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.

REFERENCES

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 über Quecksilberhaltige Farbstoffe. Zeit. fur Chemotherapie (Original abhandlungen), 1912, ii, 71.

KLAGES AND SCHREIBER: Chemotherapy and toxicology of mercury compounds. 17th Intern. Cong. Med. (1913), Section of Therapeutics, 65–71.

LOMHOLT AND CHRISTIANSEN: Bestimmung kleiner Mengen Quecksilber in organischen Substanzen. Biochem. Zeit., 1913, lv, 216.

CLARK, W. M., AND LUBS, H. A.: Colorimetric determination of hydrogen ion

concentration. Jour. Bacteriology, 1917, ii, 1.

SHOHL, A. T., AND JANNEY, 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, Baltimore, Maryland

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.

1 Preliminary report.

Browning, Gulbransen, Kennaway and Thornton have described certain properties of proflavine and acriflavine. These authors have shown that acriflavine (diamino-methyl-acridinium chloride) is a very powerful antiseptic, and that it differs from all the antiseptics in general use in that its strength is increased by the presence of serum. In the latter medium "its bactericidal potency for staphylococcus aureus is 800 times that of chloramine-T. or carbolic acid, and 20 times that of corrosive sublimate." They also state that with the ordinary antiseptics an efficient concentration is also sufficient to terminate all effective phagocytic action; while in the case of acriflavine, phagocytosis proceeds actively even in a concentration 200 times greater than is necessary to kill micro-organisms.

Considering the previously described loss of antiseptic action of so many of our own synthetic compounds when diluted with urine in a test tube, and considering the potency of the flavines in serum, as observed by the English authors, it was thought worth while to test the antiseptic efficiency of the latter compounds in a urine medium. Experiments conducted along these lines showed that the flavines are likewise efficient in urine, particularly so in alkaline urine. Experiments to determine their route of excretion then showed that these drugs, administered to animals either intravenously or per os, appeared in the urine. Furthermore, preliminary experiments indicate that the antiseptic strength of acriflavine is not lost by passage through the animal body, and that doses sufficient to render the urine antiseptic are not toxic. On account of the was it was necessary to discontinue this investigation just after it was well under way, and the data are therefore quite incomplete. The following results, however, seem of sufficient interest to record.

ANTISEPTIC STRENGTH IN URINE

The antiseptic strength of acriflavine and proflavine, in both acid and alkaline urine, against the colon bacillus and the staphylococcus aureus, was determined. In order that the reaction of the acid and alkaline urine used from day to day in these experi