RECENT CLINICAL NOTES ON KRYOFINE, (Methoxacet-p-phenetidin.) BY Professor Dr, H. Eichhorst, Director of the Medical Clinic of the Zurich University. 0. BISOHOPP & 00., 87 # 80 PARK PLACE, NRW'YORK No. 2. Reprint from “Deutsche Medicinische Wochenschrift No. 17, 1897.” *From the Medical Clinic of the University of Zurich. KRYOFINE. A NEW ANTIPYRETIC. BT PROF. DR. HERMANN EICHHORST. The Privat-docent of chemistry of this place, Dr. Bischler, has for years studied the theory of fever remedies and as can readily be understood his studies have led him to evolve a series of antipyretics which should meet his views. As in the first instance, onljr purely scientific questions were concerned, I have gladly granted the request of Dr. Bischler to test the practical application of these drugs at the bedside. In this manner a whole series of remedies has passed through my hands in the course of several years, of which a few would be quite capable of causing serious competition to the newer antipyretics. It is not my intention to give a resume in the following of all my experiences, but I shall return later on to this subject which obviously is of great theoretical and practical importance. For the present may it suffice to point out one of these drugs which seems to me on account of its certain antipyretic action even in small doses and the generally complete absence of unpleasant collateral effects to be very well suited to be introduced into med- ical practice. In order to avoid misunderstanding let it be specially remarked that we have not indeed applied the drug in question because we consider a reduction of increased body-temperature an absolutely worthy aim of the physician; on the contrary, we only very rarely make use of antipyretics at the Zurich Clinic, and deviated from this precept merely to find occasion to test the drug. *The translator has endeavored to retain the author’s style as much as possible and to make the English version virtually literal, believing this to be an interesting feature of the report. The name Kryofine is of course chosen only for the sake of simplicity. According to its chemical composition the drug represents Methoxacet-p-phenetidin. The considerations which caused Dr. Bischler to expect a temperature reducing action from this drug in particular, I give in the original words of the discoverer. “ Kryofine is, like phenacetin, a p-phenetidin derivative, and indeed it is the condensation product from phenetidin and methoxy- acetic acid. It is produced by heating p-phenetidin with methoxy- acetic acid to 248°-2G6° F ; it crystallizes from water in needles with a melting point at 208.4°-210.2° F. Methoxacet-p-phenetidin results according to the equation : CH3OCHaCOOH+NH2C6H40C2H5= =CH30CH2C0NHC6H40C2Hs+H2O The following considerations gave rise to the production of this substance; From the investigations of W. Ostwald (Ueber die Affinitaets- groessen organischer Saeuren, Zeitschrift fuer physikalische Chemie III), it appears that the alkylglycolic acids are remarkably stronger than the glycolic acid itself and manifold stronger than the acetic acid. Thus for instance for Methoxy acetic acid K=0,0335, for acetic acid K=o,oolBo. This noteworthy difference between acetic acid and methoxy- acetic acid must in any event show itself also in derivatives of these acids, viz: in their condensation products with aromatic bases like anilin, phenetidin, etc. Now there exists in fact between acet-p- -phenetidin (Phenacetin) and methoxacet-p-phenetidin (Kryofine) a great difference in behavior toward saponifying agents. There are for example, saponified in boiling with alcoholic caustic potash solu- tion under circumstances otherwise equal, 10% of Phenacetin and 60% of Kryofine; by means of hydrochloric acid also, phenacetin is saponified with much more difficulty than Kryofine.” Now, as is well known, the acid gastric juice acts as also does the alkali of the duodenum on such substances as a saponifier; there could therefore appear in some manner a perceptible difference in the behavior of these substances within the organism. It was therefore indicated to investigate Kryofine for antipyretic action. Kryofine forms white, odorless crystals, which have no taste and are therefor very conveniently taken in powder form. Its solubility in water is 1:52 in boiling and 1:600 in cold water. In concentrated solution Kryofine tastes bitter and biting. At the medical clinic the antipyretic was given exclusively in powder form, and enclosed in wafers. As a reliably active dose grains of Kryofine lias been ascertained to be sufficient j one achieves therewith a result like with 15 grains of Phenacetin. When the action of Kry- ofine failed, then Phenacetin, Lactophenin and Antipyrin, which for the sake of comparison were repeatedly used in the same person, remained also almost unexceptional! y without influence. A few examples may be cited out of a great number of investiga- tions. to show the action of Kryofine. First Case. Girl, aged 17; severe typhoid fever, fourth week. Feb. 23-’97 7a. m. t. 102 9p. 116 10 a.m. 102.2 104 4 p.m. 104.2 108 8 p.m. 103.3 108 Feb. 24. 7 am. 101.7 92 10 am. 1013 112 4p, m. 103 3 116 8 p.m. 102.2 116 Feb. 25. 7 a m. 103 1 112 10 a. m. 101.5 108 4p. m. 103.1 108 4p. m. l'/2 grains of Kryofine 4.45 p. m. t. 101.3 p. 104 5.55 p. m. 99.5 100 7 p. m. 98.2 96 Feb. 26 7 a. m. 101.8 100 10 a. m. 100.6 104 10 a. m. 7% grains of Kryofine 11 a. m. 98.6 100 12 noon 96.8 96 1 p. m. 98.2 96 4 p. m. 99.3 96 7 p. m. 103.1 116 The patient therefor became entirely free of fever both times after the ingestion of 7)4 grs. of Kryofine, and remained so on the second day for almost twelve hours. Second Case. Man, aged 34, Typhoid fever, third week. Feb. 25-’97. Bp.m. t. 103.3 p. 100 Feb. 26. 7a. m. 103.3 100 10 a. m. 104.7 104 4 p.m. 103.1 104 Bp, m. 103 3 100 Feb. 27. 7 a. m. 102.4 104 10 a. m. 102.7 100 10.45 a. m. 4 grs. of Kryofine 12.15 p. m. 101.3 96 12.30 p. m. 102.2 100 12.45 p. m. 101.3 84 4 p.m. 103 1 116 Bp. m. 102.6 120 Feb. 28. 7 a. m. 102.6 120 10 a. m. 103.6 100 4p. m. 104. 100 8 pm. 102.9 100 Mar. 1. 7 a. m. 103.5 108 12 noon 101.7 108 4p. m. 100.6 108 Mar. 2. 7 a. m. t. 102.6 p. 104 10 a.m. 102.2 132 4 p.m. 103.1 132 Bp. m. 101.8 108 Mar. 3. 7a. m. 103.1 100 10 a. m. 102 9 100 4 p.m. 103.1 104 5 p.m. 102.4 104 6.30 p.m. 102.9 108 6.30 p. m. grains of Kryofine 7p. m. 100.6 96 7.30 p. m. 100.8 96 8 p. m. 98.6 92 9 p. m. 99.1 96 Mar. 4. 7 a. m. 101.8 100 10 a.m. 103.6 120 4p. m. 103.5 104 Bp. m. 102 9 112 The patient indeed experienced a slight, transient reduction of temperature after taking 4 grains of Kryofine on February 27, 1897, but did not become entirely free of fever; whereas on March 3, 1897, after iy2 grains of Kryofine the body-temperature sank to 98.6° F., and even the following morning the action of the Kryofine seemed to he perceptible in an unusually low febrile temperature. Female, aged 34, with pleuropneumonia of right upper and middle lobes. Third Case. July 20-’96. Fifth day of sickness 8 p. m. t, 103 6 p. 104 July 21. 7a. m. 101.7 120 9.30 a. m. grs. of Kryofine 10 a. m. 100.4 120 12 noon 100. 112 Ip. m. 99.9 116 2p. m. 98.6 120 3 p.m. 99.1 112 4p. m. 100.4 126 sp. m. 101.5 120 July 21. 6 p. m. t. 102.4 p. 116 7p. m. 103.3 132 Bp. m. 103,5 124 July 22. 7a. m. 101.5 108 10 a.m. 99.7 112 4p. m. 100. 104 8 p. m. 99.3 116 July 23 7a. m. 98.8 80 12 noon 96.6 104 4 p. m. 96.8 88 Fourth Case. Midwife, aged 38, with severe puerperal sepsis after neglected abortion. Nov. 2.’95. Bp. m. t. 102.7 p. 142 Nov. 3. 7 a. m. 104.9 152 12 noon 102.2 142 4p. m. 102.9 132 Nov. 4. 7 a. m, 105.3 120 12 noon 102.4 148 1 p m. 7]/2 grs. of Kryofine 2p. m. t 101.7 p. 124 4 pm. 99. 116 6p. m. 100. 104 Bp. m. 100. 124 Nov. 5. 7 a. m. 102.7 132 12 noon 102.2 132 4 p.m. 102.2 140 6 p. m. 104. 156 Fifth Case. Girl, aged 12, with acute febrile hemorrhagic nephritis following scarlet fever. Nov. 10-'95. 7a.m. t. 104. p. 112 10 a. m. 11/2ll/2 grs. of Phenacetin 12 noon 102 7 124 7 p. m. 102.7 128 Nov. 11. 7 a. m. 103.3 132 10 to 12 a. m. 1% grs. of Antipyrin every half hour. 12 noon 102.9 100 7 p.m. 102.7 132 Nov 12. 7 a. m. 102 4 140 10 to 12 a. m. 1V2 grs. of Antipyrin every half hour. 12 noon 103.1 140 7 p. m, 102.4 140 Nov. 13. 7 a. m. 103 1 124 11 a. m. 102.4 112 11 a. m. lyi grains of Kryofine I p. m. t 101.3 p. 120 3p. m. 100.9 100 sp. m. 101.7 124 7p. m. 102. 140 9p. m. 102.4 144 Nov. 14. 7 a. m. 103 3 116 9 a. m. 102.4 148 9 a. m. iy2 grains of Kryofine II a. m. 101.5 140 Ipm 102.9 144 3p. m, 103.5 124 sp. m. 102 9 148 7p, m. 102.7 136 Nov. 15. 7 a. m. 103.1 116 10 a. m. 103 1 140 iy2 grains of Phenacetin at 11-12 and 1 o’clock 4p. m. 102.2 116 7 p.m. 102.2 -116 From the above it is apparent that the patient was almost un- influenced in her fever in spite of large doses of Antipyrin and Phenacetin grains of Kryofine brought about a very decided temperature reducing effect. Sixth Case. Servant girl, aged 22 suffering with extensive facial erysipelas. Nov. 13- 95. 7p. in. t. 104.9 p. 112 Nov. 14. 7a, m. 104.2 108 10 a. m. 102.6 104 10 a. m. lyi grains of Kryofine 12 noon 100.9 100 2p. m. 103.5 120 4p. m. 104. 120 6p. m. 104.4 124 Bp. m. 104.9 128 Nov. 15. 7 a. m. 104. 112 11 a. m, 103.3 108 11 a. m. lyi grains of Kryofine Ip. m. 100.9 p. 104 3p. m. 102.6 U2 sp. m. 105.8 120 7p. m. 105.3 124 9p. m. 103 5 112 Nov. 16. 7a. m. 105.4 124 10 a m. 104.4 116 10 a. m. 15 grains of Phenacetin 12 noon 102.6 116 2p. m. 100 9 108 4 pm. 101.5 112 6p. m. 102.4 112 Bp. m. 102. 116 In this case we intentionally changed from Kryofine to Phenacetin to gain a comparison of the effect of both drugs. So long as the course of the disease was at its height, it appeared that Kryofine was at least equally valuable in effect with. Phenacetin, especially when one considers that of Kryofine only one-half the dose of Phenacetin had been prescribed. The number of examples could be increased by a very large figure, but the above observations may suffice to bring the proof that we have in Kryofine a febrifuge which both in effect and in safety of action may very well out-rival the antipyretics in use before this. Let it be further remarked that Kryofine has shown itself efficacious in the fever of consumptives, in streptococcus diphtheria, tubercular meningitis, and ulcerative endocarditis. Serious collateral effects we have not as yet seen. In a few patients there occurred during the fall in temperature a consider- able perspiration. Cyanosis also was occasionally perceptible Whether a slight nausea, of which exceptionally there was complaint, had any connection with the drug, remains as yet undecided. Frequently the influence of Kryofine on the pulse curve and arte- rial pressure was observed, for which purpose Dudgeon's sphygmograph was employed to obtain the pulse pictures, and for the determination of arterial pressure the sphygmomanometer of v. Basch was used. It appeared that under the influence of Kryofine the blood pressure in the radial artery rose 10-15 mm. Hg. and that in agreement therewith, an over-dicrotic pulse curve became a completely dicrotic or under-dicrotic one. In her inaugural dissertation Miss Bach will give a more particular report on the influence of Kryofine on tissue changes. Following surmise, it was advisable to investigate Kryofine for any effect in relieving pain and in fact it has frequently proven itself a good antineuralgic. In a few cases of recent sciatica its rapid effect was most startling Prominence should be given the fact, that in a man with alcoholic polyneuritis, for whose * intense pain sodium salicylate, phenacetin, antipyrin and exalgin had been prescribed without any effect, by means of Kryofine alone a very prolonged relief from pain was effected. The drug was prescribed 7y2 grains three times a day. In acute and chronic articular rheumatism it seemed to us to be less effective but always compared favorably with Phenacetin. In conclusion, I do not hesitate to recommend Kryofine as a noteworthy and commendable antipyretic and antineuralgic,