic properties of
normal dog urine. Jour. Urol., 1918, ii, 309.
URINARY ANTISEPSIS—THE SECRETION OF ANTISEPTIC URINE FOLLOWING THE INTRAVENOUS ADMINISTRATION OF ACRIFLAVINE AND PROFLAVINE'—PRELIMINARY REPORT
EDWIN G. DAVIS And EDWIN C. WHITE
From the James Buchanan Brady Urological Institute, Johns Hopkins Hospital,
The possibility of employing the principles of synthetic chemistry and subjecting a given molecule to certain modifications,, so that certain desirable physiological properties are acquired,, while the original properties are retained, has been demonstrated. In other publications (Davis, Davis and White, and Davis, White and Rosen) the synthesis and properties of chlor-mercury fluorescein, an experimentally efficient internal urinary antiseptic, have been described. This compound was logically synthesized according to certain definitely established principles, by the knowledge of which it was possible to couple an antiseptic agent with a molecule of certain definite chemical structure, known to possess the property of becoming rapidly localized in the urinary tract. It is not the purpose of this paper to discuss the need of an efficient internal urinary antiseptic, but merely to present briefly the results of preliminary experiments with acriflavine, which indicate that this drug may prove to be of value. The experiments with acriflavine differed essentially from those with chlor-mercury fluorescein in that the synthesis of the former was not the result of a logical procedure with an internal urinary antiseptic as the goal. The properties of this drug were discovered during the course of a routine examination of a large number of compounds, including many coal tar dyes studied with a view to determining their antiseptic properties in urine and chosen without regard to chemical structure.
i Preliminary report.