A STUDY OF THE Comparative Actions of Antipyrine, Phenacetine and Phenocoll ON THE Circulation andJheat Phenomena. By DAVID CERNA, H. D., Ph. D., Assistant in Physiology, Demonstrator of and Lecturer on Experimental Therapeutics in the University of Pennsylvania, Fellow of th College of Physicians of Philadelphia, Corresponding Fellow of the Sociedad Espanola de Higiene of Madrid, etc., AJND^ williAn s. Carter, m. d., Assistant in Physiology in the University of Pennsylvania. ON THE CIRCULATION. We propose in this research, as the title indicates, to make a study of the comparative actions of antipyrine, phenacetine and phenocoll on the circulation, and par- ticularly on heat phenomena. Antipyrine and phenacetine have already been largely employed experimentally and clinically, with more or less asserted success as antipyretics, but we believe that a further study of these drugs, especially when compared with the new remedy, phenocoll, will be not amiss. We feel that the results of this investi- gation may form a stronger basis for the antipyretic use of these medicaments, particularly the latter one, in practical medicine. As our study of the whole subject is directed espe- cially to investigate the behavior of these drugs on heat phenomena, which we consider of greater importance as regards their use in the treatment of disease, we have not made, perhaps, an exhaustive inquiry into the phy- siological action of the drugs in question on the circu- lation. Let this statement serve as an excuse for any shortcomings that the critical physiologist may find in our conclusions. We fully believe, however, that the results obtained with each individual drug, following the various methods emyloyed and sufficiently de- scribed in the course of this article, sustain, so far, the correctness of the conclusions indicated below. We have made an elaborate series of experiments on dogs, and the results observed are of such an interest- ing character as to warrant a serious consideration of the subject. We shall first take up the study of the actions of the drugs in question on the circulatory sys- tem, and then carefully consider their influence on heat phenomena in normal a?hd fevered animals. ANTIPYRINE. HLW this drug acts on the circulation of mammals has not bien definitely determined. The large mass of experimental evidence so far published is mainly con- tradictory, and without going into an elaborate examin- ation of the literature on the subject, we will endeavor to point out the main conclusions arrived at by various investigators when considering separately the actions of the drug on the blood-pressure, the pulse, and the blood itself. Blood-pressure.—Pavlinow ‘) has asserted that anti- pyrine causes a rise of the arterial pressure. Demme '*) has observed the same result, this being followed by a fall notwithstanding the fact that the heart continued to act well. The same rise of pressure has been noticed by Arduin *), Devraux-Armand 4) and Henry Casimir *), when small or moderate doses were employed:—On other hand, Simon and Hock—quoted by Wood*)— Wood '), Hare *) and Dujardin-Beaumetz *) sustain that antipyrine in medicinal amounts has little or no effect upon the circulation. All authors agree more or less in that large quantities of this drug produce a depressant circulatory action; but aside from this contradictory evidence, no extended studies have been made to de- cide exactly how antipyrine influences the circulation, especially as regards the pulse and the blood-pressure. We have made several experiments on normal ani- mals, with various doses, and observed that in small and moderate amounts the tendency of antipyrine is to increase the arterial pressure. We shall only d 'tail two examples. In Experiment I the pressure rose above the normal height after the second dose, which also ') Meditz. Obozr. fasc. XII, 1885, p. 1203. ’) Fortschritte der Medicin. Bd. II, 1884, p. 657. 3) These de Paris, 1885. *) These de Nancy, 1885. *) These de Lyon, 1886. «) Therapeutics: Its Principles and Practice, Edition of 1891, 7) Ibid. 8) Fever: Its Pathology and Treatment, 1891. *) Therapeutic Gazette, September 15, 1885. 2 produced convulsions, but these soon disappeared. The pressure continued high during the rest of the experi- ment, and, as is observed, no more convulsions oc- curred. The pressure only fell just before death. Although there was at first a slight diminution in the respiratory movements, these became increased in rate afterwards. The temperature remained unaffected, and in the final fatal issue both the respiration and heart stopped simultaneously. In Experiment II, in which comparatively larger amounts were employed, there was a fall after each in- jection, due, undoubtedly, to a direct depressant action of the drug upon the cardiac viscus, since such a fall was inevitably followed soon afterwards by the usual rise above the norm. The effect on respiration was similar to that of the first experiment, while the tempera- ture was raised o. 2 of a degree before the occurrence of death, this taking place through failure of the respi- ration. We append these two experiments in tabular form as follows: EXPERIMENT I. Normal. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. Remarks. H Dog Wgt. 5.6 kilos. O 120 I40 57 39.6. Antipyrint Solu tion 10 per cent. 3 3° loec. 120 140 57 Inj. begun into ju gular vein. 4 oo 120 140 57 Inj. ended. 16 30 20cc. I29 144 48 Inj. begun. 11 10 13* 160 33 Convulsions. 11 40 141 170 3° Inj. ended. 12 30 150 I90 42 39-6* 15 40 iocc. •59 ‘Z4 72 Inj. begun. 16 10 16 40 159 174 ISO 190 48 42 Inj. ended. 23 10 20CC. 174 170 60 Inj. begun. 24 10 *59 170 60 In], ended. 24 40 153 192 30.6. Respiration irre- gular and shallow. From this on the pressure and pulse rate gradually fell till the occurence of death 3 minutes later. Respiration and heart stopped together. Fig. I. (Normal).* EXPERIMENT II. Normal. Time Dose Pulse Pressure Respira- tion W Remarks. 4in. Sec. Grammes per Min. M.M. per Min. t-1 Dog Wgt. 13.4 kilos. O 132 I30 >5 39.8. Antipyrine Solu- tion 10 per cent. 2 00 4OCC. 132 130 >5 Inj. begun into ju- gular vein. 3 00 123 >34 12 4 00 132 140 1 t Inj. ended.—Con- 5 00 141 150 12 vulsions. 6 00 io5 160 39 39.7. Convulsions 7 c» 132 160 l8 ceased. i3 15 00 00 IOCC. 135 144 4-. Cn 0 0 12 21 Inj. begun. >5 20 144 140 18 Inj. ended. Strug 17 20 IOCC. 144 >5° 30 Inj. begun. •7 5° 90 150 39 Inj. ended. 21 40 30CC. 132 >5° >5 Inj. begun. 22 4° 78 170 42 Struggles. 23 40 150 180 27 Inj. ended. 24 00 120 220 18 24 40 20CC. 132 200 18 Inj. begun. 25 40 129 210 >5 Inj. ended.—Con- vulsions. 26 40 >47 160 >5 27 40 129 180 12 28 40 i65 200 12 Convulsions. 29 3° >59 200 >5 39.9. Animal died • from respiratory failure 2l/2 minutes dose of 20cc. ANTIPYRINE.—Tracing ot a dog, weighing 14 kilos. Injected into jugular vein 30CC. of a 10 # in 3 equal doses, with intervals ot 2 minutes. Fig. II. (Normal.) We have found, in the course of our experimenta- tion, that the fatal dose of this drug in dogs, intraven ously injected, is io cc. of a io per cent, solution, or i gramme per kilo of the body weight. ANTIPYRINE.—The same, . minute after the last injection. * All these tracings have been reduced to jiist cm?-hal their original size. 3 Fig. III. (Normal). EXPERIMENT III. Curarized. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. Remarks. Dog Wgt 9.29 kilos. O 96 I30 Antipyrine. 10 per cent. Solution. I OO IOCC. 96 13° Inj. begun intojugular vein. 2 00 93 IOO Inj. ended. 5 30 4OCC. 99 130 In], begun. 6 3° I°5 130 7 3° io5 130 8 3° 120 I40 Inj. ended. 16 00 20CC. 156 180 Inj. begun. 17 10 144 160 Inj. ended. 17 5° 123 I40 24 30 60CC. 156 184 Inj. begun. 25 3° 141 130 26 30 117 116 27 3° 120 120 28 3° 114 IOO Inj. ended. 39 30 5OCC. 183 200 Inj. begun. 40 3° 144 150 4i 30 129 IIO 42 3° 129 IOO 43 3° 117 90 Inj. ended. Pulse waves large. 49 OO *35 9° Animal died under another dose of 400c. 2 minutes later. ANTIPYRINE.—The same. 5% minutes after the last injection. In studying the cause of the rise of pressure we shall avoid an unnecessary lengthy discussion of the subject. We believe that the rise cannot be attributed to the con- vulsant action of antipyrine, or to changes in the respi- ratory function, since the same result is observed in curarized animals. In dogs under the influence of cu- rare, and in which artificial respiration was kept up, thus preventing the occurrence of the said convulsant action of the drug, and, at the same time, any changes that might be due to respiratory disturbances, antipy- rine produced phenomena similar to those effected in normal animals. This is proven by Experiment III, an example of others performed. In this experiment, it will be observed, there was a fall of pressure after each injection, but it was only temporary and due, without doubt, to a depressant action of the drug upon the heart. The lowering of the pressure was soon fol- lowed by a considerable rise above the normal point, accompanied, as in the case of normal experiments, by an increase in the rate of the heart beats, this being in itself of great significance. This is shown in the table given below. Fig. V. (Curarized). ANTIPYRINE.—The same, 6 minutes after last injection. Eight minutes after gave 30CC. of same solution, in the course of 2 minutes. Fig. VI. (Curarized). Fig. IV. (Curarized) ANTIPYRINE.—Tracing ot dog, weighing jo.s kilos. After the animal was under the influence p{ curare, injected 30 c, c, of 10 y, solution, Jij % doses, with an interval of 5 mihHfes, - same, 15 minute* alter the third injection 4 Identical results in regard to the arterial pressure were obtained in animals whose vagi had been previ- ously cut, and, similarly, in those in which both the pneumogastrics and spinal cord had been severed, with the application, in these latter instances, of artificial respiration. The following experiments, detailed in tabular form, are self-explanatory: It is perhaps needless for us to add that the reduction of the arterial pressure* produced by antipyrine, under large and toxic amounts, is, independent of the vaso- motor apparatus, also due to a depressant action of the drug upon the heart. The Pulse.—As will be noticed from the experiments on normal animals, the rate of the pulse, pari passu with the rise of the pressure, was generally increased. Some- times there would occur a primary decrease, especially after the injection, due, probably, to an overwhelming action of the drug upon the heart; this decrease, how- ever, was soon recovered from, followed by the usual increase above the normal rate. A more or less perma- nent secondary diminution in the number of heart beats, accompanied with a markedly large size of the individ- ual pulse waves, was often observed. After previous division of the pneumogastrics anti- pyrine, with a single exception, was unable to increase the rapidity of the heart. The drug, on the contrary, under such conditions, produced a reduction of the pulse-rate. Similar phenomena were obtained (as an examination of the experiments shows) when all nerve- gupply to the heart was cut off by previous section of the vagi and the spinal cord. These results lead us to the conclusion that the primary rapid pulse is due to paralysis of the cardio-inhibitory centres; the secondary decrease to an action upon the heart itself. Antipyrine does undoubtedly exercise, in sufficiently large doses, a direct depressant influence upon the heart of mammals, in the same way as it does upon that of the frog according to the observations of Arduin*), Demme*), Hare*), FAVAL’a), and Batten and Boken- ham *), although this is denied by Coppola *). The organ is generally arrested in diastole, and this we have con- firmed by post-mortem examination in some of the ani- mals killed by the drug. The Blood.—We have never been able to notice any changes in the character of the blood produced by anti- pyrine when administered in comparatively small or medicinal doses. This appears to be in accord with the observations of Arduin*), Pavlinow’) Huchard') Crolas and Hugounenq *), and Hare *'). In large or Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. d H Remarks. Dog Wgt. 28.117 kilos. O 225 170 ! 39.6. Antipyrine Solu- tion 10 per cent. IO 30 2occ. 225 170 Inj. begun into ju- gular vein. 11 10 213 170 Inj. ended. 12 10 201 176 •5 40 2occ. IQ2 170 Inj. begun. 16 20 I»6 170 Inj. ended. 17 5° 189 190 39- 22 00 2occ. 177 170 Inj. begun. 22 40 168 130 Inj. ended. 28 00 174 190 28 50 *74 180 ' 38. Respirat. frequent. 34 20 3000. «74 174 Inj. begun. 35 40 15° 150 Inj. ended. Ani- mal struggles. Respirat. about 60 per minute. 44 10 186 160 Respir. about 100 per minute. 49 10 171 180 38. Quiet again; respi- ration about 10 per minute. Killed afterwards with ether. EXPERIMENT IV. Vagi Cut. EXPERIMRNT V. Cord and Vagi Cut. Time Min. See. Dose Grammes Pulse per Min. Pressure M M. Respira- tion per Min. Remarks. Dog Wgt. 9.2 kilos. O 168 44 Antipyrine. 15 OO 4 grin. 168 44 Inj. begun into jugular vein. 16 OO 162 44 17 00 I44 5° Pulse waves very large. 17 50 >35 50 Inj. ended.—Pu 1 se waves large. Convul- sions. *8 50 45 36 Pulse waves very large. 19 50 60 32 Pulse waves very large. 22 50 i grin. 54 5° Inj. begun. 23 20 162 5° Inj. ended. 23 5' — Heart entirely stopped for 10 seconds and it then began to beat again; pulse waves very large. 24 50 3grm 39 3° Injected at short inter- vals, the heart being finally paralized in diastole. >) Loc. citat. *) Loc. citat. *) Loc. citat. 3a) Th6se de Lyon, 1887. British Medical Journal, June 1. 1890. s) Robert’s Jahresbericht, p. 314, 1885. *) Bull. General, de Therap., March 30, 1885. 7) Meditz. Obozr. fasc. XII, p. 1203, 1885. *) La Semaine Medicale, March 3, 1889, . 9) Lyon Medicale, March 3, 1889. >°) Loc, citat. It is evident from these results, that antipyrine exer- cises no apparent influence on the vaso-motor system, and that its stimulating effect upon blood-pressure, when adminstered in small and moderate dp&es, is chiefly, if not wholly, of a cardiac origin, 5 toxic amounts antipyrine produces (and this we have sometimes observed) a chocolate color of the blood, which is probably due to an alteration of the haemoglo- bin into methaemoglobin. Lepine *) affirms, after a careful spectroscopic examination of the blood of ani- mals poisoned by antipyrine, that such changes occur, an observation upheld by Hare and others, and ap- parently sustained by a large mass of clinical evidence. In regard to the corpuscular elements, these undergo no appreciable change, according to Crolas and Hu- gounenq 8) and Pisemski 8), who have made special re- searches on this point. The latter author states that ultimately the blood corpuscles may be diminished in number, but believes that such a phenomenon results, not through a direct action exercised by antipyrine, but from exhaustion of the animal experimented upon. We are in accord with the preceding statements, and there is scarcely any doubt that they are entirely cor- rect. We may state in passing, that as regards the respira- tory function, this was markedly increased even by small doses of antipyrine, and since this stimulation occurred similarly after previous division of the pneu- mogastric nerves, it is safe to assume that it is due to a direct action of the drug upon the respiratory centres in the medulla oblongata. The temperature in normal dogs, as the records show, was practically unaffected; but we shall return to this when we especially treat of heat phenomena. Conclusions.—A summary of the actions of antipy- rine on the circulation is now given: 1. Antipyrine in small and moderate amounts pro- duces a rise of the arterial pressure, this stimulating effect being due to an action upon the heart. 2. The lowering of the pressure by large or toxic doses is due similarly to a depressant action of the drug upon the cardiac organ. The remedy does not seem to influence the vaso-motor system. 3. Antipyrine causes an increase in the pulse-rate through paralysis of the cardio-inhibitory centres. The secondary decrease in the number of pulsations is of a purely cardiac origin, the drug exercising a depressant effect upon the heart itself. 4. Antipyrine, in excessive doses only, changes the haemoglobin of the blood into methaemoglobin. phenacetine. The literature concerning the study of the actions of phenacetine upon the circulatory system is almost nil. The first investigators to study the general action of the drug were Hinsberg and Kast ’), yet they did not make a thorough research regarding the influence that this remedy exercises upon the circulation. The authors just quoted found, among other effects produced upon the nervous system and respiration, that phenacetine caused cyanosis and discoloration of the blood, attriub- uting this phenomenon to the conversion of haemo- globin into methaemoglobin. Ott a) in studying the actions of phenacetine upon heat phenomena, has as- serted that this drug causes, while distinctly decreasing heat production, no alteration of the blood-pressure. Hare *) who has experimented with the remedy quite extensively, affirms likewise that phenacetine acts with comparatively little power upon the circulation, and that even very large doses do not influence the pulse-rate and the blood-pressure. We dissent from these views, and we cannot under- stand how such an able investigator and careful ob- server as Hare has failed to obtain the sufficiently marked effects that we believe the drug under consid- eration produces upon both the blood-pressure and pulse, judging from the results of the experiments that we shall presently detail. Phenacetine is an insoluble substance, and we do fear that Hare did not inject into the animal the quantity supposed to have been admin- istered. Such has happened to us in many instances, especially when the canula connected with the vein would be so small as to be easily occluded by the un- dissolved drug, and it was under such circumstances that no apparent effect could be noticed on the circula- tion. Several experiments were performed with a view to ascertain the actions of phenacetine on blood-pressure and pulse in normal animals, but only some of the most striking of said experiments will be detailed. The Blood-pressure.—For Exp. I a dog weighing 9.9 kilos was employed, administering, in varying amounts, a 2 % solution of the drug. After the first injection of 10 cc. the normal pressure which was 136 mm. was elevated to 140 by the end of the injection, which occu- pied 40 seconds. The column of mercury in the mano- meter soon returned to normal. Subsequent injections produced identical results, the pressure remaining above the normal for a period of fully 39 minutes, during which seven doses of from 10 to 40 cc. each were given at intervals of from 1 to 11 minutes. The respiration was not observed. The temperature was increased o. 2 of a degree by the end of the experiment. >) Lyon Medicale, Vol. III. s) Loc. citat. 3) St. Petersburg Inaugural Dissertation, p. 48, 1887. ') Centralbl. f. Gesammt. Therap., April, 1887. *) Journal of Nervous and Mental Diseases, XV., p. 598, 1888. 3) Loc. citat. 6 In Exp. II a 5 % solution was used in a dog weigh- ing 20 kilos. In this instance the first injection of 10 cc. produced a fall of pressure, but such was recovered from in 5 minutes. No change followed a second dose of the same amount. There was a slight reduction after the third injection of a similar quantity, the pressure re- turning to the original point in the course of 3 minutes. Three other doses of 20 cc. each caused a fall, the pres- sure never going back to the norm. The respiration was decreased in rate, and only slightly increased after the sixth dose of 20 cc. No record was taken of the temperature. For Exp. Ill a dog weighing 28 kilos was selected. Each of the four one-gramme doses was followed by an increase of the arterial pressure. The fifth injection of 4 grammes caused a fall which was gradual till the oc- currence of death, this being preceded by a tetanic con- vulsion. The respiratory function was unaffected after the third, and more so after the fourth dose. It became markedly rapid at the beginning of the fifth large dose, stopping finally two minutes afterwards, while the heart continued to act for 1 minutes longer. Death resulted, therefore, from respiratory failure. The temperature was reduced 0.4 of a degree. A small dog weighing 5.8 kilos was used for Exp. IV. A lowering of the pressure occurred immediately after the single injection of one gramme, and so con- tinued for about six minutes. It then returned to 120 nim., the normal height being 130 m. In the course of three minutes longer there was a sudden fall of pres- sure and the animal ceased breathing, while the heart continued to beat for two minutes later when it also stopped. The respiration, though irregular, was in- creased in rate, and before death it became markedly shallow. Failure of the respiratory function was the cause of death. The temperature was diminished 1.3 of a degree. It is thus seen that in two of these experiments, in which comparatively moderate quantities of phenace- tine were employed, the arterial pressure was increased. In the other two instances in which larger and toxic- amounts were ingested, the pressure was notably de- creased, and so continued till the final fatal effect. The lethal dose of phenacetine, intravenously ad- ministered, we have calculated to be o 26 grammes per kilo of the body-weight of the animal. We accompany the preceding experiments in tabu- lar form, as follows: EXPERIMENT I Normal. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. U Remarks. H Dog Wgt. 9.9. kilos. O 126 136 39.7. Phenacetine So lution 2 per cent. 2 OO IOCC. 126 !36 Inj. begun into ju gular vein. 2 40 156 140 Ini. ended. 3 20 20CC. 126 136 Inj. begun. 4 20 120 144 Ini. ended. 7 20 3OCC. 126 140 Inj. begun. 9 20 78 •5° 39.7. Inj. ended. II 40 *5° 150 14 IO 20CC. Inj. made. l8 OO 126 150 20 30 20CC. 108 140 Inj. made. 22 OO 108 148 25 30 20CC. 114 140 26 40 132 •54 28 OO 126 146 39-9- 33 00 — — Animal vomits and defecates. 36 00 40CC. 114 140 Inj. begun. 39 00 96 140 Inj. ended. Animal died unUci another dose of iocc. 3 minutes later. EXPERIMENT II. Normal. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. Remarks. Dor WKt. ao kilos. O 93 160 30 l'henacetine Solution 5 per cent. O o-> o IOCC. 93 160 3° Inj. begun intojugular vein. I 3° 99 148 3° Inj. ended. 2 IO 159 150 30 5 40 IOCC. 177 160 *5 Inj. begun. 6 io 168 160 *4 Ini. ended. 7 io IOCC. 165 160 *5 Inj. begun. 7 40 165 *50 15 Inj. ended. 8 io 174 160 l8 io 40 20CC. 141 160 12 Inj. begun. 11 40 102 120 18 Inj. ended. 12 20 96 *50 21 22 20 20CC. *32 *56 *5 Inj. begun. 23 10 *32 *44 *5 Inj. ended. 24 00 *47 156 24 25 30 20CC. 132 *56 24 Inj. begun. 26 20 *°5 140 36 Inj. ended. Same result followed under another injec- tion of iocc. Animal was afterwards killed with ether. Fio. a. (Normal) PHENACETINE.—Tracing of Dog, weighing 28 kilos. Gave intravenous in- jection of 1 gramme of drug, suspended in water EXPERIMENT III. Normal 7 Fig. c. (Normal). Time Dose • Pulse Pressure Respira- tion I . y Remarks. Min. Sec, Grammes per Min. M.M. per Min H r)°g Wgt. 28 kilos. O 174 136 33 40.3. Phenacetine. O 30 1 grm. 174 136 33 Inj. begun into ju gular vein. I 20 144 136 33 Inj. ended. 2 IO 144 I40 33 6 40 1 grm. 180 I44 27 Inj. begun. 7 30 180 140 27 Inj. ended. X IO 180 144 27 40. 11 40 1 grm. 132 144 33 Inj. begun. i ■>. 20 144 I44 36 13 OO 138 150 36 Inj. ended. •5 3° 1 grm. 108 I5t> 42 Inj. begun. 16 20 63 13* 45 39.9. Inj. ended. '9 20 III 140 18 20 20 72 15° 54 25 50 4 grm. 180 150 111 Inj. begun. 26 30 144 136 99 27 OO 96 IIO 45 Inj. ended. 27 50 129 140 21 Tetanic Convuls. 28 30 i5° 70 — Respir. stopped. 29 OO 52 3° Heart ceased 134 minutes later. PHENACETINF..—The same, 5 minutes after last record, or 12 minutes after injection. The results of the following experiment performed in a curarized dog, shows that, under such circum- stances, phenacetine is still able to elevate the arterial pressure: EXPERIMENT IV. Normal. EXPERIMENT V. Curarized. Time Min. Sec Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. Remarks. Dog Wgt. 15.873 kilos. O 15° 154' Phenacetine. 5 00 I grin. 15° *54 Inj. begun into jugular vein. 6 00 171 166 Inj. ended. 6 40 171 166 7 40 i65 170 11 10 i47 170 16 10 I grm. 183 160 Inj. begun. 17 10 i95 160 Inj. ended. 17 5° 201 164 22 20 1 grm. 207 160 Inj. begun. 23 40 222 170 Inj. ended. 24 40 249 156 27 10 2 grm. 246 156 Inj. begun. 28 10 246 13° Inj. ended. 28 40 264 120 36 40 264 140 Killed afterwards with ether. Time Dose Pulse Pressure Respira- tion Remarks. 0 Min. Sec. Grammes per Min. M.M. per Min. H Dog Wgt. 5.896 kilos. O io5 130 24 38.8. Phenacetine. I OO I grm. I30 24 Inj. begun into ju- gular vein. I 30 99 52 27 Inj. ended. 2 30 96 48 33 4 30 15 24 42 38. Respiration irre- 48 36 gular; pulse waves large. 5 3° 45 6 40 84 120 — 37.5. Respir. shallow; almost impercep- tible. 7 40 15 i Respir. stopped; heart continued to beat for two min- utes longer, when it ceased. Fig. b. (Noimal). Fig. d. (Curarized). PHENACETINE,—The same, 7 minutes after injection 1 HRNACETINE.— Tracing of Dog, weighing 22 kilos. After the animal was under the influence of curare, injected 1 gramme of drug. 8 Furthermore, an increase of pressure is observed in dogs whose pneumogastric nerves have been previously divided. This is shown in the following two experi- ments in which at the same time an increase in both the pulse and the respiratory rate also occurred: Fig. f. (Vagi Cut). EXPERIMENT VI. Vagi Cut. Time Dose Pulse Pressure Respira- tion U Remarks. Min. Sec. Grammes per Min. M.M. per Min. H Dog Wgt. n.791 kilos. O 165 146 306 40.2. Phenacetine. I I OO I grm. 165 146 306 Inj. begun into ju- gular vein. II 5° 174 60 327 Inj. ended. 12 20 222 136 195 Respir. deeper. 12 5° 213 204 390 Respir. shallow. 13 40 189 202 405 39-7- l6 20 I grin. I92 I96 360 Inj. begun. 17 OO 24I 120 342 Inj. ended. 18 OO 222 204 39° Respir. shallow. 18 5° 249 176 180 38.1. Respir. deeper. 24 20 213 210 360 Respir. shallow. 3° 20 1 grin. 219 178 330 Inj. begun. 3« OO 228 I40 294 Inj. ended. 31 5° 249 l6o 210 32 10 I grin. 249 l6o 210 Inj. begun. 33 00 249 140 150 Inj. ended. 33 40 231 166 — Respir. almost im- 36 10 222 176 288 perceptible. Died under a 2 grm. dose; heart and respir. stopped simultaneously. PHENACETINE.—Tracing of Dog, weighing 12 kilos. Injected 2c minutes after section ofvagi, 1 gramme ot drug, intravenously. Fig. g. (Vagi Cut). EXPERIMENT VII Vagi Cut. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. U Remarks. H Dog Wgt. 5 891 kilos. O 180 140 18 39.50. Phenacetine. II oo 0.5 grm. 180 I40 18 Inj. begun into jugular vein. II 50 180 no 27 Inj. ended. 12 50 180 130 48 l6 20 204 160 51 l8 OO 216 160 30 38.8. 21 30 0.5 grm. 210 146 I98 Inj. begun. 22 IO 201 104 210 Inj. ended. 23 OO 201 114 102 24 3° 209 136 60 26 30 219 144 60 38.6. 3* 3° 2l6 I36 39 Was afterwards killed with ether. PHENACETINE.—The same, 3 minutes after injection. Uppermost line represents the respiratory movements. In animals in which the spinal cord and the vagi have been previously severed, thus cutting off all nerve supply to the heart, with the complete production of vaso-motor paralysis, phenacetine was no longer able to produce a rise of the arterial pressure. The fall which the drug caused under such circumstances was recov- ered from in the course of a few minutes, but the pres- sure never went beyond the normal point. The follow- ing example explains itself: Fig. e. (Curarized) EXPERIMENT IX. Cord and Vagi Cut. Time Dose Pulse Pressure Respira- tion Remarks. Min. Sec. Grammes per Min. M.M. per Min. Dor WRt. 6.4 kilos. o 102 46 Phenacetine. 6 50 I grin. 96 36 Inj. begun into jugular vein. 7 20 99 34 Inj. ended. 8 20 96 24 Inj. begun. 9 00 0.5 grin. 96 24 9 20 93 12 Inj. ended. I leart stopped a minute later. PHENACETINE.—The same, 1% minutes alter injection- 9 A study of these results, with the significant fact be- fore us that the rate of the pulse and the column of the arterial pressure run a similar course, that is, increasing and diminishing together, would seem to show that both the rise and fall of the pressure are mainly of a cardiac origin. On the other hand, however, the fail- ure of phenacetine to elevate the pressure after section of the spinal cord, would indicate that in part at least the drug exercises, in normal animals and under mod- erate doses, a stimulating influence on the vaso-motor system. The fall of pressure produced by the remedy in large or toxic doses, is due chiefly to an action upon the heart itself. The Pulse.—An examination of the preceding experi- ments shows that, although in an irregular manner, the tendency of the drug in question is to produce, in more or less ordinary doses, an increase in the rapidity of the pulse. This rapidity is followed by a decrease in rate, though the force is sometimes manifestly increased as is attested by the large size of the individual pulse- waves, especially when larger amounts of the drug are adminstered. After the vagi have been previously di- vided the increased pulse-rate persists, but no secondary diminution is observed unless very late in the poisoning when overwhelming quantities of the drug have been ingested. It is apparent, then, that small and moderate doses of phenacetine increase cardiac action by influ- encing the heart itself, and that large amounts stimulate the cardio-inhibitory apparatus and thus cause a reduc- tion of the pulse-rate. But the inability of the drug to produce the usual increased pulse-rate after the heart has been deprived of all its nerve-supply, as is noticed in the example given, would seem to raise the question as to whether another factor must be taken into consideration for the » explanation of the first result, that is, as to whether the drug, besides acting upon the heart itself, also stimu- lates the cardio-accelerating nerve apparatus. It is so difficulty to decide positively how drugs influence, if they do at all, the accelerating centres, owing to the passive condition of these as regards activity, that we have deemed it wise to leave the point at issue in the present instance in statu quo, the clearing up of which is reserved to more thorough future researches. There appears to be no doubt, however, that phenacetine in large quantities reduces the pulse-rate by a double action : stimulation of the cardio-inhibitory centres and, later, depression of the heart itself. The Blood. — Although some observers, notably Hingsberg and Kast ‘), have stated that phenacetine alters the character of the blood, we have not, in our experimentation, been able to notice such phenomenon. The authors just cited claim to have proven, by spec- troscopic analysis, that the dark color of the blood caused by the drug is due to the presence of methaemo- globin. Hare *) concurs in the same opinion. Among other actions of the remedy under consid- eration, the most prominent is that exercised upon the respiratory function. Ordinary amounts produce no effect; but large quantities cause a marked quickening of the respiratory movements. As the same results take place after previous section of the vagi (see Fig. g.), it is evident that the drug acts directly upon the centres of the medulla. Death by phenacetine is caused by respiratory failure. The temperature in normal ani- mals was reduced more markedly than in the case of antipyrine; this action will be more fully discussed later. Conclusions.—We will now give the main conclu- sions regarding the actions of phenacetine upon the circulation, as found in the substance of the preceding discussion: 1. Phenacetine, in moderate doses, causes a rise of the arterial pressure by acting upon the heart, and prob- ably likewise by a stimulating influence exercised on the vaso-motor system. 2. The reduction of pressure by the drug in large amounts is mainly of a cardiac origin. 3. The remedy increases in small doses the force of the heart by a direct action. 4. Phenacetine increases the pulse-rate chiefly by cardiac stimulation, and possibly also by influencing the cardio-accelerating apparatus. 5. The drug reduces the number of pulsations, espe- cially in large quantities, primarily by stimulating the cardio-inhibitory centres, and, later, by a depressant action upon the heart. PHF.NOCOLL. This substance is a white, crystalline powder. It is soluble in water at a temperature of 62° F., in the pro- portion of 1 to 16 parts. It is more soluble in hot water and alcohol, but barely in chloroform, ether or benzol. Phenocoll is closely related to phenacetine, and is pre- pared by the interaction of para-amidophenotol (phene- tidin) and amido-acetic acid (glycocoll). Acording to chemists phenocoll is represented by this formula : OCjH, C«h<3° 30 I 40 150 66 30 Inj. ended. 2 oo 129 50 27 Respfr. shallow.. 2 3° 116 60 26 8 oo 135 100 27 IO 30 I2CC. *59 150 30 Inj. begun. ii 00 160 90 26 ii 20 144 40 24 Inj. ended. 12 OO L20 56 27 Respir. shallow. 13 30 132 88 30 39.2. Inj. begun. M Inj. ended. >7 18 20 20 20CC. I48 I44 ’8 30 30 18 5° I44 80 30 38.2. Died 2 minutes. later. Respir. fl_ of death. The respiration was comparatively unaffect- ed, but somewhat shallow and diminished in frequency. The temperature was lowered only just before death. No change was observed in the character of the blood. Death was produced by respiratory failure. EXPERIMENT II. Normal. Time Min. Sec. Dose Grammes Pulse per Min. Pressvre M.M. Respira- tion per Min. Remarks. Dojf Wfjt. 12.698 kilos. O 141 170 39 Phenocoll Solution 4 per cent. Prepared one of the vagi. o 40 5CC. 141 170 39 Inj. begun. I 10 180 IOO 33 Inj. ended. I 40 183 160 33 2 IO I92 160 36 Stim. of central end of . cut vagus; no re- sponse. 2 50 6cc. l8o 170 27 Inj. begun. 3 20 174 120 30 Inj. ended. 3 30 180 l6o 36 4 00 180 160 3° Another inj. of iocc. produced death from respiratory paralysis. EXPERIMENT III. Normal. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. O Remarks. 0 H Dog Wgt. 18.140 kilos. O 204 120 33 40.7. Phenocoll Solu- tion 4 per cent. I oo i6cc. 204 120 33 Inj. begun. I 30 171 84 33 I 50 156 70 33 Inj. ended. 2 30 165 96 27 Respir. shallow. 8 00 i6cc. 195 120 24 40. Inj. begun. 9 00 123 70 *5 Inj. ended. 9 30 122 3° 16 IO 00 114 20 — Respir. ceased. IO 30 54 20 — Pulse waves large. ii 00 54 20 — Pulse waves large. Heart ceased one minute later. >) Deut. Med. Wochenschr., April 9, 1891. *) Notes on New Remedies, February, 1892. 3) Loc. citat. *) Loc. citat. *) Loc. citat. *) Loc. citat. 1). Notes on New Remedies, Vol. IV, p. 27, 1891. 11 Exp. II, for which a dog weighing 12.6 kilos was used, gave practically the same results. For Exp. Ill a dog weighing 18.14 kilos was selected. The first injection of 16 cc. was followed by a reduction of pres- sure, but this soon recovered completely. A second dose of the same amount, administered eight minutes later, produced a fall which was progressive up to death. The respiration was decreased in rate and shallow in character ; it soon ceased under the second dose. The temperature was only slightly influenced; it had only fallen 0.7 of a degree at the time of the injection of the second dose. EXPERIMENT V, Curarized. Time Min. Sec. Dose Grammes Pulse per Min. Pressure M.M. Respira- tion per Min. Remarks. Dog Wgt. 13.152 kilos. O l86 150 Phenocoll Solution 4 per cent. Waited 20 minutes. O 3° IOCC. 186 150 Inj. begun. I 5° 186 no I 20 165 5o Inj. ended. 2 IO 144 70 •« 4 40 189 130 Inj. begun. S 30 IOCC. 168 60 Inj. ended. 6 20 165 90 9 50 IOCC. 204 130 Inj. begun. IO IO 168 60 Inj. ended. ri OO 153 80 The last dose of IOCC. was followed by the same results and the animal died under it. EXPERIMENT IV Time Dose Pulse Pressure Respira- tion CJ Remarks. Min, Sec. Grammes per Min. MvM. per Min. H DogWgt 15.2 kilos. 0 96 140 41. Phenocoll Solution 1 percent. 2 20 20CC. 142 Ini. begun. 3 lo I23 no Inj. ended. 4 10 131 150 5 00 2'OCC. 114 156 Inj. begun. 6 00 129 160 Inj. ended. 6 30 150 170 7 JO tocc. 144 160 Inj. begun. 7 50 144 160 Inj. ended. 50 120 160 40.9. Struggles. 15 30 30CC. 126 156 Inj. begun. *7 00 90 160 160 Inj. ended; pulse waves large. :7 5° 129 23 20 40CC. 135 160 Inj. begun. 25 IO 108 140 Inj. ended. 2S 5° 129 170 28 20 144 176 41. 32 10 30CC. 156 170 Inj. begun. 33 10 120 140 Inj. ended. 34 00 144 170 39 40 20CC. 165 160 Inj. begun. 40 10 168 140 Inj. ended. 40 50 144 180 4i-5 46 20 IOCC. ■ 174 170 4 per cent. Solution used; inj. begun. 46 40 126 140 Inj. ended. 47 OO ioce. 168 160 4percent. Solution used; inj. begun. 47 20 150 120 Inj. ended. 47 40 IOCC. 120 140 Inj. begun of 4 per eent. Solution. 48 OO 120 . 160 Inj. ended. 48 20 126 66 48 40 114 160 41.8. Respir. stopped. 49 IO 142 230 Pulse irregular; from this time pres- sure went down gradually till heart ceased. Normal. EXPERIMENT VI. Vagi Cut. Time Dose Pulse Pressure Respira- U Remarks. iicm Min. Sec. Grammes per Min. M.M. per Min. H Dog Wgt. 9.514 kilos. O 192 150 27 39.3. Fhenocoll Solu- tioa4 per oent. o 30 5CC, 192 150 27 Ini. begun. I 00 165 100 27 In], ended. I 5° 156 130 24 5 20 5CC. 174 .150 15 Inj. begun. 5 5° 171 100 15 Inj. ended. ii 5° 126 130 21 38.9. J9 20 50c. 123 136 18 Inj, begun. 20 00 120 90 24 Inj. ended. 20 00 105 120 21 Pulse waves large. 27 30 IOCC. 96 140 J5 38.8. Inj. begun. 28 33 20 50 105 114 72 128 15 Inj, ended. 38.0. Killed afterwards .. .4': . with ether. EXPERIMENT VII. Cord and Vagi Cut. Time Min. Sec. Dose Pulse Grammes per Min. Pressure M.M. Respira- tion per Min. Remarks. Dog Wgt. 19 kilos. O 186 14 Phenocoll Solution 5 per cent. I oo iocc. 186 14 Ini. begun. I 5° ’ 144 8 Inj, ended. 2 50 ; ”7 6 3 5° hi 6 4 5° 120 8 IO 20 IOCC. 126 8 Inj. begun. 11 00 ! 120 4 Inj. ended ; animal died 2 minutes later. marked 170 mm., the normal being 140 mm.; it re- mained above this point under subsequent injections, but finally fell under three doses of 10 cc. each of a 4% solution. At the time of the stoppage of the respira- tion the needle of the manometer marked 230 mm., this perhaps being due to asphyxia. The temperature fell o. 1 of a degree after 50 cc. of the 1% solution had been ingested, but it went back to normal, and even rose to 0.8 above the normal before death; the animal died from respiratory failure. A \% solution of phenocoll was used for other ex- periments of which Exp. IV is an example. The animal used here weighed 15.2 kilos. An injection of 20 cc. caused a momentary fall of pressure which was soon recovered from. The column of mercury was then rais- ed above the normal height, so that about minutes after the second dose of the same amount, the pressure 12 Fig. h. (Normal). Fig. k. (Normal). PHENOCOLL.—Tracing of Dog, weighing ia.6 kilos. Injected into jugular vein 5CC. of a 1 per cent, solution of drug. Curves in centre represent the respiratory movements Fig. i. (Normal). PHENOCOLL.—The same, 6 minutes after injection. The action of phenocoll upon the arterial pressure, in medicinal doses, although slightly stimulating, is prac- tically unimportant. The more marked effect, espe- cially when comparatively large quantities are ingested, is that of depression, such phenomenon occurring simi- larly not only in curarized animals, but also in those in which section of the spinal cord and the pneumogas- trics has been practiced beforehand. These results and the significant elevation of the reduced pressure by asphyxia, as is seen in the latter part of Exp. IV, all would seem to show that the vaso-motor system is not influenced by the drug. PHENOCOLL.—The same, 3 minutes after injection. No other changes occurred in over half an hour. Fig. j. (Normal). Fig. 1. (Normal). PHENOCOLL.—'Tracing of Dor, weighing 10.2 kilos. Injected into jugular vein iocc. of a 4 per cent, solution of drug, between x—x marks. Uppermost curves represent respiratory movements. PHENOCOLL.—The same, 9 minutes later 13 Fig. m. (Vagi Cut). Conclusions.—We conclude, then, that 1. Phenocoll, in ordinary amounts, has practically no effect upon the circulation. 2. Large doses diminish the blood-pressure by influ- encing the heart. 3. Phenocoll reduces the pulse-rate by stimulating the cardio-inhibitory centres. It then increases the ra- pidity of the pulse by paralyzing said centres. The final diminution is of cardiac origin. 4. Upon the blood itself phenocoll has no action. ON HEAT PHENOMENA. The manner in which antipyretics act on tempera- ture is imperfectly understood. It seems to be the gen- eral concensus of opinion that they act through the nervous mechanism controlling the temperature of the body. Sawadowski, quoted by Ott1), has failed to get the usual effect of antipyrine after destruction of the corpora striata. This has been confirmed by Ott1). Nearly all experimenters have failed to get with nor- mal animals the decided action obtained with fevered animals. This fact signifies that metabolism is not af- fected directly, or we would have a constant action on heat phenomena. We shall study in this paper the effect of anti- pyrine, phenacetine and phenocoll on the normal ani- mal and then on an animal in a state of fever. The experiments have been made with the ordinary calorimeter described by Reichert *). The animals were all healthy dogs, which had been fed the night previous to the experiment and not allowed to eat or drink during the course of the experiment. The heat production (H.P.) and the heat dissipitation (H.D.) were measured for periods of one hour. The normal H.P. and H.D. were taken for two hours, and then the drug given, and the heat production and heat dissipitation observed for three hours more. In the normal animals the drugs were injected subcutaneously. In studying the results obtained we must not be too hasty to say slight changes result from the drug. In the first place it must be borne in mind that the heat production and heat dissipitation vary a great deal from hour to hour normally. Further, Reichert 4) has shown that confine- ment in a box for several consecutive hours causes a fall of animal temperature. Before we can study the effect of antipyretics on fevered animals, we must try to determine how the fever is produced. Most of our experimental fevers PHENOCOLL.—Tracing of Dog. weighing 6.5 kilos. Injected intravenousl 5cc. of a 4 per cent, solution of drug. Fig. n. (Vagi Cut). PHENOCOLL.—The same, 4 minutes after injection. The Pulse.—The heart-beat in the normal animal, was at first diminished, the reduction being generally followed by an increase above the original rate. The same result was noticed in curarized dogs. The rapidity of the pulse was prevented by previous section of the vagi and of all the nerves supplying the heart, as is ob- served in Exp. VII. It may be inferred from such re- sults that the primary reduction of the pulse-rate is due to stimulation of the cardio-inhibitory centres ; the sec- ondary quickening to paralysis of the same. A further proof of this last assertion is found in Exp. II, in which electrical irritation of the central end of a vagus pro- duced no effect. The final diminution of the pulse-rate, which was often accompanied by a marked increase in the size of the pulse-waves, may be said to be due to an action upon the heart. The Blood.—As far as we have been able to observe, phenocoll exercises no action upon this tissue. >) Modern Antipyretics, 1891. 2) Loc. citat. 3) University Medical Magazine, January, 1890. 4) University Medical Magazine, February, 1890. 14 were produced by intravenous injection of putrid blood. The subcutaneous injection of both putrid blood and albumoses failed to produce an immediate fever. The method of injecting one large dose of putrid blood is very undesirable because it causes an intense fever, whose maximum is soon reached and then gradually falls. In the experiments given in this paper the blood was injected every hour in 5 drop doses, after the normal temperature had been taken for two hours. This produced a steady fever. On the second day, the same dog, under the same circumstances, was placed in the calorimeter and his H.P. and H.D. taken; then after that, 5 drops of putrid blood were again injected every hour. After the first hour of fever the drug was given by the stom- ach, in order that the relative time of absorption might be determined. The fever was produced the first day by an increase of the H.P. We give below a composite curve show- ing how fever was produced in twenty experiments. It will be seen that with H.D. there was scarcely any disturbance; but the H. P. rises enormously at first, causing the elevation of temperature. After the fever is established, the heat production falls although the temperature continues to rise, because the H.P. is con- stantly in excess of the H. D. HEAT DISSIPATION. I. 21.32 16.82 17.17 *5-75 12.15 I3-22 n. 30-51 29.07 29.45 32.15 29.00 28.77 hi. 20.95 22.77 24-57 22.15 24.17 20.45 IV. 38.90 30.27 33-22 29.92 3,-82 26.42 V. 28.26 25.86 28.12 25.42 24.22 24.40 VI. 28-55 29.70 27.00 27.20 24-95 23-35 VII. 27.82 26.67 27.42 73.02 17.10 14.16 VIII. *5-45 16.15 U6.65 20.22 18.62 *5-97 Average 26.42 24.66 25-45 24.48 22-75 20.84 TEMPERATURES. I. 38.8 38.1 38.1 38.2 37-9 37-9 II. 38.3 38.1 38.1 38.1 38.3 III. 38.8 38.8 38.7 384 38.5 *8.6 IV. 38-3 39-5 38.2 38.3 38.3 38.4 V. 38-4 38.3 38.3 38.2 38.1 38.1 VI. 384 38.6 384 38-3 38.1 38.1 VII. 3».< 38.3 38.3 37-9 37-9 37-9 VIII. 38.8 38.6 38.7 38.2 38.2 38.0 Average 38.54 38.56 38.85 38.20 38.« 3 38.16 Fig. p. Fig. o. Above is seen a compositive curve showing the effects of antipyrine in the normal animal. The numer- als to the left represent heat-units. The continuous line represents heat production, and the dotted line heat dissipation. The curve below (continuous Heavy black line) represents the temperature in degrees centi- grade. We see here a slight fall of temperature for three hours after the drug was given. This occurs with a corresponding fall in H.P. and H. D., all of which was so slight that we cannot say that the whole change would not have occurred without any drug, as the result of the animals being confined in the calorimeter for several consecutive hours. The effect of antipyrine in fever is seen in the fol- lowing table : ANTIPYRINE. We tabulate below the results of antipyrine on nor- mal animals : ANTIPYRINE IN NORMAL ANIMALS. HEAT PRODUCTION. No. of Exp. Wgt. p. kilo. Before inj. Dose Sub. p. kilo After injection. 5th h. 1st hour. 1 st h. 2nd h. 3rd h. 4th h. I. 10-54 20.56 O. I grm. IO.4I 17.51 16.42 9-95 13.22 II. 13-37 28.97 O.I t« 28.64 27-31 32.04 28.25 29.64 III. 5.10 i9-5& O. I i t 22-53 24.00 21.17 24.50 20.89 IV. 11.66 36.96 O.I ( k 31 76 30.89 30.68 31-35 27-63 V. ”•55 26.87 O.I t < 24.84 27-75 24-31 24.04 24.40 VI. 12.92 25-91 O.25 i t 3«07 25.8,5 26.93 22.31 28.62 VII. 12.81 2341 O.4 25-63 27.32 19.74 16.28 14.67 VIII. 10.99 10.87 0.4 < < 13.86 15-85 16.09 18.97 13-77 Average 24.14 23-59 24.50 23-42 21.96 21.61 15 HEAT PRODUCTION. ANTIPYRINE IN FEVER. First Day. No. of Exp. Wgt. in kilos. In normal state. Dose of p. blood. In fever state (no drug) 1st h. 2nd h. p. hour. 1st h. 2nd h. 3rd h. 1. 9.62 33-ii 29.OO 5 drops 47-77 34-42 27.58 II. 9.29 21.05 23-17 5 “ 43.10 34.08 34.86 III. 9.07 21.77 21.82 5 “ 29.05 26.73 24.29 IV. 12.34 26.00 27.28 5 “ 29.74 38-94 37-16 V. 12.13 28.39 27.44 * 5 “ 28.30 3°-47 32-33 Average IO.49 26.06 25-74 35-59 32-93 1 tsi Second Day. Normally. Dose of p. blood, p. hour. In fever. Dose of Antipyrine p. kilo. 1st h. After drug. 2nd h. 3rd h. 21.00 5 drops 37-03 1.86 grin. 23-54 12.70 20.91 26.51 5 “ 35-84 0.93 “ 44-97 25.62 15 37 I9.26 5 “ 33-3o 0.93 “ 30.48 32.63 Death. 25-25 5 “ 30.76 0.41 “ 17.66 25.48 23.66 28.10 5 “ 45.24 0.41 “ 27.15 31-31 21.47 24.02 36-43 0.93 grin. 28.76 25-55 20.35 HEAT DISSIPATION. I. II. First Day. 34-63 30.15 30.45 35-57 28.35 24-75 26.87 34.22 28.90 30.42 III. 23-25 22.19 19.80 18.59 22.81 IV. 28.50 25-75 25-74 28.44 31.16 V. 33-79 28.34 25.6b 25-57 24.23 Average 28.98 26.67 27.16 27.41 27-39 Second Day. 24.08 20.86 35 86 23-43 19-37 25.07 27.15 50.77 28.52 22.62 l929 22.89 35-55 24.30 Death. 25.25 2731 36.90 32.88 26.62 29.07 32.15 ' • 39-37 25-49 25-35 22-53 26.07 39-69 26.93 23-49 TEMPERATURES. Second Day. 39-2 4i-3 39-7 38.3 38.5 40.5 41.7 40.9 40.5 39-5 40.5 4I-95 41.25 42.4 Death. 40.5 41.85 39-9 39-15 38.85 40.3 41.65 40.4 41.0 40.6 40.2 41.69 40.43 40.27 39-36 First Day. I. 39-4 39-25 4i-5 41.7 41.6 II. 39-4 38-9 40.1 40.8 41.4 III. 39-2 39-16 40.4 41-5 41.7 IV. 39-25 39-4 39-8 40.85 41-45 V. 39-4 39-3 39-6 40.3 41.2 Average 39.13 39-2 40.28 41.03 41.47 Fig. q. An examination of the results obtained from the ex- periments with antipyrine in fever shows that the fever is produced the first day by an increase of heat produc- tion without any alteration in the heat dissipation. This increase is greatest the first hour, and the temperature continnes to rise although the heat production falls some after the fever is established. The second day we see the fever produced again, as on the previous day, by an increase of heat production. But the very next hour, after the administration of anti- pyrine by the stomach, we observe in the composite curve a fall of 1.2.° C., produced by a double action: an increase of heat dissipation and a reduction of heat production. The fall of temperature continues till the end of the experiment. It would seem from this that antipyrine, to cause this double action, must influence the thermotaxic mechanism. PHENACETINE. Very little experimental work has been done with phenacetine. Ott1) has studied the effect of this drug on the heat functions and concludes that phenacetine reduces the temperature by causing a fall of both heat production and heat dissipation. *) Journal of Nervous and Mental Diseases, 1888, p. 598. 16 An examination of our experiment with phenacetine in normal animals shows practically no changes. There is a slight fall of temperature the third hour after the drug was given, but so slight that it cannot be said to be due to the effect of the remedy. In the fever experiments we see again the fever pro- duced by an increase of H.P. On the second day we notice in the average of the results a decrease of ten heat units in the heat production during the first hour after the administration of the drug per stomach. The temperature, however, does not fall much until the third hour; and the heat production reaches the mini- mum at this time. The H.D. is very slightly affected. It would, therefore, seem that phenacetine does not act as promptly as antipyrine, and that it causes a fall of temperature by producing a diminution of heat produc- tion . In order to see if phenacetine would act differ- ently in a fever produced in another manner the follow- ing experiments were performed: First hour 2563 22.59 40.95 0.2 gram. Albumose per jugular, ami 5.2 gram. Phenacetine per stomach. First hour after the ingestion of drug 33-39 31.21 41.85 0.2 gram. Albumose per jugular. Second hour after drug 27.52 30.43 4>-3 0.2 gram Albumose per jugular. Third hour after drug 24.70 26.87 41.05 0.2 gram. Albumose per jugular. Fourth hour after drug 22.21 26.99 40.5 0.2 gram. Albumose per jugular. Fifth hour after drug 21.99 28.08 39-8 Second Day.—Animal reduced to 10.88 kilos. It will be seen from this that albumoses produce fever also by a rise of heat production, and that phena- cetine keeps the temperature from rising to the height attained during the first day, by diminishing the heat production. The heat dissipation is not affected by the drug. We append the following tables showing the actions of phenacetine on normal and fevered animals : PHENACETINE IN NORMAL ANIMALS. EXPERIMENT A.—Dog-weight, 10.31 kilos. HEAT PRODUCTION. First hour H.P. . 20.00 H.D. 24.94 TEMP. 39-0 0.267 gram. Albumose per jugular. Second hour 44.64 24-43 41-45 0.267 gram. Albumose per jugular. Third hour • 3*85 26.05 4215 Fo injection. Fourth hour . 28.07 26.32 42-35 First Day. No. of Wgt. in Before injection. Dose Sub After injection. Exp. kilos. 1st h. 2nd h. p. kilo. X8t h. 2ndn. 3rd h. t 10.21 32-63 26.21 0.1 grm. 24.96 22.92 20.47 II. 9-5* 20.93 23.78 0.1 “ 23-41 22.50 — III. 9.07 47.08 47.01 0.1 “ 49-37 41-9* 39-94 IV. 12.92 35-94 32-59 0.1 “ 32.64 30.72 3*-97 V. 9.51 28.28 26.06 0.1 “ 26.72 24.40 17.01 Average 10.24 32-97 3**3 0. i grm. 3>-42 28.45 27-35 HEAT DISSIPATION. Second Day.—Animal reduced to 10.09 kilos I. 35-°7 28.00 25-45 25.98 22.10 n. 20.17 24.92 24-55 22.50 — hi. 47.80 48.45 47.92 42.27 41-75 IV. 40.07 34-65 34-70 30.72 33-0° V. 29.80 25.30 27.10 24.02 20.05 Average 3458 .32.26 3>-96 29.19 29.22 First hour 19.26 24.10 39-0 0.2 gram. Albumose per jugular. Second hour *. 35.06 22.15 40.9 0.2 gram. Albumose per jugular, and 4.8 gram. Phenacetine per stomach, (0.48 gram, per kilo). Third hour 21.87 23.88 40.05 0.2 gram. Albumose per jugular. Fourth hour 26.01 24.00 40.9 0.2 gram. Albumose per jugular. Fifth hour 21.17 26.81 40.2 TEMPERATURES. I. 39-4 39-2 39 1 38-7 38.5 II. 39* 3»-95 38.8 38.8 — III. 39-3 39' 39-3 39-25 39-o IV. 39-o 38.8 38.6 38.6 38.5 V. 39-5 39-6 39-55 39-6 39-2 Average 39-3 39-> 39-> 39-o 38.8 EXPERIMENT B.—Dog-weight 11.55 kilos. Fig. r. First Day. H.P. H.D. TEMP. First hour 36.99 39-4 Second hour . . 36.61 38.45 39-2 0.2 gram. Albumose per jugular. Third hour ■ 4I-76 34-37 40.0 0.2 gram. Albumose per jugular. Fourth hour . . 37.20 32»4 40.55 0.2 gram. Albumose per jugular. Fifth hour 28.30 41.2 17 HEAT PRODUCTION. PHENACETINE IN FEVER. First Day. No. of Exp. Wet. in kilos. In normal state. Dose of p. blood. In fever state (no drug;) 1st h. 2nd h. p. hour. 1st h. 2nd h. 3rd h. T. 8.16 21.64 22.97 5 drops 26.29 24.Il 26.96 TI. 9.26 20.40 33-42 5 “ 27-37 30-55 24.36 TIT. IO.23 36.81 32-45 5 “ 4I.O9 44.OI 44-58 IV. IO.83 29.21 32-34 5 “ 43-87 27.78 39-24 V. IO.23 19.67 17.90 5 “ 28.14 24.49 — Average 9.62 25-55 27.81 33-35 3°. 18 33-78 Second Day. Normally Dose of p. blood. I11 level- Dose of Phenacetine. After druR. p. hour. p. kilo. 1st h. 2nd h. 3rd h 16.98 5 drops 28.92 0.48 grm. *9-53 27.48 22.21 25-9I 5 “ 42.21 0.48 “ 29.60 33-88 23.06 28.76 5 “ 40.12 0.48 ‘‘ 35-87 39-29 24.52 25.98 5 “ 48.88 0.48 “ 28.69 35-74 32.4I 20.42 5 “ 29.OO 0.48 “ 22.76 25-56 I7.I9 23.61 37.82 0.48 grm. 27.29 32-39 23.87 HEAT DISSIPATION. I. First Day. 20.67 24.27 23-03 18.90 21.10 II. 21.95 33-05 26.25 30-55 22.86 ITT. 39-42 32.88 37-o8 40.10 25-45 IV. 32-93 33-58 35-60 27.78 35-94 V. 22-55 17.90 21.96 19.14 — Average 27.50 28.33 28.78 27.29 26.33 Second Day. 18.93 22.40 23.76 25.20 27.42 26.65 30.84 28.86 34.26 33-42 32.46 33-58 31-38 40.IO 35-15 30.07 32-93 34.82 38.19 33-22 21.23 21.23 21.13 21.88 27.00 25.89 28.19 27.99 31.92 31.24 TEMPERATURES. I. First Day. 39-4 39-2 39-7 40.5 41.4 II. 39-2 39-25 39-4 39-4 41.4 III. 38.9 38.85 39-3 39-75 40.08 IV. 39-35 39-2 40.2 40.2 40.6 V. 39-25 39-25 40.0 40.65 — Average 39.2 39-15 39-7 40.1 41-05 Second Day. 40.8 41.8 40.15 40.5 39-7 39-4 40.95 4I.O5 41.0 39-6 40.25 4I.O5 41.6 4i-5 40.2 39-7 41.65 40.9 40.6 40.5 40.I 41.05 4I.25 41.7 40.5 40.05 41-3 40.99 41.06 40.1 Fig. s. o/' jEx-.ax. in 7*evet' PHENOCOLL. As far as we know no calorimetrical studies have been made with phenocoll. An examination of our experiments with this drug in normal animals shows that it exercises no effect on the heat functions. There is a slight fall of temperature at the end of the experiments', but this is so slight that jt is probably the result of the animal being kept in the calorimeter for several consecutive hours, and not that of the action of the drug. The following experiments given in tabular form sufficiently explain themselves: PHENOCOLL IN NORMAL ANIMALS. HEAT PRODUCTION. No. of Wet. in Before iniection Dose Sub. After iniection. Exp. kilos. 1st h. 2nd h. p. kilo. 1 st h 2nd h. 3rd h. I. 7-7 23.46 24.19 0.15 grm. 17.94 19.11 n. 8.61 18.25 20.60 •■5 “ 26.00 24.18 22.57 hi. 13.60 57-31 44.98 2.0 “ 34-84 38-49 IV. 7-25 16.60 23-41 1-5 “ 20.22 19.95 — V. 10.23 23-75 34-9* 1.6 “ 31-95 26.58 32.61 Average 9.88 27.87 29.61 I.25 grm, 26.19 25,64 27-59 18 HEAT DISSIPATION. I. 25-3° 24.80 20.40 18.50 — 11. 19.62 21.97 25-32 22.12 23-25 111. 5i «7 47-15 37.00 39-57 — IV. 16.60 22.25 23.12 22.75 — V. 28.65 35-72 29.50 29.85 33-42 Average 28.46 30.37 27.07 26.56 28.33 The experiments on fevered animals show a decided action of phenocoll on the animal temperature. The fever was produced as before by an increase of heat production. The diminution in heat dissipation with the beginning of fever in these experiments was caused by the unusual results in Exp. IV. On the second day there was an enormous rise of heat production with the introduction of putrid blood. The next hour after the administration of phenocoll by the stomach the tem- perature fell almost to the normal, and continued fall- ing during the rest of the experiment. This fall of tem- perature was caused by a corresponding diminution of heat production. The heat dissipation is not affected. CONCLUSIONS. 1. Antipyrine, Phenacetine and Phenocoll all fail to produce any effect on the heat functions of the normal animal. 2. Antipyrine produces a decided fall of temperature in the first hour after its administration in the fevered animal. This reduction is due to a great increase in heat dissipation, together with a fall in the heat produc- tion. 3. Phenacetine, both in septic and albumose fevers, produces a very slight fall of temperature during the first and second hours after its ingestion by the stomach, but the greatest reduction occurs the third hour after its ingestion. The fall of temperature results chiefly from TEMPERATURES. I. 39'1 39-° 38.6 38.7 — TI. 39-4 39-2 39-3 39° 39-i III. 40.0 39-8 39-6 39-5 IV. 39-4 39-6 39-1 38.6 — V. 39-1 39-1 39-3 389 38.8 Average 39.4 39-3 39-2 389 38-9 Fig. t. HEAT PRODUCTION. PHENOCOLL IN FEVER. First Dav. No. of Exp. Wgt. in kuos. In normal state. Dose ot p. blood. In fever state (no drug) 1st h. and h. p. hour. 1 st h. 2nd h. 3rd h. I. 11.66 22.30 25.88 5 drops 48.17 36.28 31 -95 II. 12.13 47-49 43-24 5 “ 56-56 56.36 49.61 III. 11.11 Same dog as in Experiment II. IV. 10.23 23- 29.87 5 drops I9.20 35*6 23-54 V. 38.38 35-58 35-21 5 “ 29.44 31-76 32.88 Average 10.70 32.22 33-55 38-34 39.88 34-49 Second L)av. Normally Dose of |>. blood. I11 fever. Dose of I’henacetir 1 r After druK. p. hour. p. kilo. 1st h. 2nd h. 3rd h. 4th it. 18.99 5 drops 45-79 0.28 grm. 26.19 24.21 2I.3O 24.26 34-79 5 “ 61.21 0.28 “ 11.77 54.02 39-22 28.22 3*-27 5 “ 55-7i 0.28 “ 29.76 38.64 30-43 — 33-16 5 “ 5I27 0.28 “ 34-5° 27.68 23-30 — 21.00 5 “ 26.29 0.28 “ 24.65 18.85 12.57 — 27.84 48.05 0.28 grm. 25.37 32.88 25-36* 26.24 HEAT DISSIPATION. First Day. T. 27.95 26.35 27.90 32-52 34-77 II. 55-10 45-27 41.85 44.20 50.62 in. Same dog as in [Experiment II. IV. 24-32 29.87 1307 3«-o> 15.68 V. 32-93 30.88 23.40 28 40 29.52 Average 35.07 33-°9 26-55 34-03 32-51 Second Day. 20.85 28-55 39-70 20.80 27-35 27.05 37-70 43-75 30.20 48.20 39-70 36-95 54.82 40.75 47.80 37-32 35-75 — 3438 36-55 43.08 38.08 25-75 — 23.68 23.28 18.29 20.52 20.95 — 30.28 34-56 35-8* 34-78 29.90 32.00 TEMPERATURES. I. First Day. 39-i 3905 41.2 41.6 4i-3 11. 39-15 38-95 40.4 41.6 4i-5 III. — — — — IV. 39-2 39-2 39-95 40.45 41-35 V. 38-95 39-6 40.5 41.0 4i 5 Average 39.* 39-* 4°-5 4M 41-4 Second Day. 39-35 41.2 39-75 39 *5 38-5 28.2 39-6 41.4 39 5 40.1 40.05 39 *5 39-9 41.6 30.05 39-7 39-6 — 39-6 41 4 40.35 39-2 38-9 — 40.1 40.55 41-5 41.25 40.00 — — — ■ ■" ■ ■ - — —— 39-91 41-23 40.13 39.88 38.67 19 Fig. v. erf S. J5x-per*i-mvnts zv-ith' jpfv&noieurl/', a decrease in heat production, with a slight increase in the heat dissipation. The increase in dissipation is not as great as with antipyrine. Probably the delayed ac- tion of the drug depends on its insolubility. 4. Phenocoll causes in fever a very decided fall in temperature, which occurs the first hour after the ad- ministration of the drug by the stomach. This reduc- tion is the result of an enormous diminution of heat production, without any alteration of heat dissipation. Our experiments with antipyrine are in accord with the results obtained by Martin1). Wood, Reichert and Hare s), together with Destree s), have reached the conclusion that antipyrine reduces the temperature by a decrease in heat production, and that heat dissipation also falls with the production. In our experiments with antipyrine the composite curve shows the rise of heat dissipation. We believe, therefore, that this phenomenon is effected through a thermotaxic rather than through a thermogenic mechan- ism. We further believe that phenacetine and pheno- coll reduce the temperature by a decrease in the heat production through their action on a thermogenic nerv- ous centre. The fact that all drugs here studied fail to produce any effect on the normal heat function proves that they affect these functions through the nervous sys- tem. Probably the fact pointed out by Hare in his ex- cellent essay 4) that many investigators do not take into account other circumstances, such as tying ani- mals down, and confinement in a box, may explain many of the results obtained by some observers in the normal animal. In concluding this study we are justified, judging from the results of our experimentation, in saying that of the three drugs in question, the safest for practical purposes, especially as regards an action upon abnormal temperatures, would be phenocoll. Phenacetine is slow on account, no doubt, of its insolubility, and is comparatively feeble as antipyretic. Antipyrine, it is true, is soluble and prompt in reducing feverish con- ditions, but its action upon the circulation, par- ticularly upon the heart, is so pronounced, even when administered in therapeutic doses, that it is, for this reason, a dangerous substance to use. Phenocoll, on the other hand, is readily soluble, rapidly absorbed, and, undoubtedly, promptly eliminated. Its power to reduce ab- normal high temperatures is very decided, and it does this in therapeutic doses, without de- pressing the circulation. Phenocoll, therefore, would seem to be superior to antipyrine and phenacetine as an antipyretic. Physiological Laboratory of the University of Pennsylvania. ') Therapeutic Gazette, 1887. 2) Therapeutic Gazette, Vol. II, p. 803. 3) Jour, de Medecine de Bruxelles, July 20, 1888. 4) Fever: Its Pathology and Treatment, Boylston Prize Essay, 1890.