Frank B. Cooper

Urinary Concretions Caused by Sulfapyridine

Sulfapyridine is being widely used in clinical experiments because of its alleged lack of toxicity and the promising results reported by Whitby, 1 and by Evans and Gaisford. 2 However, our investigations, 3 , 4 as well as those of others, 5 , 6 have failed to confirm Whitbys claims that the drug is capable of protecting mice against 10,000 fatal doses of pneumococci; and we have pointed out that the order of efficacy of this drug and of sulfanilamide is approximately the same in rats. Marshall, Bratton and Litchfield 7 have recently issued a warning in regard to the erratic absorption and the potential toxicity of the drug, stating that sulfapyridine should not be used where sulfanilamide is indicated. Long and Finestone 6 have also drawn attention to the fact that the absorption and excretion of sulfapyridine are erratic. In the course of an investigation concerning the delayed deaths of rats treated with sulfapyridine, we noted that although the infections were in some instances apparently cured, the kidneys were enlarged and soft, the pelves and ureters dilated, and the bladders empty and contracted. Careful examination of the urinary tract revealed crystalline, spiculated, white or yellow concretions and sand, often impacted, with more or less complete urinary obstruction. A chemical analysis of these concretions indicated 6.4% sulfapyridine and 64.1% acetylsulfapyridine. These findings were absent in untreated rats, and in rats treated with sulfanilamide; all of which had been on the same diet. The dosage employed was the same for both drugs: one-half to one gram per kilo per day for 8 to 14 days. Higgins 8 has produced urinary calculi in rats with vitamin A deficient diet.

Action of P-Aminobenzenesulfonamide on Type III Pneumococcus Infections in Mice

Conclusions The oral administration of p-aminobenzenesulfonamide is capable of prolonging, and in some cases of saving, the lives of mice infected subcutaneously with approximately 10 minimal lethal doses of highly virulent Type 111 pneuniococci.†, ‡

Efficacy of p-Aminobenzenesulfonamide in Experimental Type III Pneumococcus Pneumonia of Rats

Conclusions P-aminobenzenesulfonamide therapy is effective in prolonging, and in many instances saving, the lives of rats infected intrabronchially with Type I11 pneumococci suspended in mucin.

Para-Aminobenzenesulfonamide Therapy in Experimental Type III Pneumococcal Pneumonia

Conclusion P-aminobenzenesulfonamide given orally to rats suffering from experimental Type III (“420” strain) pneumococcal pneumonia reduced the mortality and increased the survival-period. The effectiveness of this treatment varied inversely with the interval Ijetween infection and initial treatment, and with the magnitude of the infecting dose. The treated rats which succumbed showed less bacteremia and a lower incidence of peritonitis than the untreated ones which succumbed. The course and extent of the pneumonia was not appreciably affected. Treatment apparently enables many of the animals to survive the associated toxemia which is commonly fatal to similarly infected, but untreated, rats.

Sulfanilamide, Antipneumococcus Serum and Vitamin G Therapy in Type II Pneumococcal Pneumonia of Rats:

Conclusion 1. Sulfanilamide was at least as effective as specific antiserum, in the doses employed, in treating Type II pneumococcal rat pneumonia. A probable clinical application to similar human pneumonia is thereby suggested. 2. The combination of sulfanilamide and serum was no more effective than sulfanilamide alone. 3. Contrary to the observations in rabbits (Locke and Mellon), in rats Vitamin C alone, or in any combination tried, is ineffective.

Inhibition of Streptococcal Hemolysin by Sulfonamide Compounds

Conclusions Sulfanilamide causes a slight, almost negligible, inhibition of the hemolytic activity of streptococcal and staphylococcal hemotoxin. More marked inhibition of streptococcal hemolysin is produced by prontosil II, normal rabbit serum, rabbit Serum heated to 61°C., eosin, phenol, mercuric chloride, and sodium carbonate. The administration of sulfanilamide in vivo or its addition to serum in vitro does not enhance the inhibitory effect of rabbit serum upon streptococcal hemolysin. Prontosil I was found to have no inhibitory effect upon streptococcal hemolysin.

Chemotherapy of B. pertussis Infections of Mice

Conclusion Sulfanilamide, 4,4′-di- (acetylamino)-diphenylsulfone, and 4,4′-diaminobenzenesulfonanilide have no therapeutic value in the treatment of mice infected intraäbdominally with virulent B. pertussis.

Effect of Splenectomy on the Therapeutic Action of p-Amino-benzenesulfonamide on Mice Infected with Hemolytic Streptococcus

Conclusions 1. P-aminobenzenesulfonamide is capable of protecting splenectomized mice against fatal doses of highly virulent hemolytic streptococci. 2. The degree of protection observed in splenectomized mice was identical with that obtained with normal animals.

Chemotherapeutic Evaluation of Some N1- and N4-Heterocyclic Derivatives of Sulfanilamide

Conclusions 2-(Sulfanilamido)-5-ethyl-4-thiazolone (sulfaethyl-thiazolone) has less antistreptococcic activity and approximately the same antipneumococcic activity as sulfapyridine. Its antistaphylococcic activity is of the same order as that of sulfathiazole and sulfadiazine. Sulfadiazine produces urolithiasis medicamentosa capable of causing death by acute suppression of urine in mice and rats, whereas sulfaethylthiazolone is free of this defect, but may cause fatal anemia.

P-Aminobenzenesulfonamide and Antipneumococcai Serum Therapy in Type I Pneumococcal Infections of Rats

Although Hörlein 1 claimed that Prontosil was effective against Type III pneumococcal infections, experimental proof for this assertion was lacking until Rosenthal 2 and Cooper, Gross, and Mellon 3 independently investigated this problem. They demonstrated that P-aminobenzenesulfonamide gave mice a certain degree of protection against lethal doses of the particular strains of Type III pneumococcus employed. Buttle, Parish, Mc-Leod, and Stephenson, 4 however, were unable to demonstrate any significant protection in mice infected with Types I and II pneumo-cocci, whereas Rosenthal 2 obtained protection against all 3 fixed types. The lack of parallelism between pneumococcal septicemia in mice and pneumonia in man led to the choice of the experimental pneumococcal pneumonia in the rat 5 , 6 as a closer approximation to human pneumonia. The encouraging results obtained by treating such experimental Type III pneumonia with p-aminobenzenesulfonamide 7 , 8 have been duplicated in the treatment of human Type III pneumo-coccal pneumonia as reported by Heintzelman, Hadley and Mellon. 9 The relative therapeutic efficacy of p-aminobenzenesulfonamide and of potent specific antipneumococcal serum was investigated in rats infected intrabronchially with the Type I (Neufeld) strain. The inoculum, 0.1 cc. of which was injected, consisted of an 18-hour broth culture diluted 1000 times with broth, and sufficient mucin (Armour) added to give a viscous solution. Fifty-six rats, infected in this manner, were divided into 4 groups of 14 each: Group A—Untreated controls. Group B—Given 250 units of Type I antipneumococcal serum intraabdominally 6 hours after infection, followed by 2 similar daily doses. Group C—Given 125 mg. of p-aminobenzenesulfonamide∗ by mouth 6 hours after infection, followed by 10 daily similar doses. Group D—Treated 6 hours after infection by a combination of the treatments used in Groups B and C. Animals surviving to the 15th day were killed with ether. All animals of each group were necropsied and smears from the blood (femoral vein), peritoneum, and pleura, were stained by Grams method. Sections were made from all lobes of the lungs of each rat. The effect of the various types of treatment on the survival-time and rate is shown graphically in Fig. 1. The gross and microscopic anatomic changes in the lungs, as well as the bacteriologic findings, are tabulated in Table I. A summary of the findings is given in Table II. Contrary to the results reported by Gunn and Nungester 6 and by us, 7 , 8 a lobar type of pneumonia developed in only a few rats. Curiously enough, the most extensive and fully developed lobar type was seen in the non-survivors of the treated groups. Inflammatory changes were found in the lungs of every animal. Grossly, the changes were often minimal and not recognized. Bilateral empyema was frequently the outstanding postmortem finding. The most constant change was the interstitial pneumonia, more severe in the survivors than in the rats which died early. These interstitial changes represented, no doubt, the residues of subsiding pneumonias. The reduction in the mortality-rate from 93% in the control group to 21% in the groups treated with serum or the drug, and to 14% in the group treated with both, clearly indicates that p-aminoben-zenesulfonamide may have a definite place in the treatment of human Type I pneumococcal pneumonia in conjunction with specific anti-serum; and particularly where antiserum is not available for economic or other reasons. Concomitant with the drop in mortality-rate there was a reduction in bacteremia, peritonitis (determined by the smears), and empyema (Table II). The deaths in the drug-treated Group C occurred later than those of the serum-treated Group B, although they were numerically equal. Also, in the drug-treated group, 64% of the rats had no broncho- or lobar pneumonia, whereas only 50% of the rats in the serum-treated group were so spared. A rough approximation of the degree of microscopic involvement indicates less impairment in the group treated with p-aminobenzenesulfonamide than in the group treated with serum.