`
`REPLACEMENT EXHIBIT 2044 
`
`REPLACEMENT EXHIBIT Z044
`
`         
`
`

`
`JOURNAL “OF PHARMACOLOGY
`
`.9éi\JD
`
`EXPERIMENTAL
`
`'-:i.’.r
`
`‘ ‘fiPEUTI‘CS~
`
`Vol. XLIII
`
`NOVEMBER, 1931
`
`No. 3
`
`
`
`%“i.:
`
`.5.
`
`:5.
`
`
`
`EDITED BYV
`
`JOHN J. ABEL, The Johnslflopkins University
`AND.
`
`WALTER E. DIXON, University‘of -Cambridge
`
`'
`
`G. ‘BA'RBOUR‘
`‘ ~3_(nle_Univer§ity
`J. T.'CA,SH‘,'
`"
`University of Aberdeen
`A‘. J. CLARK,
`»
`»
`'
`University of Edinburgh
`H. H. DALE,
`‘ London
`J. I;)1;i.!.1NG,
`niversity of 'Liv‘erp00I
`
`
`
` ."
`
`{
`
`.Ug_xiversity of Oxford
`J; H'ANZLIK,
`(Stanford University
`
`IN ASSOCIATION WITH
`
`R. A. HATCH ER,
`Cornell Universi
`College '
`
`ty Medina}
`
`V. E. HENDERSON,
`‘University of Toronto ‘
`A. D. HIRBCHFELDER,
`University of Minnesota
`SIR FREDERICK G. Horxms,
`' University oficémbridge I
`REID HUNT
`\
`Harvard U’niversity
`P. D. LAnisoN,
`Vanderbilt University
`KW. DEB. MAQNIDER,
`University of North Carolina.
`C. R. M'ARs_HA_I..L,
`University of Aberdeen
`
`PUBLISHED n§(oN'rHLr
`
`E. K. MARs‘ru,_L1,*,, JR”:
`. Johns Hopkins University
`E. MELLANBY,
`.
`.
`V
`Sheflieid University
`F,-. Rmsoxu,
`»
`London '
`
`V A. N. R.I(’1H‘;'u3DS,V
`. University ‘at 1?e1insyLv¢_a.nia
`‘TOEALD SDDEELANN,» ,
`': Western-‘fiéssrxrfs University
`_R; Srocxifilizv,
`/ Univsrsigy ‘of’ Ghs§ow'
`"N
`_
`—_CAE;..Vor«:G'rLIN,
`.
`-[National Institute cg Healigb
`B. WALLACE, '“
`University and Beliefigus Hog-J‘
`pita1‘Médica.1rColl§ge'/~.‘-‘
`A
`
`.
`
`THE WILLIAMS & WILKINS COMPANY
`U MOUNT ROYAL AND (;UILEoED’AvENUEs
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`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 39
`
`

`
`THE JOURNAL
`
`PHARMACOLOGY
`AND
`
`EXPERIMENTAL THERAPEUTICS
`
`Enrrsn BY
`
`JOHN J. ABEL
`Johns Hopkins University
`AND
`
`WALTER E. DIXON
`University of Cambridge
`IN ASSOCIATION WITH
`
`H. G. BARBOUR,
`University of Louisville
`J. T. CASH,
`University of Aberdeen
`A. J. CLARK,
`University of Edinburgh
`H. H. DALE,
`London
`W. J. DILLING,
`University of Liverpool
`C. W. EDMUNDS,
`University of Michignn
`S. FLEXNEB,
`Rockefeller Institute for Medical ‘Research
`J. A. GUNN,
`University of Oxford
`P. J. HANZLIK,
`Leland Stanford Junior University
`R. A. HATCHEB,
`Cornell University Medical College
`V. E. HENDERSON,
`University of Toronto
`A. D. HIRSCHFELDEB,
`University of Minnesota
`Sm FREDERICK G. HOPKINS,
`University of Cambridge
`Rmn HUNT,
`Harvard University
`
`P. D. LAMsoN,
`Vanderbilt University
`
`W. DEB. MACNIDER,
`University of North Carolina
`
`C. R. MARSHALL,
`University of Aberdeen
`
`E. K. MARSHALL, JR.,
`Johns Hopkins University
`E. MELLANBY,
`Shefiield University
`
`F. RANsoM,
`London
`
`A. N. RICHARDS,
`University of PennsYlvanis.
`
`TORALD SOLLMANN,
`Western Reserve University
`
`R. STOCKMAN,
`University of Glasgow
`
`CARL VOEGTLIN,
`U. S. Public Health and Marine Hospital
`Service
`
`G. B. WALLACE,
`University and Bellevue Hospital Medical
`College
`
`
`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 39
`
`

`
`INDEX TO VOLUME XLIII
`
`79
`
`Absorption and excretion of hexylresorcinol and heptylresorcinol, Quantita-
`tive studies on the, under different conditions .
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`. 325
`——~— and retention of calcium chloride and calcium-magnesium inosite-hexa-
`phosphoric acid calcium .
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`—— and utilization of the carbohydrate of Arctium Lappa as shown by a
`protein—sparing action on the diet of dogs .
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`. 187
`of calcium preparations, A method of comparing the .
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`. 531
`Aconitine, veratrine and protoveratrine, Modification of nerve response by. .
`. 163
`Adrenal cortex, The relation of acquired morphine tolerance to the .
`.
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`.
`51
`Adrenaline, physostigmine, pilocarpine—Xenopus laevis (the South African
`clawed toad) .
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`. .. 653
`Aeschlimann, John A., and Reinert, Marc. The pharmacological action of
`some analogues of physostigmine .
`.
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`. 413
`Aglomerular and glomerular fish, Albuminuria in .
`,
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`r
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`. 407
`: kidney, The action of some diuretics upon the.
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`. .. 399
`.
`Albuminuria in glomerular and aglomerular fish.
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`. .. 407
`Alcohol, Continued drinking of, in low concentrations: some experimental
`' results .
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`Alimentary canal, excised Batrachian, The responses of the, to autonomic
`drugs .
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`. 653
`'—— canal in unanesthetized dogs, ‘Effect of ephedrine on contractions o
`the...... .
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`. ..477
`.
`— canal, The action of papaverine on the muscular activity of the .
`.
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`. 551
`Amytal, avertin, chloral, dial, and iso propyl allyl barbituric acid, A study
`of the relative eificiency as “basal anesthetics” of .
`.
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`. 449
`——, Effect of, on the autonomic nervous system as indicated by the salivary
`glands .
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`. .. 499
`Analogues of physostigrnine, The pharmacological action of some.. .
`.
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`. 413
`Anesthesia, Avertin, in experimental nephritis .
`.
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`. 637
`—-—, avertin, The action of ephedrine in .
`. .
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`. .. 209
`——, ether, ethylene and nitrous oxide, The effect of carbon dioxide on. .
`.
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`. 445
`Anesthetic action of furan, On the .
`.
`. .
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`. ..
`85
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`potency in the cyclo hydrocarbon series .
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`89
`Anterior lobe of the pituitary body and of pregnancy-urine, The gonad—
`93
`stimulating substances of the .
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`-— pituitary preparations, commercial desiccated, The iodine content of. .
`.
`. 131
`Arctium Lappa, Absorption and utilization of the carbohydrate of, as shown
`by a protein-sparing action on the diet of dogs .
`.
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`. 187
`Autonomic drugs, The responses of the excised Batrachian alimentary canal
`to autonomic drugs. .
`.
`,. .
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`. 653
`709
`
`339
`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 39
`
`

`
`CONTENTS
`
`NUMBER 1, SEPTEMBER, 1931
`
`1
`
`13
`
`51
`
`I. The Action of Oestrin on the Oxygen Consumption of the Uteri of Mice.
`By J. Christodoss David. .
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`._ .
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`II. The Pharmacological Action of the Principles Isolated from Ch‘an Su, the
`Dried Venom of the Chinese Toad. By K. K. Chen, H. Jensen and A.
`Ling Chen .
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`III. The Relation of Acquired Morphine Tolerance to the Adrenal Cortex.
`By Eaton M. MacKay .
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`IV. Studies in Cancer Chemotherapy. X. The Effect of Thorium, Cerium,
`Erbium, Yttrium, Didymium, Praseodymium, Manganese, and Lead
`upon Transplantable Rat Tumors. By L. C. Maxwell and Fritz
`Bischoff. With the technical assistance of Ella May Ottery .
`.
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`V. The Chemotherapy of Streptococcus Infections of Mice with Special Ref-
`erence to Salicyl Compounds. By John A. Kolmer and George W.
`Raiziss. With the assistance of Anna M. Rule .
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`VI. Absorption and Retention of Calcium Chloride and Calcium-Magnesium-
`inosite-hexaphosphoric Acid Calcium. By J. C. Forbes and Hazelwood
`Irving .
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`VII. On the Anesthetic Action of Furan. By J. F. A. Johnston .
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`VIII. Anesthetic Potency in the Cyclo Hydrocarbon Series. By V. E. Hen-
`derson_and J. F. A. Johnston.
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`IX. The Gonad-stimulating Substances of the Anterior Lobe of the Pituitary
`Body and of Pregnancy-urine. By Zonja Wallen-Lawrence and H. B.
`Van Dyke .
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`. ..
`X. Effect of Ultra-violet Rays on Epinephrine and Related Products.
`(Pre-
`liminary Report.) By Paul L. Ewing, Philip Blickensdorfer and Hugh
`A. McGuigan .
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`. .. 125
`. XI. The Iodine Content of Commercial Desiccated Anterior Pituitary Prep-
`arations. By Karl Closs .
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`. 131
`XII. Studies on Calcium. V. Blood and Urine Levels of Calcium after Per-
`oral and Deep Muscular Administration of Calcium Gluconate in Man.
`By Arnold L. Lieberman.
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`. 139
`XIII. Heat Regulation and Water Exchange. XII. The Underlying Mech-
`anism of Fever as Illustrated by Cocaine Poisoned Rabbits. By Henry
`G. Barbour and Hubert T. Marshall .
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`. 147
`XIV. Modification of Nerve Response by Veratrine, Protoveratrine and Aco-
`nitine. By Helen Tredway Graham and Herbert S. Gasser .
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`. 163
`XV. Absorption and Utilization of the Carbohydrate of Arctium Lappa as
`Shown by a Protein-sparing Action on the Diet of Dogs. By John C.
`Krantz, Jr., and C. Jellelf Carr .
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`. .. 187
`iii
`
`61
`
`71
`
`79
`85
`
`89
`
`93_
`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 39
`
`

`
`iv
`
`CONTENTS
`
`I. Ro-
`XVI. Toxicological Studies of Derris Elliptica and Its Constituents.
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`. 193
`.
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`tenone. By H. B. Haag .
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`XVII. The Action of Ephedrine in Avertin Anesthesia. By B. B. Raginsky
`\_
`and Wesley Bourne .
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`. 209
`XVIII» The Eflect of Avertin upon the Circulation. By B. B. Raginsky,
`-
`Wesley Bourne and Maurice Bruger .
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`. 219
`XIX. The Influence of Electrolytes on the Permeability of Tissues to Crystal-
`line Insulin. By R. J. Hamburger .
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`
`NUMBER 2, OCTOBER, 1931
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`XX. The Influence of Lactic Acid on Hemolysis. By J. Sladek, I. A. Parfent—
`jev and B. Sokoloff .
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`XXI. Ergotoxine Miosis. By F. F. Yonkman.
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`XXII. The Response of the Submaxillary and Parotid Glands of the Dog to
`Histamine. By George Stavraky, .
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`. 265
`XXIII. The Influence of Sodium Barbital upon the Reactions of Normal Rab-
`bits to Successive Doses of Insulin. By Eugene L. Jackson .
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`. 277
`XXIV. The Hypoglycemic Action of the Hypophysectomized Dog’s Blood.
`By R. J. Cowley .
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`XXV. The Mechanism of "the Hypoglycemia Produced by Guanidine and
`Carbon Tetrachloride Poisoning and Its Relief by Calcium Medication.
`By A. S. Minot .
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`. 295
`XXVI. Pharmacological Effect of Impurities in Ether. By Walter L. Men-
`denhall and Ruth Connolly.
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`. 315
`XXVII. Quantitative Studies on the Absorption and Excretion of Hexylre-
`sorcinol and Heptylresorcinol under Different Conditions. By B. H.
`Robbins .
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`XXVIII. A Method for the Quantitative Determination of Hexylresorcinol
`in Tissues, Blood and Excreta. By B. H. Robbins and L. G. Wesson.. 335
`XXIX. Continued Drinking of Alcohol in Low Concentrations: Some Ex-
`perimental Results. By P. J. Hanzlik .
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`. 339
`XXX. Studies on the Metabolism of Tartrates.
`I. A Colorimetric Method
`. for the Determination of Tartaric. Acid. By Frank P. Underhill, F. I.
`Peterman and A. G. Krause. With the cooperation of C. S. Leonard and
`T. C. Jaleski .
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`. .. 351
`XXXI. Studies on the Metabolism of Tartrates.
`II. The Behavior of Tar-
`trate in the Organism of the Rabbit, Dog, Rat and Guinea Pig. By
`Frank P. Underhill, Q}. S. Leonard, E. G. Gross and T. C. Jaleski.. .. .. 359
`XXXII. Studies on the Metabolism of Tartrates.
`III. The Behavior of
`' Tartrates in the Human Body. By Frank P. Underhill, F. I . Peterman,
`T. C. Jaleski and C. S. Leonard .
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`. .. 381
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`NUMBER 3, NOVEMBER, 1931
`
`XXXIII. The Action of Some Diuretics upon the Aglomerular Kidney. By
`Raymond N. Bieter .
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`. 399
`XXXIV. Albuminuria in Glomerular and Aglomerular Fish. By Raymond
`N. Bieter .
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`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 5 of 39
`
`

`
`CONTENTS
`
`V
`
`XXXV. The Pharmacological Action of Some Analogues of Physostigmine.
`By John A. Aeschlimann and Marc Reinert .
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`. 413
`XXXVI. The Effect of Carbon Dioxide on Ether, Ethylene and Nitrous Ox-
`ide Anesthesia. By George B. Kleindorfer .
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`XXXVII. A Study of the Relative Efliciency as “Basal Anesthetics” of Aver-
`tin, Amytal, Chloral, Dial, and Iso Propyl Allyl Barbituric Acid. By
`George B. Kleindorfer and J. T. Halsey .
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`XXXVIII. Caffeine Effect 'on the Crest Uniformity of Muscular Fatigue
`Curves. By Ralph H. Cheney .
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`. 457
`XXXIX. The Pharmacologic Properties of an Insulin-free Extract of Pan-
`creas and the Circulatory Hormone of Frey. By Albert H. Elliot and
`Franklin R. Nuzum .
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`. 463
`XL. Effect of Ephedrine on Contractions of the Alimentary Canal in Unanes-
`thetized Dogs. By J. H. Kinnaman and O. H. Plant .
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`. .. 477
`XLI. Behavior of Papain in the Peritoneal Cavity. By Robert P. Walton. 487
`XLII. Effect of Amytal on the Autonomic Nervous System as Indicated by
`the Salivary Glands. By George W. Stavraky.
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`. 499
`XLIII. Interaction of Pilocarpine and Histamin on the Intestine. By Fred-
`erick Bernheim .
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`._ 509
`XLIV. A Note on Tin Compounds in the Chemotherapy of Experimental
`Staphylococcus Infections. By John A. Kolmer, Herman Brown and
`Malcolm J. Harkins .
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`XLV. The Degree of Infection in Relation to the Parasiticidal Activity of
`Chemotherapeutic Compounds. By John A. Kolmer. With the assist-
`ance of Anna M. Rule .
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`. .. 521
`XLVI. A Method of Comparing the Absorption of Calcium Preparations.
`By Frank Wokes .
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`XLVII. The Action of Papaverine on the Muscular Activity of the ‘Alimen-
`tary Canal. By Erwin G. Gross and Donald H. Slaughter .
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`. 551
`XLVIII. The Action of Blister Fluid on the Isolated Rat’s Uterus. By G. H.
`Percival and C. M. Scott .
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`. 563
`XLIX. Pharmacology and Toxicology of
`lV[onohydroxy-mercuri-di-iodo-
`resorcin-sulphonphthalein. By David I. Macht and Helen M. Cook . .
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`. 571
`
`NUMBER 4, DECEMBER, 1931’
`
`/
`
`L. Magnesium Absorption in Dogs and Its Effect upon the Metabolism of
`Calcium. By Henry G. Barbour and James E. Winter .
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`LI. Some Factors Influencing the Stability of the Fluid Extract of Ergot.
`By Maurice I. Smith and E. F. Stohlman .
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`. 621
`LII. Avertin Anesthesia in Experimental Nephritis. By J. Ross Veal, J. R.
`Phillips and Clyde Brooks .
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`. 637
`LIII. The Importance of a Standard of Reference in Toxicity Determina-
`tions of Mercurochrome. By J. H. Burn and G. D. Greville .
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`. .. 645
`LIV. The Responses of the Excised Batrachian Alimentary Canal to Auto-
`nomic Drugs.
`I. Xenopus Laevis (The South African Clawed Toad)—~
`Pilocarpine, Physostigrnine, Adrenaline. By David Epstein .
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`. .. 653
`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 6 of 39
`
`

`
`vi
`
`‘CONTENTS
`
`693
`
`LV. Bulbocapnine Catalepsy and the Grasp Reflex. By Curt P. Richter and
`Arthur S. Paterson .
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`. 677
`LVI. A Comparison of the Rat and Mouse Units in the Assay of the Female
`Sex Hormone. By T. J. Becker, C. H. Mellish, F. E. D’Arnour and R. G.
`Gustavson .
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`LVII. The Tolerance of
`the Toad towards Strophanthin. By David
`Epstein .
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`LVIII. Index .
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`
`NOVARTIS EXHIBIT 2044
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 7 of 39
`
`

`
`.
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`'
`
`0;.
`
`THE PHARMACOLOGICAL ACTION OF SOME
`ANALOGUES OF PHYSOSTIGMINE
`
`JOHN A. AESCHLIMANN AND MARC REINERT
`From tht"Rochs" Chemical and Pharmacological LalJoral;orie., BlUle
`
`Received for publication June I, 1931
`
`Physostigmine (Eserin) is of interest chemically as an example
`of an alkaloid whose pharmacological action depends on the pres(cid:173)
`ence in the molecule of a particular group, in this case the methyl(cid:173)
`carbamic ester group CHaNHCOO. . It has been shown by Sted(cid:173)
`man (1, ·2), Stedman and Stedman (3), White and Stedman (4)
`that other compounds containing this group possess a miotic ac(cid:173)
`tion similar to that of physostigmine. The results of his exten(cid:173)
`sive investigation can be summarized as follows:
`All the compounds which possessed .miotic activity were basi(cid:173)
`cally substituted phenylesters of monoalkylcarbamic acids of the
`general formula RNHCOOC.H4R', where R was a methyl or ethyl
`group and R' a basic substituent such as -N(CH.h or -CHtN-
`(CH,)s, etc.
`.
`The activity was greatest when R was a methyl group,-i.e.
`when the compound was similar to physostigmine in that it
`contained the group CH,NHCOO. No activity was observed
`when R was a phenyl group.
`The miotic activity varied according tb whether Rt was in the
`0, m or p-posiiion and the activity of the hydrochlorides was in
`some cases greater Rnd in others smaller than that of the quater(cid:173)
`nary salts.
`. There is an evident analogy with the case of cocaine, which is a
`benzoic ester of a bicyclic alkamine, whereas phYsostigmine is a
`In the same
`methylcarbamic ester of a tricyclic basic phenol.
`way as many synthetic esters of simpler alkamines possess local
`anesthetic properties similar to those of cocaine, so do the methyl.
`carbamic esters . of the simpler basic phenols synthesized by
`413
`
`

`
`414
`
`JOHN A. AESCHLUlANN AND MARC REiNERT
`
`Stedman pOSBesspharmacological properties similar to those of
`physostigmine. It was therefore of interest to investigate the
`variation of the pharmacological properties in this series on modi(cid:173)
`fying the carbamic acid group on the one hand and the phenolic
`residue on the other. It also seemed probable that a. systematic
`investigation might·result in obtaining a compound suitable for
`therapeutic use which would be free from the inherent disadvant(cid:173)
`ages of physostigmine, particularly the ease with which it de(cid:173)
`composes in solution.
`
`PRELIMINARY WORK
`In the first place several of the compounds whose miotic action
`. had been observed by Stedman were investigated for toxicity,
`miotic action, and action on the rabbit's intestine. It was found
`that many of the quaternary salts of this series were highly toxic
`substances, having the characteristic action on the central ner(cid:173)
`vous system and causing increased salivation like physostigmine.
`The quaternary salts examined were found to have .. a stronger
`action on the intestine than the hydrochlorides of the corresPond(cid:173)
`ing tertiary bases and to be more readily decompOsed. This
`decomposition takes place in 'aqueous or alcoholic solution and
`was also observed by stedman (l,p. 733). It occurs with elim(cid:173)
`ination of alkyl or aryl isocyanate the odor of which is evident
`after some hours standing in the cold or immediately on boiling.
`The carbamic ester group iii transformed into a phenolic hydroxyl
`~oup according to equation A.
`RNHCOOC.H,R' - RNCO + HOC.H,R'
`(A)
`As the presence of a solvent, water or alcohol, is necessary for the
`. decomposition to take place below 100°, it is probable that the
`solvent plays an important part in initiating the decomposition.
`In aqueous solution the isocyanate then reacts with water accord-
`. ing to equation B to form the disubstituted urea.
`2RNCO + HaD -
`(RNH),co + COt
`(B)
`CHaNCO + H.NCtH. - CHaNHCONHC.H.
`(C)
`The change could be particularly welJ followed in the case of
`. phenylcarbamic esters, where insoluble diphenyl urea is produced.
`
`

`
`PHARMACOLOGICAL ACTION OF PHYSOSTIGM(NE
`
`415
`
`In the case of the methylisocyanic esters the dimethYl urea
`formed remains in solution but by adding aniline to the solution
`insoluble methylphenyl urea is formed according to equation C.
`In the presence of excess of alkali the end products of thehy(cid:173)
`drolysis are the phenol, amine, and alkali carbonate, but even
`. then the . first stage is an elimination of isocyanate, the odor of
`which can be observed if the solution is made only just alkaline.
`The tentative suggestion had already been made by Stedman
`(l,.p. 733) that the activity of these compounds might be due to
`the action of one of the products of hydrolysis liberated in the
`body. An experiment was therefore made with N-bromaceta-
`
`mide CHa.CON<:r which readily splits offHBr in vitro produc(cid:173)
`ing methylisoeyanate. It was found, however, that it produced
`none of the characteristic symptoms of physostigmine poisonUig.
`When the solution of the carbamic ester is made slightly acid
`(pH on the acid side of 5) the decomposition can be greatly sup(cid:173)
`pressed. It was only after this discovery that we were able to
`obtahi concordant results in the evaluation of the pharmacolog(cid:173)
`icalactivity of many of the compounds mentioned below, which
`were tested in buffered solutions, a method which proved to be
`satisfactory for experimental purposes.
`
`ESTERS OF DISU1JSTITUTED · CARB.A1dIC ACIDS
`In order to obtain compounds which might be less readily de(cid:173)
`composed than the monoalkylcarbamic esters previously pre(cid:173)
`pared, some dialleyl and arylalkylcarbamic esteJ'S were pre(cid:173)
`pared. These contain instead of the group R· NHCOO, the group
`
`:l)NCOO -. It was considered that a decomposition analo(cid:173)
`gous to that of the monosubstituted carbamic esters would be
`far less likely to take place as it would involve the migration of
`an alkyl or aryl radical instead of a hydrogen atom as in. equa(cid:173)
`tion A. H the decomposition took place in an analogous manner'
`a phenolic ether would be produced as in equation D, a course
`which seemed unlikely.
`R )NCOOC.H4R' __ RNCO + R,O.C.H.R'
`R,
`
`(D)
`
`

`
`416
`
`JOHN A. AESCHLIMANN AND MARC REINERT
`
`In one compound investigated the nitrogen of the carbamic ester
`group formed part of a heterocyclic ring, Rand R1being in that
`case together represented by the pentamethylene group C.H1o
`so that such a decomposition was completely excluded.
`It was of course possible that owing to the improbability of
`isocyanate liberation, a simple hydrolysis would take place in
`these cases forming the secondary amine and carbon dioxide. On
`heating the neutral aqueous solution of such disubstituted car(cid:173)
`bamic esters no amine could, however be detected or determined
`quantitatively. The ~umption that this class of compounds
`. would be more stable in vitro thus proved to be justified and it
`was found that many of them had a high pharmacological
`activity.
`
`PHARMACOLOGICAL INVESTIGATION
`The results of the investigation ,are given in table 1 and concern
`the following properties: (a) Toxicity (intravenously and orally);
`(b) miotic action; (c) peristaltic action (on the surviving intes(cid:173)
`tine (Magnus) and in some cases in situ (Trendelenburg); (d)
`aQtion on the frOg~s heart.
`.
`The intensity of these effects could be measured quantitatively
`with sufficient accuracy for comparison with the correspondblg
`effe~ts of physostigmine. Using the figures obtained as a basis,
`the compounds could be classified according to their Hphysostig(cid:173)
`mine activity." The various properties were not always present
`in the same degree, 8. few ·substances, for · inatance showing a
`relatively weak miotic action but having a strong action on intes(cid:173)
`tinal peristalsis. The various pharmacological properties are
`therefore treated separately in the discussion.
`
`METHODS
`1. Toxicity. The toxicity was determined in the usual way,
`the minimum dose to cause death of over 80 per cent of the
`animals being. recorded. This naturally gives somewhat higher
`figures for the toxicity than the 1150 per cent-deaths" method
`adopted by White and Stedman (4), but where the same sub(cid:173)
`stances have been examined the toxicities are in the same order
`
`

`
`PRARMACOLOGICAL ACTION OF PHYSOSTIGMINE
`
`417
`
`In table 2 the values ob(cid:173)
`as those observed by these authors.
`tained by the "50 per cent-deaths" method are given for com(cid:173)
`parison in the case of two of the compounds and physostigmine,
`the values showing agreement with those of White and Stedman
`for physostigmine.
`In the compounds marked with an asterisk
`the toxicity and other pharmacological effects were measured in
`stabilized solutions of pH about 3.7 . . These were usually pre(cid:173)
`pared by dissolving 1 gram of substance in 95 cc. of decinormal
`glycine-sodium-chloride sOlution + 5 cc. of decinormal hydro(cid:173)
`chloric acid (Sf/frensen buffer solution, Clark (5» a.nd diluting to
`the required strength With Ringer solution. The buffer solution
`itself was non-toxic. Mice were usually used for toxicity
`determinations.
`2. Miotic action. This was observed on the cat, 2 drops of the
`solution to be examined being instilled into one eye and the two
`eyes subsequently compared at interva.ls. To obtain a complete
`comparison of the various compounds it would be necessary to
`take account of the duration as well as the intensity of the maxi(cid:173)
`mum miotic effect produced bya given concentration. The
`duration of the action was only noted in a few cases in which the
`action was strongest.
`3. Action on the small inteatine (raQbit). a. Surviving intestine.
`The action of the substances on the isOlated rabbit intestine sus(cid:173)
`pended in 50 cc. of Da.le's solution kept, like the washing solution,
`at 3", was studied. The apparatus of Guggenheim arid LOilier
`(6), which enables the test to be carried out on two pieces of
`intestine simultaneousiy, was used . . The test pieces were taken
`from various parts of the small intestine and were about 2cm.
`long. Portions of the ileum wereusu~y found to be more sen(cid:173)
`sitivethan those 'from the duodenum. Each substance was
`directly compared with physostigmine so as to eliminate as far
`as possible differences due to varying sensitivity of the test
`object.
`b. Intutina in situ. A few of the substances were a1s9 tested
`by the method of P. Trendelenburg (7) on the intestine in situ
`of a. rabbit kept in deep narcosis by 0.5 cC. per kilogram of
`IIRoehe-Numal," a solution conta.ining 10 per cent of allylisopro-
`
`

`
`418
`
`JOHN A. AESCHLIMANN AND MARC REINERT
`
`pyl barbituric acid. The injections were made into the vena
`jugularis, into which a cannula which could be closed· by a cock
`was fixed.
`4. Action on the Jrog-heart. The heart action was studied on
`the isolated esculenta heart by the method of Straub.
`5. Actimi. on blood pressure and respiration. The blood pres(cid:173)
`sure tests were carried out on the rabbit narcotized as above.
`The method of P.Trendelenburg (8), which enables the experi(cid:173)
`ment to be carried out for many hours on one animal without
`fear of coagulation, was used .
`. In investigating the action OIl respiration both the effect on the
`volume and on the frequency of respiration was observed. A
`gasometer of 1 liter capacity with two one-way valves regulating
`inspiration and expiration was connected bya cannula to the'
`trachea of the animal.' A spindle on the gasometer malces ,a
`complete revolution when 1 liter of gas passes through the meter
`and carries two radial wires in the form of' a cross. Each time
`250 cc. of gas have passed through the meter one of the wires
`closes a circuit actuating an electromagnet and a stroke is reg(cid:173)
`. istered. In parallel with the meter a Marey's, tambOur was
`arranged to register the respiratory frequency on the sam.~ graph
`as blood-pressure and volume.
`
`DISCUSSION OF RESULTS (TABLE 1)
`TOxiCity.' In discussing the toxicity it is convenient to divide
`the' compounds into three classes, the members of which show
`certain similarities: (a) Salts of weak tertiary aromatic bases
`from which the base is liberated in neutral or slightly alkaline
`solution (i.e., in the intestine) ; (b) salts of strong tertlary bases
`having the nitrogen in the side chain, from which the base is
`liberated only in alkaline solution; (c) quaternary salts, which
`remain in solution in alkali.
`The members of class (a) are in general less toxic than those of
`classes (b) and (c). When given orally salts of class (a) are
`considerably less toxic than when injected intravenously,possibly
`because the free base is only slowly absorbed through the intesti(cid:173)
`nal walls. Salts of class (b) show chemically the closest rela-
`
`

`
`PHARMACOLOGICAL ACTION OF PHYSOSTIGMINE
`
`419
`
`tionship to physostigmine and their toxicities are of the same
`order as that of the natural alkaloid. The difference between
`. the .lethal doses by the oral and intravenous route is here less
`pronounced, although several of the compounds are, like phy(cid:173)
`sostigmine, unstable and might be expected to decompose in the
`alimentary tract. The relatively high toxicity of physostigmine
`by the mouth might possibly be due to the inhibiting action it
`exerts on hydrolysis by esterases (Stedman (9» a:s it might con(cid:173)
`ceivably inhibit the action of the enzymes of th