A MANUAL OF BIOLOGICAL THERAPEUTICS CORNELL UNIVERSITY LIBRARY FROM wm.w.leffingwell *lllliii?iIiii!«i'iii?ltii,K?.'.°5''=''' therapeutics- or,n,J 1924 031 226 867 Cornell University Library The original of tliis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924031226867 A Manual of Biological Therapeutics SERA BAGTERINS PHYLAGOGENS TUBERGULINS GLANDULAR EXTRAGTS TOXINS, GULTURES, ANTIGENS, ETG. PRESS OF PARKE, DAVIS & COMPANY " 1914 Copyrighted by PABKE, DAVIS & CO. 1914 TABLE OF CONTENTS. Adrenalin 159 Agglutinins 12 Agglutination. Test, the new method of 80 Agglutometer No. 1 80 Agglutometer No. 2 82 Allergic reactions of serum 26 Antigen, gonococcus 88 Antlgonococoic Serum 32 Antimeningitic Serum 34 Antistreptococcic Serum 35 Antitetanic Serum 29 Antitetanic Dusting Powder 32 Antitoxic unit 19 Antitoxin, Diphtheria, Concentrated 24 Antitubercule Serum 32 Bacillus Lactis Bulgaricus 96 Bacteria 7 Bacteria, preparing the suspension of ' 44 Biology 1 Biological Farm 169 , Bleeding the horse, operation of 18 ' Elood-corpuscles, preparing the 44 Bordet-Gengou Reaction 86 Coagulose ■. 99 Corpora Lutea (Desiccated) 165 Desensitization 27 Diphtheria Antitoxic Serum, prophylactic use of 24 Diphtheria, topical and constitutional treatment of 25 Diphtheria, treatment of advanced cases of. 23 Diazo-reaction, Bhrlich's 85 Disease, how serums and vaccines prevent 48 Dosage, Antidiphtheric Serum, remarks on 23 Dose of Diphtheria Antitoxic Serum 22 Globulins, Antitetanic (Dry) 31 Horse, immunizing the 17 Immunity 8 Immunity, natural 11 Immunity, theories of 10 Laboratory, research 173 Lactic Acid Bacteria, suppositories of . . 99 Lactone 9!i Leucocytes, counting the 45 Lysins 12 Organotherapy 151 Ophthalmic Test, how to make 136 Opsonic index 42 Parathyroid glands 154 Phases, negative and positive 46 Phylacogens 103 Phylacogens, clinical testing of 110 Phylacogen, Erysipelas 117 Phylacogen, Gonorrhea 115 Phylacogen, Mixed Infection 114 Phylacogen, Pneumonia 115 Phylacogens, preparation of 107 Phylacogen, Rheumatism 117 Phylacogen theory 104 Phylacogen, Typhoid 119 Pituitrin 163 Pituitary gland 154 Precipitins 12 Prophylactic use of piphtheria Antitoxic Serum 24 III IV TABLE OF CONTENTS Sera, antitoxic, preparation of ! . . 14 Sera, preparation and uses of 13 Sera, process of in detail 15 Sera, therapeutic action of 21 Serum, allergic reactions of 26 Serum, how tested is Serum, standardization of the 19 Serums, when to use 49 Serums and vaccines, how they prevent disease 48 Serum, Antidiphtheric 21 Serum, Diphtheria Antitoxic, the dose of 22 Serum, Diphtheria Antitoxic, prophylactic use of ; 24 Serum, Antidiphtheric, therapeutic uses of 29 Serum, Antigronococcic 32 Serum, Antimeningitic 34 Serum, Antistreptococcic (Polyvalent) 3,5 Serum, Antitetanic 29 Serum, Antitetanic, therapeutics of 30 Serum, Antitubercle 32 Suprarenal glands 154 Suprarenal Glands (Desiccated) 162 Test, agglutination 78 Tests of serum, safety 20 Thymus Gland (Desiccated) 158 Thyroid gland 152 Thyroid Glands (Desiccated) 157 Thyreoidectin 165 Thyroprotein (Beebe) 156 Toxins, culture products, etc 95 Toxin, the production of the 16 Toxin, the strength of the 18 Tuberculin Discs, preparation of 136 Tuberculin in diagnosis 127 Tuberculin in treatment 138 Tuberculin, tablets of 143 Tuberculin T. R. (dilute) 142 Tuberculin, standardization of 126 Tuberculins 121 Tuberculins, preparations of 124 Typhoid fever, diagnosis of 77 Vaccine, Acne , 51 Vaccine, Colon 53 Vaccine Combined, Acne 52 Vaccine Combined, Bacterial (Van Cott) 54 Vaccine Combined, Catarrhal 52 Vaccine Combined, Gonorrheal 56 Vaccine Combined, Pertussis 61 Vaccine Combined, Pneumonia 64 Vaccine Combined, Pyorrhea Alveolaris (Harris) 65 Vaccine Combined, Urethritis 73 Vaccine. Furunculosis 55 Vaccine, Gonococcus 55 Vaccine, Meningococcus (Prophylactic) 57 Vaccine, Pasteur Antirabic (Cumming) 58 Vaccine, Pertussis 60 Vaccine, Pneumococcus 62 Vaccines, Staphylococcus 67 Vaccine Streptococcus 68 Vaccine, Typhoid Prophylactic 68 Vaccine, Typhoid, the curative effect of 70 Vaccine, Typhoid, in juvenile cases 69 Vaccine, Typhoid-Paratyphoid, Prophylactic 71 Vaccines, Bacterial (Bacterins) 39 Vaccines, indications for 47 Vaccines, methods of administration of 74 Vaccines, when to use Bacterial 49 Virus, Vaccine (smallpox) 74 Wassermann reaction 92 INDEX OF SUBJECTS. Abscess, rectal, treat- ment of 53 Acne, mixed type of... 52 Acne, pustular, treat- ment of 55 Acne rosacea, treat- ment of 52 Acne Vaccine, dose of.. 51 Acne Vaccine, how sup- plied 51 Acne Vaccine, therapeu- tics of 51 Acne Vac *ne. Combined 52 Acne Vaccine Combined, dose of 52 Acne Vaccine Combined, therapeutics of 52 Acne vulgaris 51 Adrenalin 154, 169 Adrenalin Inhalant 26 Adrenalin, literature of. 160 Adrenalin, preparations of 162 Adrenalin, therapeutics of 160 Adrenalin with addition of Cocaine 161 Adrenalin with Novo- caine 161 Agglutinins 12 Agglutometer No. 1.... 80 Agglutometer No. 2.... 82 Agglutination Test, new method of 80 Agglutination Test, value of 83 Agglutination Test, without microscope... 78 Allergic reactions 26 Amboceptor, antisheep. . 92 Amboceptor, typhoid... 86 Animals, classification of 1, 4 Animal derivatives, other 167 Animals, studies of phy- lacogen on 110 Antibodies, sera contain 49 Antibodies, vaccines do not contain 49 Antigens 12 Antigen, gonococcus ... 87 Antigen, typhoid 86 Antidiphtheric Serum, conservative dose of.. 22 Antidiphtheric Serum, doge of 22 Antidiphtheric Serum, intravenous injection of 24 Antidiphtheric Serum, unusual therapeutic uses of 29 Antigonococcic Serum, mode of preparation of 33 Antigonococcic Serum, therapeutic indica- tions of 33 Antimeningitio Serum, dose of Zi Antimeningitic Serum, how supplied 35 Antimeningitic Serum, therapeutics of 34 Antirabic Vaccine (Gum- ming), Pasteur 58 Antirabic Vaccine, how supplied 60 Antistreptococcic Serum, dosage of 36 Antistreptococcic Serum, how supplied 37 Antistreptococcic Serum, therapeutics of 35 Antitetanic Dusting Powder, the advan- tages of the use of. 30, 32 Antitfetanio Globulins (Dry), the convenience of 31 Antitetanic Serum, mar- keted packages of.... 32 Antitetanic Serum, the proper use of 29 Antitetanic Serum, ther- apeutics of 30 Antitoxin, safety tests of 20 Antitoxic Test, how made 19 Antitoxic unit 19 Antitoxic value, test of. 19 Antitubercle Serum .... 32 Arthritis, gonorrheal ... 33 Arthritis, gonorrheal, treatment of 56 Asepsis, care taken to maintain 18 Bacillen Emulsion, Koch (B. E.) 126 Bacillus, Klebs-Loeffler. 18 Bacillus Lactis Bulgari- cus, tablets of 96 Bacillus Lactis Bulgari- cus, therapeutics of.. 97 Bacillus prodigiosus ... 95 Bacteria, classification of 7 Bacteria unicellular plants of varying shapes 7 Bacterial Vaccine Com- bined, dose of 54 Bacteria, preparing the suspension of 44 VI INDEX OF SUBJECTS Bacterial Vaccines, source of cultures of the 40 Bacterial Vaccines, tiier- apeutic action of 41 Bacterins 39 Bacteriology, the sub- science of 6 Bacteriolytic, Antistrep- tococcic Serum be- lieved to be 35 Blood corpuscles, pre- paring the 44 Blood to be tested, col- lecting the 43 Boils, treatment of... 52, 55 Bordet-Gengou reaction. 86 Bouillon Filtrate, Denys (B. F.) 126 Carbuncles, treatment of 52, 55, 67 Cases, selecting, for vac- cine treatment 47 Catarrh, acute and chronic, treatment of. 53 Catarrhal Vaccine Com- bined, therapeutics of 52 Cholecystitis, treatment of 53 Chromogen, urine con- tains a 85 Complement fixation test, explanation of the reactions of 91 Complement fixation test, making the 90 Complement fixation test, recording the re- action of 91 Clinical buildings 171 Clock, Dr. R. 97 Coagulose 99 Coagulose, directions for use of 101 Coagulose, dose of 101 Coagulose, therapeutics of 100 Cocaine, Adrenalin vifith addition of 161 Cohen, Dr. S. S 159 Coley, Dr. W. B 95 Colon infections, treat- ment of 53 Colon, ulceration of.... 53 Colon Vaccine, dose of. 53 Colon Vaccine, thera- peutics of 53 Corpora Lutea (Desic- cated), study of 165 Corpora Lutea, thera- peutics of 167 Gumming, Dr. J. G 58 Cure of bacterial dis- eases, autoinoculation the 47 Cystitis, treatment of.53, 67 Dagnino and Poynton and Paine 117 Desensitization 27 Diarrhea, infantile, treatment of 98 Diazo-reaction, Ehr- lich's 85 Diphtheria, how pro- duced 18 Diphtheria, topical and constitutional treat- ment of 25 Diphtheria, treatment of advanced cases of.... 23 Diphtheria Antitoxin Concentrated, advan- tages of 24 Diphtheria Antitoxic Se- rum, prophylactic use of 24 Diplococcus intracellu- laris meningitidis .... 34 Disease, how serums and vaccines prevent 48 Discs, tuberculin 136 Dosage, remarks on.... 23 Dosage of Antidiphther- ic Serum 22 Ductless glands, rela- tionship to the 155 Eczema, treatment of.52, 67 Ehrlich's diazo-reaction, when obtained 86 Bhrlich, our debt to.... 10 Endocarditis 36 Endocarditis, malignant, treatment of 54 Endocarditis, septic, treatment of 68 Endocarditis, ulcerative, treatment of 67 Epididymitis 35 E£ididymitis, treatment of 56 Erysipelas 36, 68 Erysipelas, treatment of 54, 68 Erysipelas Phylacogen. . 117 Erysipelas and Frodigio- sus Toxins 95 Erysipelas and Frodigio- sus Toxins, dose of... 95 Erysipelas and Prodigio- sus Toxins, therapeu- tics of 95 Farm, the ibiological. . . . 169 Farm, topography of biological 169 Ferment, hemostatic ... 99 Film, preparing the.... 45 Fistula in ano, treat- ment of 53 Pistulse, infected, treat- ment of 67 Furunculosis Vaccine, dose of 55 INDEX OF SUBJECTS VM Furunculosis Vaccine. therapeutics of 55 Furunculosis, treatment of 55, 67 Glands, ductless 131 Glands, parathyroid .... 154 Gland, pituitary 154 Glands, suprarenal 154 Gland, thyroid 152 Gleet, treatment of 5B Gonorrhea, treatment of. 56 Gonococcus antigen .... SS Gonorrhea, complement fixation test in diag- nosis of 8S Gonorrhea, complement reaction test for 116 Gonorrhea, diagnosis of. 8!S Gonorrhea, subacute and chronic, treatment of. 73 Gonorrhea Phylacogen.. 115 Gonorrheal Infection, chronic 36 Gonorrheal infections, with staphylococcic complications, treat- ment of 57 Gonorrheal Vaccine oK Gonorrheal Vaccine, dose of 66 Gonococcus Vaccine, therapeutics of 56 Gonorrheal Vaccine Combined, dose of. . . . 57 Gonorrheal Vaccine Combined, therapeu- tics of 56 Graves' Disease 153 Hamill, Carpenter and Cope, confirmation of .134 Heinemann, confirma- tion of 134 Hemolysis S7 Hemolytic serum S6 Hemophilia 100 Hemorrhages, treat- ment of various 101 Hormones 151 Horse, immunizing the. 17 Horse, operation of bleeding the 18 Horse, period of immu- nizing the 18 Hydrogen peroxide, use of 26 Hypophysis, the 163 Immunity 8 Immunity, active 9 Immunity, artificial .... 9 Immune, lower animals (to certain diseases prevalent in man) .... 8 Immunity, natural ....8, 11 Immunity, theories of. 8, 10 Immunity, widely vary- ing degrees of S Impetigo contagiosa, treatment of 55 Inflammations of tlie skin, treatment of.... 52 Inflammation of vaginal tract, treatment of non-specific 99 Infecting agent, where derived from 47 Infection, microbic 47 Infections, septic, treat- ment of 67 Infectious diseases, caused by patliogenic bacteria 21 Intracutaneous test .... 135 Iritis 36 Jaundice, acute 53 Laboratory, the research 173 Lactic Acid Bacteria, suppositories of 99 Lactone 9s Lactone, uses of 98 Leucocytes 42 Lupus vulgaris, treat- ment of GS Lyphangitis, treatment of 6S L + dose of toxin 20 Leucocytes, their part in natural immunity .... 10 Loomis Research Lab- orator.v 33 Lysins lu Mastoiditis, treatment of 54 Mayer, studies of 117 Meningitis 36 Meningitis, cerebrospinal, its diagnosis and treatment 34 Meningitis, cerebrospinal, prophylactic treatment of 57 Meningococcus carriers, treatment of 58 Meningococcus Vaccine. 57 Meningococcus Vaccine, dose of 57 Meningococcus Vaccine (Prophylactic), thera- peutics of 57 Microorganisms, count- ing of 45 Mixed Infection Phylac- ogen 114 Mixed Infection Phylac- ogen, therapeutic in- dications of. 114 Moro, confirmation of... 134 Moro Test 133 Opsonic index, what it is 42 Opsonic index, controll- ing factor 46 Opsonins 42 vin INDEX OF SUBJECTS Ophthalmia, gonorrheal, treatment of 56 Ophthalmic test 136 Ophthalmic test, how to make the 136 Ophthalmic test, caution necessary in 13S Ophthalmic test, to re- peat the 137 Ophthalmic test, reac- tion of the 138 Orchitis 33 Organisms, quotient of number of, in patient's blooa 46 Organotherapy 151 Osteomyelitis, treatment of 67 Dtitis media, treatment of 67 Parathyroid glands .... 1S4 Patterson, Dr. H. S., confirmation of 135 Pasteur 39 Pasteur and the knowl- edge of microbes 6 Percutaneous test 13'2 Pertussis ' Vaccine, dose of 61 Pert'issis "Vaccine, ther- apeutics of 60 Pertussis Vaccine Com- bined, dose of 62 Pertussis Vaccine Com- bined, therapeutics of. 61 Pharyngitis, septic 36 Phases, negative and positive 46 Phlegmon, treatment of 54, 68 Phylacogen, aerobic and anaerobic tests of.... 108 Phylaoogens, clinical testing of the 110 Phylacogens, culture and safety tests of the lOS Phylacogens, degree of potency of the 109 Phylacogen, dose of any 111 Phylacogen, Erysipelas. Ill Phylacogerts, general de- scription of the 103 Phylacogen, Gonorrhea.. 115 Phylacogen, intracervl- cal injection of 113 Phylacogen, intramus- cular injection of. . . . 112 Phylacogen, intravenous dose of 112 Phylacogens, marketed packages of the 113 Phylacogen, Mixed In- fection 114 Phylacogen, Pneumonia. 115 Phylacogens, present use of the 109 Phylacogens, prepara- tion of the 107 Phylacogens, reaction caused by administra- tion of the 112 Phylacogen, Rheuma- tism 117 Phylacogen, subcutane- ous dose of Ill Phylacogen, subcutane- ous injection of 113 Phylacogen theory 104 Phylacogen, the term... 106 Phylacogen, therapeu- tics of Erysipelas.... 117 Phylacogen, therapeutics of Gonorrhea 116 Phylacogen, therapeutics of Pneumonia 115 Phylacogen, therapeutics of Rheumatism 118 Phylacogen, therapeutics of Typhoid 119 Phylacogen, Typhoid ... 119 Physiology 2 Physiology and pathol- ogy applied to cell theory 5 Pituitrin 163 Pituitary gland 154 Pituitrin, therapeutics of 164 Pleurisy 36 Pneumococcus Vaccine.. 62 Pneuraococcus Vaccine. dose of 63 Pneumococcus Vaccine, therapeutics of 63 Pneumonia 36 Pneumonia, treatment of 63, 65 Pneumonia Phylacogen. 115 Pneumonia Vaccine Com- bined 64 Pneumonia Vaccine Com- bined, dose of 65 Pneumonia Vaccine Com- bined, therapeutics of. 65 Precipitins 12 Prostatitis 33 Prostatitis, treatment of 53, 56 Psoas abscess, treatment of 67 Purpura hemorrhagica.. 36 Puerperal asepsis 36 Pyelitis, treatment of . . . 53 Pyorrhea Alveolaris Vac- cine Combined (Har- ris) 65 Pyorrhea Alveolaris Com- bined, dose of 66 Pyorrhea Alveolaris Vac- cine Combined (Har- ris), therapeutics oC. 66 Pyorrhea alveolaris, treatment of 66 Pyosalpinx, treatment of 53 IXDEX OF SUBJECTS IX Rajbid animals, persons bitten by 59 Rabies, prophylactic treatment of 59 Reaction, Bordet-Gen- gou 86 Rheumatism, articular.. US Rheumatism, clinical ex- perience with lis Rheumatism Phylacogen 117 Rheumatism Phylacogen, Therapeutics of 118 Russell, Major 69 Salt solution, used in suspension 44 Sarcoma, treatment of.. 95 Scarlet fever, malignant 36 Schafer, Dr. A. F 103 Septicemia 36 Sepsis, puerperal, treat- ment of 54, 68 Sera, antibacterial 13 Sera, antitoxic 13 Sera, care and prepara- tion of the horse for production of 14 Sera, hypodermatic in- jection of 37 Sera, methods of admin- istration of the 37 Sera, intraspinal injec- tion of. 37 Sera, intravenous injec- tion of 37 Sera, process of prepa- ration of 14 Serum, rectal adminis- tration of 37 Sera, when to use 49 Serum, allergic reaction attending the admin- istration of 26 Serum, Antidiphtheric. . . 21 Serum. Antigonococcic. . 32 Serum, Antimeningitic. . 34 Serum, Antistreptococcic (Polyvalent) 35 Serum, Antitetanic, how and when to use 29 Serum, Antitetanic, ther- apeutics of 30 Serum, Anti tubercle .... 32 Serum, Normal Blood: Its destructive effect on many varieties of bacteria 9 Serum, process and prep- aration of diphtheria bacterium to produce the 15 Serum sickness 26 Serum sickness, preven- tion of 2S Serum, standardization of 19 Serums and vaccines, how they prevent dis- ease 4S Sinuses, tuberculous, treatment of 68 Sore throat, streptococ- cus 36 Spinal fluid, withdrawal of 34 Staphylococcus Vaccines 67 Staphylococcus Vaccines, dose of 67 Streptococcus erysipe- latis 95 Streptococcus Va,ccine... 68 Streptococcus Vaccine, dose of 68 Streptococcus Vaccine, therapeutics of 68 Suprarenal glands 154 Suprarenal Glands (Des- iccated) 162 Suprarenal Liciuid with Chloretone 163 Sycosis, treatment of... 52 Sycosis staphylogens, treatment of 55 Synergistic action, how to obtain 36 Syphilitic serum 9.4 Terms, confusion of 49 Tests, aerobic and an- aerobic 108 Test, agglutination, the new method 80 Test, agglutination, without microscope. . . 78 Test, combining for the opsonin 45 Test, complement fixa- tion, in gonorrhea.... 88 Test, Ehrlich's diazo- reaction 85 Test, reagents for com- plement fixation 89 Test, Widal, in typhoid fever 77 Thrombin 100 Thymus Gland (Desic- cated) 158 Thymus Gland (Desic- cated), therapeutics of 158 Thyroid gland 152 Thyroid Glands (Desic- cated) 157 Thyroid Glands (Desic- cated), therapeutics of 157 Thyreoidectin 155 Thyreoidectin, therapeu- tics of V 155 Thyroprotein (Beebe)... 156 Thyroprotein (Beebe), therapeutics of 156 Tonsillitis, acute, treat- ment of 54 Tonsillitis, acute 36 Toxins, Erysipelas and Prodlgiosus (Coley's Mixture) 95 Toxin. production and preparation of 16 INDEX OF SUBJECTS Toxin, strength of IS luberculin B. E., prep- aration of tablets of. 144 Tuberculin, cutaneous test with 129 Tuberculin Discs, prep- aration of 136 Tuberculin, dosage of. . 139 Tuberculins, general survey of 121 Tuberculin, graduate method of dose of.... 148 Tuberculin in diagnosis. 127 Tuberculin in treatment 13S Tuberculin, Old, Koch (O. T.) 123 Tuberculins, packages of 149 Tuberculins, prepara- tions of 124 Tuberculin, preparations of tablets of 144 Tuberculin Residue, Koch (T. R.) 125 Tuberculin, subcutane- ous test with 128 Tuberculin, standardiza- tion of 126 Tuberculin, syringe method of dose of.... 147 Tuberculin T. R., prep- aration of tajblets of. 143 Tuberculin T. R., dilute 142 Tuberculin T. R. and B. E., directions for mak- ing dilutions of 140 Tuberculin, tables of di- lution of 141 Tuberculin, tablets of.. 143 Tuberculin tablets, the advantages of 144 Tuberculin tablets, ta- bles for dilution of.. 147 Tuberculin tablets, the method of dose of... 145 Typhoid Agglutometer, a useful instrument .... 84 Typhoid amboceptor ... 86 Typhoid antigen 86 Typhoid fever, diagnosis of 77 Typhoid Vaccine, con- traindications of 70 Typhoid Vaccine, cura- tive effect of 70 Typhoid Vaccine, dose for curative effect of.. 70 Typhoid Vaccine in juvenile cases 69 Typhoid Phylacogen . . . 119 Typhoid Phylacogen, dose of 119 Typhoid Vaccine, dose of 69 Typhoid Vaccine, Pro- phylactic, therapeutics of 69 Typhoid Vaccine, Pro- phylactic 68 Typhoid-Paratyphoid Vaccine, Prophylactic. 71 Typhoid-Paratyphoid Vaccine, dose of 72 Typhoid-Paratyphoid Vaccine, Prophylactic, therapeutics of 71 Ulcers, chronic, treat- ment of 52 Urethritis Vaccine Com- bined 73 Urethritis Vaccine Com- bined, dose of 73 Urethritis Vaccine Com- bined, therapeutics of. 73 Vaccine, Acne 51 Vaccines, autogenous ... 40 Vaccines, administration of, the factor of op- sonic index 46 Vaccines, bacterial 39 Vaccines, bacterial, what they are 40 Vaccine, Combined Bac- terial (Van Cott), therapeutics of 54 Vaccines, hypodermatic injection .of 74 Vaccines, indications for 47 Vaccines, methods of ad- ministration of 74 Vaccines, oral adminis- tration of 74 Vaccines, rectal injec- tions of 74 Vaccines subjected to purity tests 40 Vaccines, stock 40 Vaccines, the proved value of 39 Vaccines, when to use.. 49 Vaccinia, virus of 39 Vaccination, results of.. 43 Vaccine virus (small- pox) 74 Vaccine virus, care in preparation of 75 Vaccine virus (small- pox), how supplied... 76 Vaginal tract, inflamma- tory conditions of.... 99 Vesiculitis, seminal, treatment of. 56 Von Pirquet test 129 Vulvovaginitis qt chil- dren, treatment of.... 53 Walker and Beaton 117 Wassermann reaction... 92 Wassermann reaction, the reagents necessary to perform the 93 Widal and Gruber 79 Widal test, precaution of using the 83 Widal test, the 77 Section 1. BIOLOGY. Biology (Greek, — /Szo?, life; \oyo?, dis- course) has only one true meaning — i.e., its literal one, which is the science of life. In other words, it is the study of the action of life upon matter. Man, even in his most primitive state, is gifted with the faculty of observation and has separated living matter into its two great divisions of plants and animals, and these again into tree, shrub, and herb, bird, beast, and fish; and in so far as he was able to do this he was to that extent a biologist. Two classes of naturalists were thus produced: botanists and zoologists. Going back to the years 499-120 B. C. and scanning Greek history, we find this division arising; for on the one hand we observe Hip- pocrates studying the human body and dis- carding the old theory which attributed dis- ease to the wrath of the gods, and Aristotle beginning the classification of animals and speculating as to the differences between and the relative value of life in animals and life in plants. On the other hand we have The- ophrastus classifying over 500 different kinds of plants as trees, shrubs and herbs. BIOLOGY THE DAWN OF ANATOMY. Here we see the anatomist arising, and dur- ing the years A. D. 70-200 PUny, the zoolo- gist, and Galen began the study of the com- ponent parts of a hving organism, by describ- ing two sets of nerves and proving that the arteries contain blood. During the Middle Ages all science seemed lost in the glamor of alchemy, and little or no progress was made with the study of biology until the sixteenth century. Then Vesalius made some advances in the study of anatomy, and Gesner began the formation of a botanical garden and a zoological cabinet. Csesalpinus followed and made the first systematic classification of plants on Gesner 's plan. Each of these pio- neers of the sixteenth century had sketched out a rough plan of classification, so that bot- any, zoology and anatomy, the three sub- sciences of biology then extant, were begin- ning to assume a scientific aspect. In the seventeenth century progress was accelerated. Fabricius Aquapendente dis- covered valves in the veins, and Harvey dis- covered the mechanism of the circulation of the blood, and thus a new branch of the sci- ence of anatomy was opened up. From that time biology must be regarded as composed of the two subsciences of morphology and phys- iology, morphology being concerned with the analysis of a living organism with its parts. BIOLOGY 3 and phsyiology with living matter in action and the functions of the parts described. Harvey, furthermore, commenced the study of embryology, asserting that all animal life is produced from the ovum. Gaspard Aselius discovered the lacteal vessels which aid in the work of absorbing fat for the blood, and Riid- beck discovered the lymphatics. THE APPLICATION OF THE MICROSCOPE. Malpighi now took up the microscope, and applied it to the study of physiology, finding air cells in the lungs and the Malpighian layer in the skin. With Grew he discovered the cellular structure of plants and the stomata in leaves. Ray and Willoughby then classified the whole animal and vegetable kingdoms and thus laid the foundations of the study of ana- tomical classifications. In the eighteenth century the advance was even more rapid. During this period Boer- haave began to create the science of organic chemistry, the importance of which to biology is readily understood when we notice the fact that he himself analyzed milk, blood, etc., and showed that animal life can be sustained only by the absorption of organic compounds. Dr. Haller, of Gottingen, worked on the sub- jects of muscular irritability and the circula- tion of the blood, thus inaugurating the work that was later continued and extended by 4 BIOLOGY John Hunter while involved in the study of comparative anatomy. The geographical distribution of animals upon the face of the earth was now added as a branch by Buffon, and then arose Linnaeus, who invented a mar- velous classification of plants and animals, founding the artificial or Linnsean system of anatomical classification. Again, Palissy the Potter originated in the eighteenth century the theory that fossils are authentic traces of extinct life, and so laid the foundation of the science of paleontology. Wolff further em- phasized Harvey's theory of the development of animal life from the ovum. THE ADVENT OF HISTOLOGY. The nineteenth century opened with the work of Jussieu, who founded the natural system of botany, while Cuvier followed in the classification of animals. Bichat pro- ceeded from the study of organs to the study of tissues, and so founded the science of his- tology. Then followed Sprengel, who worked on the fertilization of plants by insects. Next came Lamarck, who once again raised the question of evolution through the gradual development of organs by reason of use or disuse through environment, and who was perhaps the firstto employ the term "biology." Von Baer followed up the work of Wolff and placed embry- ology upon a sound footing. Then Schleiden BIOLOGY in the botanical and Schwann in the zoologi- cal aspects of histology resolved living organ- isms into cells, so founding the cellular theory. Dujardin and Van Mohl further resolved cells into protoplasm, while Virchow applied the cell theory to physiology and path- ology, and Bernard applied the knowledge of the protoplasm to the study of the functions of organ, tissue, and cell. In the second half of the nineteenth century Darwin and Russel Wallace simultaneously developed the evolu- tionary theory by their hypotheses of natural selection or survival of the fittest. This theory, having given an apparently reasonable explanation of biological development, seems to justify the general conception of evolution. It has therefore been adopted in sociology, which must be considered as related to biol- ogy, and has led to the development by Galton of the theory of eugenics which seeks to eluci- date all those agencies affecting racial quali- ties. Prominent with Darwin and Russel Wallace as pioneers in the evolutionary theory were Haeckel and Huxley. NATURAL SELECTION. The doctrines of the struggle for existence and natural selection led to the science of selective breeding, of which Darwin made such good use. Then again the study of medicine, the demand for new drugs, reacted upon bot- 6 BIOLOGY any and induced the cultivation of useful herbs. Further, the idea of natural selection or the survival of the fittest caused a new view to be taken of the study of mankind. Pasteur developed the study of biology to a knowledge of the microbes of chicken-chol- era and silkworm disease, and now by inocu- lation experiments we have learned how to guard against some of the most deadly of these microscopic organisms. Thus the subscience of bacteriology was founded. From this many branches of preventive medicine have been evolved. Lord Lister applied this knowledge to surgery, and his discovery of antisepsis, together with the use of local and general anes- thetics, made possible the great surgical advances of recent days. The latest method in which biology is applied to life is as yet only in its observation stage. This is the study of the science of eugenics, or the dominant perpetuation of the qualities, inherent or hereditary, that con- tribute to the ideal development of the human race. Section 2. BACTERIA. Bacteria are unicellular plants of varying shapes, spherical, ovoid, cylindrical or spiral. The cell consists of a mass of protoplasm with irregular spaces contained therein, and en- closed in a cell wall which appears to be a modification of the protoplasm itself but is usually not cellular. Some bacteria have the power of locomotion, derived from cilia or flagellse which seem to project through pores in the cell walls. The classification of bac- teria is based primarily on their shape. Micro- cocci are small spherical bacteria; when joined together in a chain they are termed strepto- cocci." Others that grow in masses or bunches are called staphylococci. Rod-like or cylindri- cal bacteria are bacilli, and those in spiral form spirilla. The connection of bacteria with certain forms of disease was conclusively demon- strated by Pasteur, though it had long been suspected that suppuration was due to the presence of organisms in wounds. The var- ious pathogenic bacteria will be considered separately in their proper places in this book, as well as the sera, bacterins, vaccines, tuber- culins and phylacogens. 8 BACTERIA IMMUNITY. By immunity is meant non-susceptibility to a given disease or to a given organism or toxin, either under natural conditions or under con- ditions experimentally produced. Immunity is, in fact, of widely varying degrees and has correspondingly' relative significance. So long as an organism continues to exist it must continue to adapt itself to its environment, and thus it becomes so modified as to effect- ually resist influences which without such modification would have brought cessation of being. The lower animals are immune to some diseases prevalent in man, and certain families have marked resistance to some dis- eases. These are examples of natural immu- nity. An individual may be immune by virtue of his being of a certain race or family. Classic is the observation, on the other hand, that one attack of certain infectious diseases affords lifelong immunity against attacks of the same disease, while in other diseases the acquired immunity is of varying duration. THE PRODUCTION OF ARTIFICIAL IMMUNITY. We can produce artificial immunity, either active or passive. Vaccination or the injec- tion of bacterial toxins produces active immu- nity, while the injection of an immunizing serum, such as diphtheria antitoxin, confers passive immunity. In other words, in the II -:.,-^' Ij&cj//us' fyy>Aos*us', c/ejrAvLT^-a^ar r/ai cu//ure. i- S/roiJ ^O CO coirs' pyogfet) IPS', a^sf s'/an/ ou/hire J^acy/Zus- /e^anj, ^ ci f /furs'. BACTERIA 9 first instance the patient supplies his own antibodies — active immunity; in the second instance the antibodies are supplied to the patient — passive immunity. In active immunity, following recovery from either an idiopathic infection or an infec- tion artificially produced, there are developed in the blood the antibodies which are inimical to the toxin or to the activity of the bacteria themselves, or which accomplish the destruc- tion of the causative agent by the action of the phagocytes. The normal blood serum has a powerful destructive efi'ect upon many varieties of bac- teria, and this power is found to be greatly increased in a patient who has been infected with these bacteria, either naturally or arti- ficially. There can be no doubt that in all cases of acquired immunity, either active or passive, the leucocytes perform a large and important part, just as they do in natural immunity. In acquired immunity the phagocytes are much more capable of absorbing or destroying bacteria than in susceptible conditions. THEORIES OF IMMUNITY. As to the various theories of immunity that have been formulated, we owe more, perhaps, to Ehrlich's than to any of the others. His hypothesis is known as the "side-chain" theory. 10 BACTERIA The toxic molecule is supposed by Ehrlich to consist of a haptophore group and a toxophore group. The protoplasm of living cells is sup- posed to consist of a central nucleus and a number of "side-chains," so called. These side-chains, or receptors, supply nutrition to the cell, and in order to perform this function they combine with or anchor molecules of nutrient materia] dissolved in the blood or lymph. Moreover, there are many varieties of pro- teins in the blood, and there are specific recep- tors for each of these various proteins. Upon the injection of a certain toxin into an animal, the haptophore group of the toxic molecule combines with the receptor, and the toxo- phore group, thus brought into communication with the protoplasm, exerts its toxic action on the central nucleus. If the dose of toxin is large, the protoplasm is fatally injured and the animal dies. When a small or non-lethal dose is injected, a certain number of side- chains necessary for the nutrition of the cell are rendered useless by combining with the toxin. The vital reaction of the tissues to injury causes other side-chains to be pro- duced. By repeating the dose of toxin, additional side-chains are formed, and if the administration of toxin in suitable doses is continued, the protoplasmic molecule may be gradually trained to produce side-chains ^^ so rapidly that many of them become detached BACTERIA 11 from the central nucleus and float freely in the blood. They however retain still their power of uniting with the toxin molecule by means of its haptophore group, thus prevent- ing its union with the protoplasm and render- ing it virtually inert, and so they constitute the antitoxin. NATURAL IMMUNITY. It is assumed that the protoplasmic mole- cule possesses a specific side-chain for all the various toxins which might act injuriously. If a toxin be injected into an animal and the side-chains of the molecules of living proto- plasm do not possess haptophore groups to fit those of the toxin, no poisoning can occur, as the toxin cannot unite with the molecule. This is the state of natural immunity. The chemical poisons do not give rise to the formation of antitoxins, owing to the fact that these unite with all parts of the molecule. PRECIPITINS. Precipitins are substances formed by the injection of a protein solution, and these cause sedimentation or precipitation when the serum of the animal is mixed with a solution of the same protein as that injected. AGGLUTININS. Agglutinins are formed as the result of invasion or injection of bacteria; and the 12 BACTERIA serum of an individual or animal so treated, when brought into contact with the same species of bacteria, causes them to collect into clumps. LYSINS. Lysins are much more complex in structure than the foregoing. A combination of ambo- ceptor and complement is necessary to produce lysin. According to Ehrlich, the production of lysins is due to the development within the serum of receptors which have the power of combining with the antigen that gives rise to them, and also combining with the comple- ment that exists in the serum of all animals whether they are infected or not. ANTIGENS. Antigens are of various kinds — e.gr., bacteria, protozoa, animal cells, blood serum, animal proteins, and vegetable products. One obser- vation is to be noted : if animal derivatives are injected into other animals, the two animals must not be of closely related species, other- wise no antibodies will be produced. Section 3. PREPARATION AND USES OF SERA. The sera now available for therapeutic uses are of two classes, the antitoxic and the anti- bacterial. The antitoxic sera are obtained by repeatedly injecting animals (horses generally) with soluble toxins produced in artificial cul- ture media by micro-organisms. The anti- bacterial sera are produced by injecting the animals with the actual bacterial substance of such pathogenic organisms as do not excrete their poisons. Typical of these two classes of sera are antidiphtheric serum (diphtheria antitoxin) and antistreptococcic serum. These were also among the earliest sera to be used therapeuti- cally; not only have they maintained their position, but their use has been successfully extended. In our list the first three mentioned below (antidiphtheric, antitetanic and antitubercle) are properly classed as antitoxic sera; and the three following (antigonococcic, antimen- ingitic and antistreptococcic) as antibacterial. As the methods of preparation of any or all of the antitoxic sera do not in any essential points differ from that of diphtheria antitoxic serum, a description of the method of prepara- 14 • SERA tion of the latter will suffice for all. Antibac- terial sera are, of course, prepared in a similar manner, only in their case the bacteria or their cell contents are used for inoculating the animal. CARE OF THE HORSES. The horses chosen for serum production must be absolutely free from disease, and with this end in view they are kept for several days under close observation in a detention stable. During this time a thorough physical exami- nation is made by a competent veterinary surgeon; this examination includes the mal- lein test to insure freedom of the animals from glanders. An injection of anti tetanic serum is then given whereby each horse is immunized against tetanus. Not only must the horses be healthy and vigorous when inoculated; they must be kept so, and they are fed, stalled, groomed and exercised with this end unremittingly in view. PREPARATION OF ANTITOXIC SERA. In brief outline of the process it may be said that diphtheria toxin is first obtained from a known strain of Bacterium diphtherise and injected into a horse, the dose being repeated and gradually increased. These injections are carried on until the antitoxin in the horse's blood has reached a high degree of concentra- SERA 15 tion. A quantity of blood is then drawn and the serum, containing the antitoxin, is decant- ed into suitable containers. Various ani- mals at different times have been used in this work, but the horse is now considered to be most convenient, most easily managed, and most sensitive to diphtheria toxin, and on account of its size yields the maximum amount of blood. THE PROCESS IN DETAIL. The first step in the process of serum prepa- ration is the cultivation of the diphtheria bacterium in a suitable fluid nutrient medium in order to obtain a solution containing diph- theria toxin. The strain of organism selected is chosen for its capacity to produce a powerful toxin. Reasoning from analogy it would seem nat- ural to suppose that the power of producing a potent toxin in the artificial culture medium would parallel the virulence of the micro- organism in man or animals; such, however, is not the case. The cultures used in our laboratories for the preparation of the toxins are originally obtained from human sources, and their power of producing a highly toxic filtrate has been developed through con- tinued long growth on the surface of fluid culture media and by repeated inoculation into guinea-pigs. It follows, therefore, that 16 SERA to prepare special antitoxins for particular epidemics by the use of micro-organisms freshly isolated from cases of infection is impracticable. THE PRODUCTION OF THE TOXIN. The nutrient medium for the cultivation of the micro-organism is usually beef or veal bouillon. This is poured into flasks, which are then plugged with cotton and carefully steri- lized by heat. The next step is to inocu- late the contents of the flasks with a pure cul- ture of diphtheria bacilli. The flasks are then placed in an incubator, where they are kept for a week to a fortnight at a temperature of 37° C. Within this interval of time the ba- cilli multiply enormously, and the bouillon in the flasks becomes charged with toxin. The culture thus obtained is then examined micro- scopically and, if found free from contamina- tion, 0.4 per cent, of trikresol is added as a preservative. After standing for twenty-four hours the killed micro-organisms are removed from the toxin solution by filtration, and the toxin is then stored away from the action of light and heat until required for use. The filtered toxin is ultimately used to establish a condition of immunity in horses, but it is first tested on guinea-pigs to ascertain its strength before an estimate may be formed of the proper dose for the horse. The toxin is so SERA 17 active that about 0.002 Cc. is fatal to a 250- gramme guinea-pig within four days. IMMUNIZING THE HORSE. Having determined the relative strength of the toxin it is now ready for use. To immu- nize the horse the injections are made sub- cutaneously, and with all possible precau- tions to preclude bacterial infection. The object is primarily to establish in the animal a "grund-immunitat" and then to increase the immunization until the antitoxin is pres- ent in the blood in high concentration. The first dose is a fraction of a cubic centimeter and is injected under the skin of the shoulder. The result of this injection is usually a rise of temperature, with symptoms of rigor, dejection and rough coat. These symptoms soon pass off, and the first dose is followed in about twenty -four hours by a larger one, and in 24 hours more by a still larger one, the gradually increased doses being continued every twenty -four to forty-eight hours, until enor- mous quantities can be injected. In the efforts put forth by nature to counteract the effects of the toxin, there is developed in the blood of the horse a powerful antidote or antitoxin. Usually, as the doses of the toxin are increased, the antitoxicity of the blood also increases, though this is not always the case, for occa- sionally horses have been treated by injections 18 SERA of the toxin for as long a period as two years without producing a serum of high antitoxic potency. In most cases, however, the horse is thoroughly immunized by the end of two to four months, at which time the trial bleedings are made. THE STRENGTH OF THE TOXIN. In the immunizing process the maximum dose of the toxin injected into the horse is quite sufficient to kill five hundred thousand guinea-pigs of 250 grammes each, and if immunization is quite successful one cubic centimeter of the horse's blood serum will neutralize sufficient toxin to kill fifty thousand guinea-pigs of 250 grammes weight. As the disease diphtheria can be conveyed only by the living Klebs-Loeffler (diphtheria) bacillus, the horse does not contract diphtheria, for the injections consist of toxin from which the bacilli, first killed, have been removed. THE BLEEDING OPERATION. The operating building, separate and apart from the general stables, is of solid concrete construction with appointments similar to those of the operating-rooms of a modern hospital. It is kept thoroughly aseptic, and all instruments, vessels and apparatus are sys- tematically sterilized after approved methods. The immunized horse is now bled, the greatest care being taken to maintain asepsis. SERA 19 A sterile cannula is inserted into the jugular vein, and a gallon or more of blood may be removed. The blood is collected in large sterile tubes or glass cylinders, which are placed in cold storage until clotting occurs. The serum is then drawn off, 0.4 per cent, of trikresol is added to it as a preservative, and it is filtered to remove particles of fibrin and to render it clear. The serum is placed in cold storage until tests have been completed and it is required for use. STANDARDIZATION OF THE SERUM. Obviously, if a serum is to be of the greatest value therapeutically, there must be some means of efficiently controlling the dosage; i. e., the serum must be standardized. This is done in terms of antitoxic units. HOW THE TEST IS MADE. To test the antitoxic value of a serum a number of guinea-pigs, each of 250 grammes weight, must be selected. Neither the guinea- pigs chosen for the test nor their parents can have been used previously for testing diph- theria toxin or antitoxin. THE ANTITOXIC UNIT. An antitoxic unit is to be apprehended by its effect only. It is capable of neutralizing an amount of toxin, or bacterial poison, that is 20 SERA in turn measurable by its fatal effect on guinea-pigs in the presence of a standard immunity unit furnished by the United States government. The immunity unit is mixed with the toxin and administered to a guinea-pig weighing 250 grammes; sufficient toxin must be used to kill the guinea-pig, not- withstanding the protection afforded by the immunity unit. This amount of toxin (that is to say, just enough to kill the protected animal) is called the L+ dose. One antitoxic unit will just save the life of a 250-gramme guinea-pig when injected together with the L+ dose of toxin. As a matter of fact the L+ dose of toxin is approximately equivalent to one hundred minimum fatal doses of toxin; so an antitoxic unit will save the life of one guinea-pig exposed to the action of one hun- dred times the minimum fatal dose of toxin (or one L+ dose), or the lives of one hundred guinea-pigs, each exposed to one minimum fatal dose. Hence 3,000 antitoxic units, a usual therapeutic dose, will protect three hundred thousand guinea-pigs from death by toxin. This affords a forceful illustration of the potency of Antidiphtheric Serum, or diphtheria antitoxin. SAFETY TESTS. The potency of the serum having thus been ascertained it is now subjected to both ster- SERA 21 ility and safety tests. The safety test is carried out by injecting the serum into guinea- pigs, the animals being kept under observation for a week or more. No serum is issued unless at the end of that time the pigs are alive and well. If the sterility test shows the absence of micro-organisms, the serum is then put into its proper containers and these are hermeti- cally sealed. THERAPEUTIC ACTION OF SERUMS. Infectious diseases are caused by pathogenic bacteria which, finding a favorable soil in the patient, multiply and develop poisons or toxins. The patient's economy endeavors to combat the disease by developing antibodies. When that process is successful the patient recovers without treatment, or he may not become acutely ill. That is, he is immune to the disease. This is active immunity. In the use of therapeutic sera the active immunity in the horse is transferred to the patient and in him becomes passive immunity. ANTIDIPHTHERIC SERUM. Antidiphtheric serum has in large measure robbed diphtheria of the dread with which it was formerly regarded. In the less than twenty years since its introduction into thera- peutics it has saved countless lives, and given to the medical profession a control over the 22 SERA one disease of all others in the presence of which the physician had previously been all but helpless. Its value, both remedial and prophylactic, rests upon .so sure a basis that it requires on our part no special commendation. It is but fitting, however, that we quote the words of an eminent American pediatrist, who says: "No tables of figures are so con- vincing to an individual as personal exper- ience, and by this argument one by one the opponents of antitoxin have been converted." THE DOSE OF DIPHTHERIA ANTITOXIC SERUM. The dose in a case of moderate severity should be not less than 3,000 units, and in severe cases 5,000 to 10,000 units should be given at once. Even larger doses are recom- mended by many authorities. The tendency is toward larger dosage — even as much as 10,000 units is recommended in tonsillar diphtheria, and 25,000 units in nasal or laryn- geal diphtheria. The use of 85,000 units has been reported in a single case, and doses of 50,000 units and higher are not uncommon. The conservative estimate as to dosage would seem to be never less than 3,000 units, and for cases of severe involvement 10,000 units, or even more. In cases which progress unfavor- ably, at least double the initial dose should be given six hours later. The same good results are not to be expected from repeated SERA 28 injections at intervals as are obtained from one large dose at the outset of an attack. If the age of the patient is allowed to have any influence on the dosage, adults should have smaller doses than children, as the prognosis in diphtheria improves with the age of the patient. FURTHER REMARKS ON DOSAGE. As it is impossible to know in any given case how much toxin has been, or will be, absorbed, it appears to be prudent to give more rather than less of the antitoxin than will sufiice to neutralize the toxin — as evi- denced by a stronger pulse, shriveling of the membrane, and less offensive odor. If the total amount of the toxin in the general circu- lation is not neutralized by the dose of the antitoxin given, then the uncombined toxin goes on with its destructive work; if, on the other hand, the antitoxin is in excess, no harm results. THE TREATMENT OF ADVANCED CASES. In hospital practice, owing to the fact that in the greater number of cases admitted the disease has reached the advanced stage, many patients do not receive the first dose before the fifth or sixth day, or even later. In such instances the dose is large, ranging from 20,000 to 50,000 units. This illustrates the 24 SERA necessity of large doses when treatment is delayed. The fact that the amount of anti- toxin which is necessary to save life increases at a rapidly accelerating rate, according to the length of time which elapses between infection and the administration of the serum, has been proved by animal experiments as well as by hospital experience. In cases demanding immediate relief, the antitoxin should be administered intraven- ously, with due caution. PROPHYLACTIC USE OF DIPHTHERIA ANTITOXIC SERUM. Diphtheria antitoxin is a valuable prophy- lactic agent, but it must always be remem- bered that the passive immunity produced by its use is only temporary, lasting probably not more than three weeks. A prophylactic dose of at least 1,000 units may be adminis- tered to all other members of the family whereof one member has been attacked by diphtheria. When once a bulb of serum has been opened it is imperative that no portion of the contents be reserved for future use; therefore it is advisable to use the whole at once in one or more cases. CONCENTRATED DIPHTHERIA ANTITOXIN. One difficulty in the administration of large doses of diphtheria antitoxin consists in the ^^ SERA 25 inconveniences attending the subcutaneous injection of bulky doses. Since its ijitroduc- tion manufacturers have persisted in attempt- ing to isolate the antitoxin from the serum. The early discovery was made that the anti- toxic element in the serum is either a globulin or so intimately associated with the globulin content as to precipitate with it. There are various methods by which this result is attained, all these methods being based on the principle of repeated precipitation. The method now being employed in our laboratory produces a globulin that is free from many of the albuminous substances which cause the undesirable by-effects of serum administra- tion. These proteins which are removed in the process of concentration are largely re- sponsible for the toxic symptoms which sera may produce in susceptible patients. With Parke, Davis & Co.'s Concentrated Antidiphtheric Serum (Globulin) and Anti- diphtheric Globulin (Dry) , it is found in practice that rashes and other undesirable symptoms occur less frequently than with untreated serum, and when they do occur they are of a milder type. TOPICAL AND CONSTITUTIONAL TREATMENT. Though curative results usually follow the use of antidiphtheric serum alone, still it is well to call to mind the fact that the serum 26 SERA is not antimicrobic, but only antitoxic, hence the additional advantage of treating the throat antiseptically. For this purpose sprays of hydrogen peroxide solution (P. D. & Co.) may be used freely; also inhalations from boiling water with the addition of fluid ben- zoin (P. D. & Co.) ; and if a tendency to hem- orrhage be present, the throat and nose may be sprayed with Adrenalin Inhalant (P. D. & Co.). In addition to the use of the serum and local treatment of the throat and nose, proper constitutional treatment should be instituted and the activity of the eliminative functions should be maintained. ALLERGIC REACTIONS ATTENDING THE ADMINISTRATION OF SERUM. Undesirable symptoms resulting from a hypersensitive condition of the patient to the injection of foreign protein are sometimes encountered in the use of serum products. In a considerable number of cases the adminis- tration of serum is attended with a symptom complex designated "serum sickness," and characterized by rashes (usually urticarial), enlargement of the lymph nodes, edema, painful joints, pyrexia, and albuminuria. The entire chain of symptoms is not present in every case of serum sickness, the only constant manifestation being the skin eruption. In patients who have never before been treated SERA 27 with serum the symptoms of serum sickness, if they are to appear at all, usually develop eight to twelve days after the injection, while in those who have received previous injec- tions they develop earlier, often within forty- eight hours, and are usually more severe. Serum sickness is an annoying but not a dan- gerous condition, the symptoms usually dis- appearing within a few days and leaving the patient none the worse for the attack. It is estimated that 20 per cent, of all cases injected with serum exhibit some of the symptoms of serum sickness. A few cases are on record of profound and even fatal collapse attending the administration of serum. In most of these cases the symptoms have developed within fifteen to twenty minutes after the injection of the serum, and in patients not previously treated with serum. The under- lying factor is believed to be a hypersensi- tiveness to the serum albumin, probably associated with an instability of the vaso- motor apparatus. Patients evidencing an overgrowth of the lymphatic tissue are re- garded as more likely to develop severe reac- tions than others. DESENSITIZATION. The use of concentrated or globulin anti- toxin has reduced the case incidence as well as the severity of serum sickness, and it is now 28 SERA believed that by proper precaution it is pos- sible to practically eliminate the danger of sudden collapse. Experiments on the lower animals have demonstrated that sensitization to a specific protein can be destroyed — in other words, that the animals can be desensitized by the injection of a very small amount of the protein, so that subsequently large doses of serum or other protein can be given without the production of toxic symptoms. The desensitization of the human subject is there- fore suggested as a rational procedure, and has been tried on an extensive scale. Besredka, of the Pasteur Institute in Paris, offers the following method of procedure: "By making serum injections into veins, first a drop, a half -minute later a few, than after a little time some more, and so on, we may safely inject any size of dose of serum without fear, the whole not requiring more than five minutes more time than we give to the same operation when taking no precaution. The in- creased safety is well worth the extra time." The more common procedure is to inject sub- cutaneously or intramuscularly a few drops of the serum (0.1 Cc.) and to withhold the balance of the injection for a period of from one-half hour to an hour. 8ERA 29 UNUSUAL USES OF ANTIDIPHTHERIC SERUM. Aside from the specific therapeutic uses of antidiphtheric serum (the prevention and cure of diphtheria) , the serum has been successfully employed and highly recommended by many clinicians in various affections, among which are the following: scarlet fever, quinsy, tonsilhtis, bronchopneumonia, measles, can- crum oris, tubercular dis'eases, conjunctival diphtheria, ocular inflammation, exophthalmic goitre, rhinorrhea, asthma, whooping-cough, boils and carbuncles, chronic skin diseases, hemorrhage, hematemesis and hemoptysis, erysipelas and other septic infections. It has been administered in most of these affections, of course, by the injection method; in some cases, however, it has been given by the mouth, and in a few cases per rectum. It would seem that this specific serum has a very wide therapeutic range, to which the general profession have paid but scant if any notice. ANTITETANIC SERUM. Antitetanic serum is obtained from the blood of horses that have been immunized to the toxin of the tetanus bacillus. Some clini- cians deny that its results are curative, although there is abundant evidence that its timely administration does prevent tetanus. The cause of failure is probably due to the fact 30 SERA that the serum frequently is not administered until muscular spasms occur, while the ration- ale of its action depends upon its early admin- istration before the neurotoxic effect occurs. When the symptoms of tetanus have devel- oped the toxin has already invaded the motor nerve cells, forming a union so strong that the antitoxin is powerless to break it up, though it may possibly chfick the further progress of the disease; whereas, if the antitoxin is given early, the toxin is neutralized before it reaches the motor cells and is thereby rendered harm- less. The numerous reported instances of recov- ery brought about by the administration of the serum, notwithstanding that convulsions had appeared before the first dose was given, emphasize the desirability of using it even in the late stage of the toxemia. Therapeutics. As a prophylactic, injections of antitetanic serum should be given in all cases of woimds soiled with garden or street dirt or with dung, also those made by splinters or bullets,. and with gunpowder. The proced- ure is to remove, by curetting, the infected tissue, and cleanse the wound thoroughly with hydrogen peroxide solution (P. D. & Co.) ; dry and pack with gauze well charged with Anti- tetanic Dusting Powder (P. D. & Co.), pro- viding free drainage, and prevent premature ^scjIAts' /uJiercir/cs-j's^ ^ro^j'n^ oiz J^ro/A. w ki Ix aureus; c/rreusi ^e/a/in a/In/j^^e/s/m pe/s//n sviaji/. s'/tsn^. s-Af/i/. Tike Gram meiAoef js" us'ed /or /Ae s-/aij7j7^ o/ /Ae'S't? s'/aoAy/ococcj. SERA 31 closure of the wound in order to avoid anaer- obic conditions; and inject immediately 1500 units of Antitetanic Serum in the neighbor- hood of the wound if that is possible — ^if not, in the subclavicular region. The prophylactic dose of 1500 units should be repeated once or twice during the succeeding ten days. When tetanus symptoms have appeared, resort should be had to large curative doses of the serum; the dose recommended is from 10,000 to 20,000 units, injected intravenously, re- peated every four to six hours until all symp- toms of the disease disappear. Cases of successful treatment are reported in which as much as 250,000 units was injected. The serum has also been administered by spinal injection, with results sufficiently favorable to warrant this procedure in very grave cases. ANTITETANIC GLOBULINS (DRY). This preparation is very convenient for the use of travelers and expeditions. It is a potent and practically a permanent product, retain- ing its peculiar properties for years in the unbroken package. It consists of the globu- lins of Antitetanic Serum, precipitated, puri- fied, and dried so that most of the serum con- stituents have been eliminated except those bearing the antitoxin. 32 SERA ANTITETANIC DUSTING POWDER. This is a mixture of equal parts of dried Antitetanic Serum and Chloretone, for use in the treatment of wounds suspected of being infected. Antitetanic Serum is supplied in plain bulbs of 1,500 units each, three bulbs in a package; also in syringe containers of 1,500 and 3,000 units, respectively; the concentrated serum (Globulin) in syringe containers of 5,000 units. Antitetanic Globulins (Dry) are sup- plied in sealed glass bulbs of 1,500 units; and the Antitetanic Dusting Powder in 1 -gramme vials. ANTITUBERCLE SERUM. This serum is obtained from the blood of horses injected with the water-soluble toxic products of Bacterium tuberculosis. We make no claims as to its therapeutic value. It is made in accordance with the best methods known and is, therefore, one of the most reli- able products of the kind on the market. There is no way by which to standardize it. Antitubercle Serum is supplied in bulbs of 1 Cc, 2 Cc, and 4 Cc, respectively. ANTIGONOCOCCIC SERUM. This serum is prepared according to the method of Dr. J. C. Torrey, of the Loomis SERA 33 Research Laboratory, New York. It is made from the blood of horses which have been inoculated with gradually increasing quanti- ties of bacterial suspensions and endotoxin from the most virulent strains of gonococci obtainable; the process throughout is similar to that employed in the production of anti- diphtheric serum. Therapeutics. This serum is especially val- uable in the treatment of chronic conditions arising from primary gonococcic infections of the prostate, epididymis, testicle, bladder and Fallopian tubes; also, those due to the entrance of the micro-organisms into the circulation, as arthritis, iritis, endocarditis, pleuritis, and meningitis. The most satisfactory results of its use have been obtained in gonorrheal arthritis ; good results have been reported in cases of epididymitis, prostatitis, and orchitis. The treatment should commence withSCc, to be repeated every two to four days. If no improvement is noted, 4 or even 6 Cc. may be given every fifth day. The majority of cases require from 30 to 50 Cc. of the serum. The places best suited for injections are the thigh, buttocks, abdomen, or the side of the breast, using in every case aseptic precautions. Other treatment, such as local applications and irrigation, should not be neglected. 34 SERA ANTIMENINGITIC SERUM. This serum is obtained from the blood of horses immunized against endotoxin and cultures of a number of strains of Diplococcus intracellularis meningitidis. In addition to the tests employed for determiningitspotency, rigid bacteriologic and physiologic tests are employed to establish its safety. Therapeutics. This serum is especially in- tended for the treatment of cerebrospinal meningitis produced by the Diplococcus intra- cellularis meningitidis. As much depends on an early diagnosis and administration of the serum, it is quite imperative that when the first lumbar puncture is made for securing the spinal fliiid for bacteriological examination the serum should be administered at once; it is not advisable to await the result of microscopic examination. It has been observed clinically that in the presence of the Diplococcus intra- cellularis meningitidis the spinal fluid is more turbid than in other types of infection. The dose usually administered to young children is 15 Cc, while for an adult or in malignant cases 30 Cc. (twosyringefuls) should be injected at each dose. In severe and ful- minant cases a dose of 45 Cc. should be injected if indications to the contrary do not exist. The amount of serum injected should be equal in volume to the amount of spinal SERA 35 fluid withdrawn. Four daily injections should be given, and in resistant types of the disease it will be found necessary to give six, eight, or even more injections. With each package is provided a special needle with a stylet. This needle aflfords a means for both withdrawing the cerebrospinal fluid and injecting the serum. The operator should take special pains to see that the stylet is fitted into place so that the bevel corre- sponds to that of the needle point before mak- ing the lumbar puncture. Rigid asepsis is essential to the successful use of the serum, therefore the same care should be exercised as in a major operation. The serum is supplied in 15-Cc. syringe con- tainers, two in a package, with the special needle and stylet, and two rubber connections for the needle. ANTISTREPTOCOCCIC SERUM (POLYVALENT) This serum is prepared by immunizing horses with increasing doses of killed bouillon cultures of streptococci representing strains from puerperal fever, erysipelas, scarlet fever, pseudo-diphtheria, endocarditis, and other forms of streptococcus septicemia. It is believed that antistreptococcic serum is mainly, if not entirely, bacteriolytic. Therapeutics. Infection with virulent strep- 36 SERA tococci is not infrequent in injuries and abor- tions, giving rise to a systemic toxemia. It occurs also in erysipelas, pneumonia, pyemia, scarlet fever, parturition, certain forms of tuberculosis, etc. When the toxemia is but slight an injection of 10 Cc. of antistreptococcic serum every eight to twelve hours may suffice, but in severe cases it is necessary to give from 20 to 40 Cc. every six to eight hours. It has been advised that in severe forms of toxemia no less than 300 Cc. should be given during twenty -four hours (60 to 80 Cc. administered every four hours for twenty-four to thirty hours). It has also been reported that a synergistic action is obtained by injecting strepto. bacterin at the same time with the serum, as the bacterin increases the amount of antibodies in the patient's blood, thereby increasing his resistance to the disease. The infections in which antistreptococcic serum is indicated are: endocarditis, puer- peral sepsis, septicemia, erysipelas, acute ton- sillitis, septic pharyngitis, malignant scarlet fever, pneumonia and pleurisy, purpura hemorrhagica, streptococcus sore throat, men- ingitis, chronic gonorrheal infection, articular rheumatism, and iritis. This serum has been administered both hypodermatically and per rectum in diseases presumably due to strepto- coccus infection, and in some in which the infective agent was not determined. SERA 37 Antistreptococcic Serum is supplied in 10- Cc. and 20-Cc. syringe containers, and in 10- Cc. glass bulbs, three bulbs to a package. The dose is 20 Cc. to 80 Cc. every four to six hours until the temperature is reduced and symp- toms of toxemia disappear. METHODS OF ADMINISTRATION OF THE SERA. Except in the case of Antimeningitic Serum, the hypodermatic injection method is adopted in the majority of cases. This method affords rapid absorption, and the dose is read- ily and exactly regulated. Aseptic precau- tions are always observed. The most approved site for the injection is between the scapulae or under the skin of the abdomen, and the serum is allowed to become absorbed natur- rally; the swelling over the point of injection readily disappears. The intravenous injection method is adopted in the more desperate cases, and its use is likely to become more general. The intraspinal injection method is used in cases of cerebrospinal meningitis, for the Antimeningitic Serum, and Antitetanic Serum has been administered by this method in grave cases with favorable results. Rectal administration of Antistreptococcic Serum, polyvalent, has shown as favorable results as those obtained by the hypoder- matic method. Section 4. BACTERIAL VACCINES OR BACTERINS. The terms "vaccine" and "vaccination" had their origin in Jenner's method of producing immunity to smallpox by means of inoculation with the virus of vaccinia. These terms have now taken on a wider application, and in any case in which inoculation with a killed culture or attenuated virus of a disease is employed to bring about a condition of immunity or resistance to that disease, the terms vaccine and vaccination are applied. The extension of the method naturally resulted in the exten- sion of meaning. Pasteur's production of a protective anthrax vaccine, and later a hydro- phobia vaccine, was the beginning of a very rapid advance, until to-day a large number of vaccines are in use for both curative and prophylactic purposes, and in a variety of diseases. Many of these have proved of great value, making possible a degree of suc- cess in the treatment of certain bacterial diseases not possible with older methods. These results have given to vaccines an estab- lished place in the treatment of germ diseases, and also in their prevention. In the case of diseases of which the bacterial 40 BACTERIAL VACCINES OB BACTERINB origin is known, pure killed cultures of the causal agent are used for the inoculation, and the vaccine is called a bacterial vaccine. Liv- ing cultures are seldom made use of; the safest and common method of vaccination is with killed cultures. Bacterial vaccines are sterilized, standard- ized suspensions of micro-organisms. They are prepared by washing the films off agar cultures into a 0.9-per-cent saline solution, sterilizing by heating to a temperature just sufficient (55° or 60° C.) to kill the organ- isms, and diluting with trikresolated normal salt solution until each cubic centimeter contains the number of micro-organisms desired. The vaccines are subjected to bacteriologi- cal tests for purity. SOURCE OF THE CULTURES. The micro-organisms used in making bac- terial vaccines are either cultivated from the patient's own disease process, in which case the vaccines are called personal or autogenous vaccines; or germs of the same species as those infecting the patient are obtained from previous similar cases, in which case the. vac- cine is called a stock vaccine. The advantages of stock vaccines out- weigh the advantages of autogenous vaccines. Stock vaccines can be kept on hand and BACTERIAL, VACCINES OR BACTERIN8 41 administered without delay to the patient upon his first visit to the physician, whereas several days are required to prepare autoge- nous vaccines. Autogenous vaccines may be more efficacious than stock vaccines in some conditions, being more exactly suited to the particular patient; on the other hand, satis- factory results in the great majority of cases follow the use of stock vaccines. However, treatment may well be begun with the stock vaccines and finished, if need be, with auto- genous vaccines. Again, autogenous vac- cines are not only impractical but impossible in gonorrhea and tuberculosis, owing to difii- culties encountered in growing the germs, and in staphylococcus infections are usually unnec- essary owing to the fact that stock vaccines do quite as well in most cases. Finally, auto- genous vaccines can be prepared only by a well-trained laboratory worker, while stock vaccines are ready for instant use by the general practitioner. THERAPEUTIC ACTION OF BACTERIAL VACCINES. When bacterial vaccines are injected into human beings they have an effect similar to that produced on the horse by the injection of toxins or killed cultures; they produce active immunity. In other words, the injec- tion of a dose of a bacterial vaccine stimulates the patient's body to produce an additional 42 BACTERIAL VACCINES OR BACTEBINS supply of antibodies and thus enables him to resist the disease. In the use of serums the antibodies are supplied to the patient; in the use of bacterial vaccines he develops his own antibodies. Serums confer passive immunity, vaccines active immunity. As bacterial vaccines are used in accordance with the principles elucidated by Sir A. E. Wright, of London, England, it is only fitting that we give here his enunciation of the opsonic index theory. THE OPSONIC INDEX. The opsonic index is the ratio between the average number of bacteria found within 50 to 100 leucocytes in a suspension containing bacteria, blood corpuscles and the patient's serum, and the average found in the same number of leucocytes in a corresponding sus- pension containing normal serum, the latter being taken as the standard. In a large number of infections, protective substances (opsonins) exist in the blood serum. The opsonins are thermolabile; the serum con- taining them is inactivated (that is, deprived of its opsonins) if heated to 56° C. for a few minutes. The opsonins act upon the bacteria, so that the latter can subsequently be ingested by the leucocytes. When the different blood specimens are compared, the variable factor BACTERIAL VACCINES OR BACTERIN8 43 is the serum and not the leucocytes. The specific opsonin is consumed when bacteria are added to a serum containing it, for if the bac- teria are then removed and the serum used with a second portion of the same suspension it is found to be inactive. The opsonins become combined with or at least absorbed by the bacteria, so that bacteria removed after treatment and placed in an inactivated serum are freely taken up by leucocytes added to the serum. By careful vaccination with small measured quantities of dead cultures of vari- ous pathogenic micro-organisms it is possible to increase markedly the opsonizing power of the serum of an individual. Regarding phago- cytosis as the main process by which bacteria are destroyed within the organism, and the opsonins as the means whereby the bacteria are prepared for ingestion, Wright concluded that the relative amount of opsonins in a given serum affords an indication of the defensive power of the individual. The technique of taking the opsonic index may be described in the following stages : 1. COLLECTING THE BLOOD TO BE TESTED. By pricking the finger or the lobule of the ear the blood is obtained. It is drawn into a Wright capsule or a Widal tube, and the con- tainer is sealed with wax. One capsule of known normal blood is drawn. The capsules 44 BACTERIAL VACCINES OR BAGTERIN8 are numbered for identification, and left until the serum separates, or it may be centrifu- galized to save time. 2. PREPARING THE BLOOD-CORPUSCLES. A few drops of blood from the finger are run into a test tube which contains sodium citrate solution, 114 per cent., until the proportion is about two-thirds citrate solution and one-third blood. The contents are then gently mixed and centrifugalized for three minutes. The fluid is pipetted off, and normal salt solution is added to the corpuscles. The centrifugalizing is repeated, and the fluid again pipetted off, leaving only the layer of red and white cor- puscles in the tube; with a pipette these cor- puscles are gently mixed, and are now ready for use. 3. PREPARING THE SUSPENSION OF BACTERIA. The organisms, grown on agar, are removed, and suspended in salt solution. If necessary to break up clumps the culture should be shaken. The suspension is centrifugalized, pipetted off into a fresh tube, and thoroughly mixed. It should then be examined as an ordinary smear preparation to be certain of its freedom from clumps. The salt solution used in the suspensionis 0.85 per cent, saline, except in the case of tubercle bacilli and the non-gram-staining cocci, for which a 1.5 per cent, saline solution is used. BACTERIAL VACCINES OR BACTERINS 45 4. COMBINING FOR THE TEST. With a pipette having a long stem, equal quantities of the washed blood-corpuscles, the bacterial suspension, and the serum to be tested are taken up, driven out on to a slide to be thoroughly mixed, and redrawn into the pi- pette; the end of the pipette is then sealed in a flame, care being taken to keep the suspen- sion away from the heated end. The pipette is then incubated at 37° C; in the case of typhoid and other coliform organisms 8 to 10 minutes is quite sufiicient, and for other organ- isms 15 to 20 minutes. 5. PREPARING THE FILM. On removing the pipette from the incubator, the sealed end is broken off, and some of the suspension expressed upon a slide and thor- oughly stirred. A drop of this mixture is then placed on another slide, and spreading it with the slightly concave edge of an ordinary slide a film is made in which all the white corpus- cles are swept to one end, where they are fixed and stained with the appropriate staining fluid. 6. COUNTING. The micro-organisms in 100 polymorpho- nuclear leucocytes are counted. The average number of bacteria per leucocyte is the phagocytic index. The consistency of the suspension of bacteria should be such as to 46 BACTERIAL VACCINES OR BACTERIDS facilitate a ready enumeration of the micro- organisms in each leucocyte. The quotient of the number of organisms in 100 leucocytes from the patient's serum, divided by the number in 100 leucocytes from the normal serum, is the opsonic index. The opsonic index may be used as the con- trolling factor in the administration of vac- cines. THE NEGATIVE AND POSITIVE PHASES. Vaccines are used to aid the natural develop- ment of immunity, and the progress of this immunizing process may be gauged with a fair degree of accuracy by taking the opsonic index from time to time, the vaccine being regularly administered, both as to time and dosage, in accordance with the index. The injection of vaccine is followed by a slight fall of the op- sonic index. This is the "negative phase," which may continue from one to several days, and is succeeded by a rise in the opsonic index, indicating a "positive phase," during which the specific opsonin is produced in excess, and in consequence resistance is increased. An average dose of vaccine given at a stated time will produce a short negative phase, fol- lowed by a prolonged positive phase. If the dose given be too large, the negative phase is prolonged. No additional injection should be given during the negative phase, as this pro- ■'';■ ■"'■' '-i^ ■'\-'*.-^':',\f^i'. . l^^^^v.y■■^,<■•'l!';■<^:^^■;;^^.■^ir'.■^^■^i'■^:■c-;^'■.kv•■^ i o' i l '^•■■i^fJy^-T '^'^^s^ll^lll - 1- @f S^^fff -^Pl fei:iJ>t .'••'•'jx" . *',:& •«*:'-! i . • -t* . ' ••";•• ■■■.v.'. ■ .•..*-:•;.•,- ,;,;. ^ o Q .1,.. ■"* >C'-- - •■-.■■• **^ 1 1 ."■■'-•*: ' < '; ' •'..•-" i«' : ■ / ' . , '. •.•••■.r. ••' i ',' ' 1 ' , •/i.v'i-;:.. ..-,•,,, • «•', >•,- - •V** -. .*! i.r ••/• -f^.:»* ■ ■• /i .■•^/y^>-'^-:;\ (/•' '.',<'*" p^ ' » '* * '' \ . ' . ' 'r- •; - .»l' ' ' i ■, ■ ^- ■:>* .'•'•' -.-•".'•.••; "P.v., Liters- G/anc/y /n fio/torrAeet/ UT'e/Aj'/'/is'-S'Aomnp pojtococcj m and aAou^ pus- cff/Zs"- a, p/anJ crw/; ^, ffonococc/; c, h/A/Ze ce/fs: *'.', .'■' K .•;-'/ 7/' -5//n^/e Goi6-ff, TAouy/ng} over - <3/>uiJc/iince of Co//oic/ /rict/c/'/a/-^; •''.■■:■■■■';/>■ - ■ -— i- . •--■n>\. I ■■-1. t .' , ' ■ ■ ■ ■ " '■■■■,, \ £"-<*. , J ^- >/ ; ■ . ■ . • . : ■ ■■ ^ ^? -& - /^/uz/arjr ^oc^ /Aroi/pA /'unc/joji a/' &n/er/pr an.^ ;',|t:; '. •) ■■^t&lltf^'' J),?o/?3 ^/ojij ertr/os'd, cjona -v vpn » ">•'•. ^ ■-■c*?' r"-. s: » .* -i - =."^1 * Bacillus coli communis, x 1000. Drawing from cover-slip preparation. Bacterium diphtherise. x 1000. BACTERIAL VACCINES OR BACTERIDS 61 ically proved, but during epidemics of pertus- sis its use is advantageous. Dose. The initial dose should be 50 mil- lions, and subsequent doses should be given at intervals of three to five days. The clinical symptoms prove the best guide both as to the size of the dose and the frequency of its repetition. The dose may be increased by 20 to 40 millions at a time. Pertussis Vaccine is supplied in rubber-stop- pered bulbs and in graduated syringes, the bulbs in packages of four, and the syringes in packages of one and four; also in bulk pack- ages of 5 Cc and 20 Cc. PERTUSSIS VACCINE COMBINED (pertussis bacterin combined). A killed culture of: Bacterium pertussis of Bordet, 50 millions; Staphylococcus aureus, 20 millions; Streptococcus pyogenes, 10 millions; Micrococcus catarrhalis, 20 millions; Bac- terium influenzae, 20 millions; total, 120 millions in each bulb or syringe, sterile and ready for use. Pertussis Vaccine (Combined) is indicated in the treatment of all stages of whooping cough (pertussis), but is especially valuable in cases which have persisted for some time, such infections being almost invariably of the mixed type. The vaccine markedly shortens the course of the disease in most cases of 62 BACTERIAL VACCINES OR BACTERIN8 whooping-cough. It decreases both the fre- quency and severity of the paroxysms, and minimizes the danger of comphcations, espe- cially the pneumonic involvements. The vaccine is absolutely harmless. Best re- sults are obtained by means of fairly large doses. Dose. An initial dose of 60 million bacteria (0.5 Cc.) may be employed. Subsequent injections should be given at intervals of from three to five days, the dose being increased at each administration, unless there are indica- tions to the contrary. The production of a marked reaction, either local or constitutional, may be considered a contraindication to an increase in dosage. In the absence of con- traindications, with each successive injection the dose should be increased over the preced- ing from 12 to 24 millions (0.1 to 0.2 Cc.) It is rarely necessary to exceed a dosage of 120 millions. Pertussis Vaccine Combined is supplied in rubber-stoppered bulbs and in graduated syringes, the bulbs in packages of four, and the syringes in packages of one and four; also in bulk packages of 5 Cc. and 20 Cc. PNEUMOCOCCUS VACCINE (PNEtTMOCOCCUS BACTEBIn) . Killed cultures of the Diplococcus pneumo- niae, supplied in two strengths, one containing BACTERIAL VACCINES OR BACTERIN8 63 200 million bacteria per Cc, the other 500 miUion bacteria per Cc. Therapeutics. Pneumonia Vaccine is indi- cated in the treatment of lobar pneumonia, and other infections caused by the pneumococcus, including some cases of broncho-pneumonia and localized infections such as ulcus serpens cornese and otitis media. The Pneumococcus Vaccine is also used as a prophylactic during the season when pneumonia is particularly prevalent and among those individuals who are most exposed to infection. Wright (Lancet, January 10, 1914, p. 87) has shown that two or three injections of sterilized cultures of the Diplococcus pneumoniae in doses from 250 to 1000 millions, given at weekly intervals, pro- duce a considerable degree of immunity to pneumonic infection. Immunity can be de- pended upon for a period of two to three months. Dose. For prophylactic treatment, three doses are given at weekly intervals — ^first, 250 millions; second, 500 millions; third, 1000 millions. For therapeutic purposes the vac- cine has been used in doses ranging from two or three millions up to 1000 millions. The best results seem to have followed the administra- tion of large doses early in the course of the disease, Wright did not find that cases treated with small doses (2^ to 50 millions) did any better than those treated by the ordinary 64 BACTERIAL VACCINES OR BACTERIN8 methods, but the prompt use of large doses (250 to 1000 millions) reduced very markedly the mortality. In view o f the exhaustive work which he has carried out and the value to be attached to his results, it is suggested that a dose of not less than 200 millions be employed. A dose of 500 millions can probably be given safely to the average case. After an interval of three days a second injection should be given, increasing the dose unless an unusually sharp reaction follows the administration in the first instance. It is believed that a dose of 1000 millions should never be exceeded. The contents of more than one bulb or syringe may be injected when doses larger than 500 mil- lions are desired; or the bulk packages of 5 Cc. or 20 Cc. may be used, each cubic centi- meter containing 200 or 500 million bacteria, as specified. Pneumococcus Vaccine (Pneumococcus Bac- terin) is supplied in single syringe containers of 200 and 500 millions each, in packages of four syringes, in packages of four 1-Cc. bulbs, in 5-Cc. vials, and in 20-Cc. vials. PNEUMONIA VACCINE COMBINED (pneumonia bactbein combined). This product consists of killed cultures of Diplococcus pneumoniae. Bacterium pneumo- niae (Friedlander) and Streptococcus pyo- genes. BACTERIAL VACCINES OR BACTERIN8 65 It is supplied in two strengths, 200 million and 1000 million bacteria per Cc, respec- tively. Therapeutics. Pneumonia Vaccine Com- bined is indicated in the treatment of all stages of pneumonia, but is especially valuable in infections of the mixed type. Dose. The initial dose of Pneumonia Vac- cine Combined should be 100 millions; sub- sequent injections should be given at intervals of three days, the dose being increased at each administration, unless there are indications to the contrary. The production of a marked reaction, either local or constitutional, may be considered a contraindication to an increase in dosage. With each subsequent injection the dose should be increased over the preced- ing by from 50 to 100 millions. Pneumonia Vaccine Combined is supplied in rubber-stoppered bulbs of 200 millions and 1000 millions, respectively, four bulbs in & package; in 1-Cc. graduated syringe con- tainers, one and four in a package; and in bulk packages of 5 Cc. and 20 Cc. PYORRHEA ALVEOLARIS VACCINE COMBINED (HARRIS) (pyOKRHEA BACTERIn). This preparation contains in each cubic centimeter Streptococcus pyogenes, 40 mil- lions; Staphylococcus pyogenes albus, 200 66 BACTERIAL VACCINES OB BACTER1N8 millions; and Diplococcus pneumoniae, 40 millions — ^the cultures being made from mate- rial obtained from pyorrhea cases. Therapeutics. Pyorrhea Alveolaris Vaccine Combined is used in the treatment of purulent inflammations of the dental periosteum. The vaccine is administered subcutaneously in the usual manner, with strict aseptic pre- cautions. The initial dose should be 140 mil- lion bacteria (0.5 Cc). Subsequent injections may be given at intervals of three to five days. Unless there are indications to the contrary, it is advisable to increase the dose by 28 mil- lions (0.1 Cc.) at each injection until a maxi- mum dose of 280 millions (1 Cc.) has been reached. In obstinate cases it may be neces- sary to give repeated injections of the maxi- mum dose before definite clinical results are obtained. To secure the best results, it is imperative that the use of the vaccine be combined with the proper surgical procedures. If this impor- tant phase of the work be overlooked the results of the use of the vaccine may be disappoint- ing. Pyorrhea Alveolaris Vaccine Combined is supplied in 1-Cc. rubber-stoppered bulbs and 1-Cc. graduated syringes, the former in pack- ages of four, the latter in packages of one and four; also in bulk packages of 5 Cc. and 20 Cc. BACTERIAL VACCINES OR BACTERIDS 67 STAPHYLOCOCCUS VACCINES (sTAPHYIiOCOCCUS BACTERINS) . These vaccines are killed cultures of staphy- lococci, and are four in number: Staphylo- coccus Albus, Staphylococcus Aureus, Staphy- lococcus Citreus, and Staphylococcus Com- bined (albus, aureus, and citreus). Therapeutics. These vaccines are used in the treatment of suppurating acne, furuncu- losis, carbuncle, sycosis, osteomyelitis, psoas abscess, infected fistulse, otitis media, sup- purating glands, eczema, septic infections, cystitis, ulcerative endocarditis, and mixed infections. Dose. Clinical observation of the use of these vaccines would indicate that a satisfac- tory initial dose ranges from 50 millions to 200 millions. A satisfactory routine is to inject 100 to 125 millions, and at the expiration of four or five days to administer double the amount of the initial dose. In like manner gradually increase the subsequent doses^ at intervals of five days. When an exact bac- teriological diagnosis can be made in any given case of staphylococcic infection the corres- ponding vaccine should, of course, be used; otherwise the combined vaccine. Each of the four several varieties of Staphy- lococcus Vaccine is supplied in rubber-stop- pered bulbs and in graduated syringes con- taining 400 millions and 1000 millions respec- 68 BACTERIAL VACCINES OR BAGTERINS lively, the bulbs in packages of four and the syringes in packages of one and four; also in bulk packages of 5 Cc. and 20 Cc. STREPTOCOCCUS VACCINE (STEEPTOCOCCUS BACTERIN). Killed cultures of the Streptococcus pyo- genes, in two dilutions. Therapeutics . This vaccine is prepared for the treatment of localized forms of infection the causative agent of which is the Strepto- coccus pyogenes. It is indicated in erysipelas, puerperal sepsis, cellulitis, phlegmon, septic endocarditis, lymphangitis, and in certain mixed infections, especially of tuberculous sinuses and lupus vulgaris. Dose. The initial dose is 20 to 40 millions, to be gradually increased and as frequently injected as the symptoms of the case indicate and the patient's condition warrants. Streptococcus Vaccine is supplied in rub- ber-stoppered bulbs and in graduated syringes of 40 millions and 200 miUions, the bulbs in packages of four, the syringes in packages of one and four; also in bulk packages of 5 Cc. and 20 Cc. TYPHOID VACCINE, PROPHYLACTIC (typhoid bacterin). Killed cultures of the Bacillus typhosus, for preventive inoculation. Uses. Typhoid vaccine is now in general BACTERIAL VACCINES OR BACTERIN8 69 use as a prophylactic against typhoid fever. As a protective agent it has been proved to be of great value. The Medical Department of the United States Army was the first to advo- cate the administration and collect tabulated clinical results from the use of this vaccine. All officers and enlisted men in the United States Army and Navy under 45 years of age are immunized against typhoid fever. The like procedure is being carried out in most of the armies of the world, and this same method is strongly advised in civil practice. Dose. The first dose is 500 millions, fol- lowed in ten days by the second dose, of 1000 millions, and after another ten days by the third dose, of 1000 millions, which completes the treatment for immunization. TYPHOID VACCINE IN JUVENILE CASES. In regard to the dose for children. Major Russell (Journal of the American Medical Asso- ciation, Aug. 10, 1913) says: "We vaccinate a great many children; the dose is determined by the weight of the child. The dose for an adult is based on an average of 150 pounds; if a child weighs 50 pounds we give one-third of the adult dose; if the fraction does not come out conveniently, we increase rather than diminish the dose. Children do not react so strongly as adults; it seems to be a rule that the younger the child the less the reaction." 70 BACTERIAL VACCINES OR BACTERIDS As typhoid fever is a disease that is rare before the age of puberty, it would seem unwise to vaccinate in early childhood; but in children nearing the age of puberty, and who are exposed to infection, vaccination is advis- able, particularly since the prophylaxis is sup- posed to continue for a period of three years or more. The contraindications are: any departure from the normal health of the patient, espe- cially when fever is present, and in women the presence or near approach of the menses. THE CURATIVE EFFECT. Current literature is recording clinical results of typhoid vaccine as a curative agent, and these results tend to show that vaccine ther- Japy in proper hands lowers the death rate, diminishes relapses, and lessens complications. The dosage of typhoid vaccine as a curative agent ranges from 10 millions for the initial dose to 800 millions, a maximum dose, the average being 200 millions. The number of doses ranges from one to eleven, at intervals of twenty -four hours to seven days — average, three days. Typhoid Vaccine is supplied in four packages — containiag respectively three bulbs, thirty bulbs, one syringe, and three syringes. In the three-bulb and three-syringe packages one of the bulbs or syringes contains 500 millions. BACTERIAL VACCINES OR BACTERIN8 71 and the other two 1000 miUions each; in the 30-bulb or "hospital" package, ten of the bulbs contain 500 millions each, and twenty 1000 millions each ; while the single syringe package contains 23^ cubic centimeters, each cubic centimeter representing 1000 millions. The bulbs are all rubber-stoppered, and the syr- inges graduated — so the vaccine can be admin- istered fractionally to children from either bulbs or syringes, or in successive doses to adults from the 23/^-Cc. syringe. TYPHOID-PARATYPHOID VACCINE, PROPHYLACTIC (typhoid-pakatyphoid bactehin). Killed cultures of the Bacillus typhosus and the Bacillus paratyphosus A and B in sterile suspension, for the prevention of typhoid and paratyphoid infections. Of our two Typhoid-Paratyphoid vaccines, one contains 4 parts of B. typhosus to 2 parts of B. paratyphosus "A" and "B;" the other equal parts of the Eberth bacillus and the paratyphoid germs. The former is supplied in doses of 500 and 1000 millions, the latter in doses of 1000 and 2000 millions, the bulk of the doses being the same in both cases. Uses. Frequently cases diagnosed typhoid fever are due to the paratyphoid bacilli. In epidemics or exposures in which there is doubt 72 BACTERIAL VACCINES OR BACTERIN8 of the presence exclusively of the Bacillus typhosus, this should be the vaccine preferred in immunization. Dose. The first dose is 500 or 1000 millions (according to which of the two Typhoid-Para- typhoid vaccines is used), followed in ten days by the second dose, of 1000 or 2000 millions, and after another ten days by the third dose, of 1000 or 2000 millions, thus completing the treatment for immunization. The contraindications would be the presence of fever, or any departure from the normal health of the patient, and in women the pres- ence or near approach of the menses. Typhoid-Paratyphoid Vaccine, is supplied in four packages — containing respectively three bulbs, thirty bulbs, one syringe, and three syringes. In the three-bulb and three- syringe packages one of the bulbs or syringes contains an initial dose, and the other two the second and third doses; in the 30-bulb or "hospital" package, ten of the bulbs contain initial doses, and twenty the successive doses; while the single syringe package contains 2^/^ Cc, each cubic centimeter representing 1000 or 2000 millions, as the case may be. The bulbs are all rubber-stoppered and the syringes graduated — so the vaccine can be adminis- tered fractionally to children from either bulbs or syringes, or in successive doses to adults from the 23/^-Cc. syringe. BACTERIAL VACCINES OR BACTERIN8 73 URETHRITIS VACCINE COMBINED (urethritis bacteuin combined). Each cubic centimeter contains killed cul- tures of Staphylococcus pyogenes albus, 150 millions; Micrococcus gonorrhese. Micrococ- cus catarrhalis. Bacillus coli communis, Bac- terium pseudo-diphtherise, Streptococcus pyo- genes, Staphylococcus pyogenes aureus, and Staphylococcus pyogenes citreus, of each 50 millions — total, 500 millions. Each of these eight organisms is represented by several separate strains. Therapeutics. It is now an established fact that in chronic cases of gonorrhea one or more of the organisms contained in this vaccine are found associated with the gonococcus in con- tinuing the inflammation and discharge. The vaccine is intended to be used in cases of sub- acute and chronic gonorrhea in which second- ary infection is present. Dose. A safe initial dose is 250 millions, to be gradually increased to 500 millions as the tolerance of the patient will allow. The clini- cal conditions will be found a safe guide to both the size of the dose and its repetition. From three to five days is usually a suitable interval between doses. Urethritis Vaccine Combined is supplied in rubber-stoppered bulbs and graduated syr- inges, the bulbs in packages of four and the 74 BACTERIAL VACCINES OR BACTERINS syringes in packages of one and four; also in bulk packages of 5 Cc. and 20 Cc. METHODS OF ADMINISTRATION OF VACCINES. The hypodermatic injection is the most usual method, and the only one regarded as of established value. By this method absorption is rapid and the dose is accurately regulated, owing to the fact that the whole amount injected is absorbed. The injection may be made in the flank, the scapular or deltoid region, or the forearm, and it should be made under the strictest aseptic precautions. Rectal injections have been recommended but are of doubtful value. Larger doses would be necessary, owing to the fact that not only is absorption slow, but a variable amount only is absorbed. Oral administration has been practiced to some extent and successfully, and in such cases a combination of normal horse serum with the vaccine is advised, thereby securing more favorable results. The dose should be given when the stomach is empty and should be larger than that given hypodermatically. VACCINE VIRUS (SMALLPOX). The term "vaccine" applies, primarily, to the refined virus from bovines, employed in vaccination against smallpox, in which by \ -N ' ^^l / ^V^ \ s, ^ V c/S Bacillus tetani with spores, x 1000. Drawing from cover-slip preparation. streptococcus pyogenes— plate culture, x 1000. From drawing. u/-<3mji mernoa. /7<3j'/en aeco/ora/jon o/^ /jjvire' ac/dnff 3 per ccji/ ir/zirjc acjJ ^o //i&aJco/ro/ ojicH /Aen w'asAmpure •3/coAo/. A^ /Ae Ajyz/e ce/Ar^re c/ecoAorJT<^^i3J7n Bacillus typhosus showing flagella. x 1000. Baoterium tuberculosis from sputum, x 1200. Drawing from cover-slip preparation. IS ' I ,\ ~/' B^cj/Zus" fyyoAos-us" x /OOO Bscj'j7us' fypAoyus- ^faiBS ess-j/y^ h^j/A ani/in elves'. An/ reae/j/y JecoJorjzes'. Cover- p/asr f'/voara/ioits' s^a/n i^re// wi/A ^frueous' s'o/ujion o/' /ucAs'jh. Py'as'A in hra'/B HHO ^'O O'-i o^ ^-^ Mg. Mg. Mg. .00001 .0001 .001 .00002 .0002 .002 .00003 .0003 .003 .00004 .0004 .004 .00005 .0005 .005 .00006 .0006 .006 .00007 .0007 .007 .00008 .0008 .008 .00009 .0009 .009 .00010 .0010 .010 .000006 .00006 .0006 .000012 .00012 .0012 .000018 .00018 .0018 .000025 .00025 .0025 .000031 .00031 .0031 .000037 .00037 .0037 .000043 .00043 .0043 .000049 .00049 .0049 .000055 .00055 .0055 .000062 .00062 .0062 .000068 .00068 .0068 .000074 .00074 .0074 .000080 .00080 .0080 .000086 .00086 .0086 .000093 .00093 .0093 .000100 .00100 .0100 Mg. .01 .02 .03 .04 .05 .06 .07 .08 .09 .10 .006 .012 .018 .025 .031 .037 .043 .049 .055 .062 .068 .074 .080 .086 .093 .100 These tables do not provide the reader with accurately graded serial doses, based on a defi- 142 TUBERCULINS nite percentage of increase from dose to dose, but with their aid such serial dilutions can be worked out. The whole matter is greatly simplified by the Tuberculin Tablets described on page 149. TUBERCULIN T. R. (DILUTE). This differs in strength from Tuberculin T. R. (Concentrated). One cubic centimeter contains one one-thousandth of a milligram of dry tubercle solids. In its preparation the refined residue is brought into solution in a mixture of glycerin and water and diluted with physiologic salt solution containing 0.2-per- cent, trikresol. Dosage. Measured in units of tubercle sol- ids, the dose is the same as that of T. R. con- centrated. Aoproxiinately. Exactly. 1 minim of Tuberculin T. R. (Dilute) contains. . . . l-16200Mg. 1-16230 Mg. 2 minims contains 1-8100 " 1-8115 " 3 " " 1-5400" 1-5410 " 4 " " 1^050" 1-4058 " 5 " " 1-3250" 1-3246 " 6 " " 1-2700" 1-2705 " 7 " " 1-2320" 1-2319 " 8 " " 1-2030" 1-2029 " 9 " " 1-1800" 1-1803 " 10 " " 1-1625" 1-1623 " U " " 1-1475" 1-1476 " 12 " " 1-1350" 1-1353 " 13 " " 1-1250" 1-1248 " 14 " " 1-1160" 1-1159 " 15 " " 1-1080" 1-1082 " 16 " " 1-1015" 1-1014 " 17 " " 1-950 " 1-955 18 " " 1-900 " 1-902 19 " " 1-850 " 1-852 20 " " 1-810 " 1-812 21 " " 1-775 " 1-773 '' TUBERCULINS 143 Approximately. Exactly. 22 minims contains 1-740 Me, 23 24 25 26 27 28 29 30 31 32 .1-700 . 1-675 , 1-660 . 1-625 . 1-600 .1-680 . 1-560 . 1-540 . 1-525 . 1-500 1-738 Mg. 1-706 1-676 1-649 1-624 1-601 1-580 1-560 1-540 1-525 1-500 TABLETS OF TUBERCULIN (FOR HYPODERMATIC USE). T. R. (Tuberculin Residue); and B. E. (Bacillary Emulsion). The preparation of accurate serial dilutions of the Tuberculins has always been a source of much annoyance and inconvenience to the busy physician. In order to overcome this, Parke, Davis & Co. have perfected a method by which it is now possible to prepare dry Tuberculins made up into soluble hypoder- matic tablets of unvarying content. The two most generally used Tuberculins are the T. R. (Tuberculin Residue) and the B. E. (Bacillary Emulsion), and these are the ones we have selected and put in the tablet form. THE PREPARATION OF TABLETS OF TUBERCULIN T. R. In making Tablets Tuberculin T. R., the mass culture is washed repeatedly, agitated again in water, washed, ground to complete disintegration, and dried. Instead of bringing the dried sediment into a suspension with 144 TUBERCULINS glycerin and water, it is thoroughly mixed with a suitable base, similar to that employed for the ordinary hypodermatic tablet, and is diluted with this base so that each tablet rep- resents a definite amount of the dry tubercle solids. THE PREPARATION OF TABLETS OF TUBERCULIN B. E. In making Tablets Tuberculin, B. E., the material is prepared, with one modification, exactly as the liquid B. E. Instead of bring- ing the dried sediment into an emulsion with glycerin, it is thoroughly mixed with a suitable base, similar to that employed for the ordinary hypodermatic tablet, and is diluted with this base so that each tablet represents a definite amount of the dry Tuberculin. TABLETS MORE CONVENIENT AND MORE STABLE THAN SOLUTIONS. The advantage of dispensing Tuberculins in tablets over the original method of putting them out cannot be overestimated. In tablet form Tuberculin is more stable, is in a more convenient form for the physician, and dilu- tions can be prepared with a minimum degree of manipulation, either in the hypodermatic syringe or by means of a small graduate. It has been known for several years that Tuber- culin in liquid form, especially in high dilu- tions, deteriorates rapidly, and for that reason TUBERCULINS 145 the practice of dispensing the product in ready- made dilutions has not appealed to the great majority of thinking physicians. In tablet form Tuberculin can be dispensed in a highly diluted form with the assurance that its strength and keeping property have not been impaired. For use at the bedside or in office practice Tuberculin tablets are ideal, and for institutional work they are also a great con- venience. THE QUESTION OF DOSE. In the use of Tuberculin Tablets the same principles of dosage as have already been discussed apply. HOW THE DOSES SHOULD BE INCREASED. It is of the greatest importance that the therapeutist proceed with caution in increas- ing the dosage, and it is upon this point that the success or failure of tuberculin therapy often depends. Attempts to increase the dose by a definite quantity of a certain solution (for instance, 1/10 Cc.) have not been satisfactory, because this does not accomplish a uniform degree of increase. In other words, if treat- ment is begun with 0.1 Cc. of 1:100,000 solu- tion, and the dose is increased by 0. 1 Cc. of the solution at each injection, the first increase is 100 per cent., the second 50 per cent., the third only 33.3 per cent. The advisability, therefore, of adopting a system of dosage 146 TUBERCULINS which affords a uniform percentage of increase is at once apparent, and the scale which has been worked out on a logarithmic basis (see Tables III and IV) is, perhaps, the best solution of this problem. DIRECTIONS FOR USE. Two methods of preparing the dilutions may be employed: the Syringe Method and the Graduate Method . Either is relatively simple, but when the ordinary hypodermatic syringe is used for the injections the Graduate Method is more accurate. In using the Syringe Method, the tablet is dissolved in a 1-Cc. graduated syringe, and the dose is controlled by the amount of solution injected. For this purpose, an accurately graduated syringe is a necessity. A special Tuberculin syringe has been designed by Dr. Fornier which can be recommended for making the serial dilutions with great con- venience and relative accuracy. This syringe is accurately graduated in hundredths of a cubic centimeter. _ The initial dose, .00001 (1/100,000) mg., is represented by 0.1 Cc. of a solution prepared by dissolving a 1-10000 tablet in 1 Cc. This is increased v.dth each injection, the amount depending upon which of the columns of the scale is followed, or, in other words, upon how rapidly the physician desires to increase the dose. TUBERCULINS 147 When the amount has been increased to 1 Cc. of this solution, treatment is continued with next strength tablet, beginning as before with 0.1 Cc. of a solution prepared by dissolv- ing one tablet in 1 Cc. of water, and inci-easing according to the scale which is being followed. It is to be noted that the last dose with any strength tablet represents the same amount of tuberculin as the first dose with the next higher strength tablet, so that one of these may be omitted. Table III (Syringe Method). Prepare a solution in the syringe by dissolv- ing one tablet in 1 Cc. of sterile water in the syringe. Inject the amount indicated. Column 1 2 3 4 5 6 7 8 9 10 11 Dose 1 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 " 2 0.32 0.22 0.18 0.16 0.15 0.14 0.13 0.13 0.13 0.12 0.12 3 1 0.47 0.32 0.25 0.22 0.20 0.18 0.17 0.16 0.15 0.15 " 4 1 0.56 0.40 0.32 0.27 0.24 0.22 0.20 0.18 0.18 5 1 0.63 0.47 0.37 0.32 0.28 0.2S 0.23 0.22 6 1 0.68 0.62 0.42 0.36 0.32 0.29 0.26 " 7 1 0.72 0.56 0.47 -0.40 0.35 0.32 " 8 1 0.75 0.60 0.50 0.43 0.38 " 9 0.77 0.63 0.53 0.47 " 10 1 0.80 0.66 0.56 " 11 1 0.80 0.68 " 12 1 0.83 " 13 1 Column 9 is the scale recommended. In explanation of this scale of dilutions, it may be pointed out that each of the columns represents a series of doses for conducting the treatment in such a way that the increase in doses is made in a definite ratio. This scale is also sufficiently elastic so that the physician 148 TUBERCULINS may increase the dosage very slowly when necessary, or with greater rapidity in cases in which it seems warranted. The various col- umns of the scale indicate the number of injec- tions employed to carry the treatment from a certain amount to a dose ten times as great. For instance, if column 2 be followed, the treatment is carried from a dose of 1/100,000 mg. to 1/10,000 mg. in four injections. If column 11 be followed, thirteen doses are employed for the same span. It is suggested that, unless there are indi- cations to the contrary, the outline of doses in column 9 of the scale be followed. This carries the treatment from any dose to one ten times as great in eleven doses and represents a degree of increase which is probably safe in most cases requiring tuberculin treatment. Table IV (Graduate Method). Dissolve a tablet in the indicated amount of water and inject 1 Cc. of the solution. Column 1 2 3 4 5 6 7 8 9 10 11 Dose 1 10 10 10 10 10 10 10 10 10 10 10 2 3.1 4.5 5.6 6.3 6.7 7.1 7.6 7.7 7.8 8.3 8.3 3 1 2.1 3.1 4 4.5 5 5.6 5.8 6.3 6.7 6.7 " i 1 1.8 2.5 3.1 3.7 4.2 4.6 5 5.6 5.7 5 1 1.6 2.1 2.7 3.1 3.8 4 4.5 4.7 " 6 1 1.5 1.9 2.3 2.8 3.1 3.6 3.8 7 1 1.4 1.7 2.2 2.S 2.9 3.1 8 1 1.3 1.7 2 2.4 2.6 " 9 1 1.3 1.6 1.9 2.2 " 10 1 1.3 1.5 1.8 " 11 1 1.2 1.5 " 12 1 1.2 " 13 1 Column 9 indicates the scale of doses recommended. ..^.5*' PARKE, DAVIS & CO. TUBBRCULINS »^-3 1 cr^n ":."^ l".=?.|.1 !■»«;;;;? PARKE, DAVIS & CO. VACCINES TUBERCULINS 149 In using the Graduate Method of preparing dilutions, the only apparatus required is a sterile 10-Cc. graduate and the ordinary hypo- dermatic syringe. The tablet is dropped into the graduate and water added as indicated in Table IV. The amount of solution to inject in each case is 1 Cc. For the first dose, the 1/10,000 tablet is dis- solved in 10 Cc. of water, and if the recom- mended increase in doses be employed (see Table IV) for the second dose a tablet is dis- solved in 7.8 Cc, for the third in 6.3 Cc, and so on down the column. In all cases 1 Cc. of the solution is injected. After the doses repre- sented in any column have been given, the treatment is continued with the next strength tablet, that is .001 mg. (1/1000), this being dissolved in 10 Cc. for the first dose of this series, as in the case of the previous series. In the same way as before the scale is followed through the remainder of the series of tablets, 1/100, 1/10, 1 and 10 mg., providing that no marked reactions are elicited. //, at any time during the treatment, a decided reaction follows an injection, an increase in dosage is contraindicated. All patients do not require the same size doses, nor will they tolerate them. TUBERCULIN PACKAGES. Tuberculin Tablets (both T. R. and B. E.) are supplied in six strengths, ten tablets in a 150 TUBERCULINS vial, as follows: .0001 mg. (1/1 0000 milligram), .001 mg., .01 mg., .1 mg., 1 mg., and 10 mg. — in single vials, and in packages of six vials, Nos. 1 to 6, inclusive. Other Tuberculins are supplied as follows: Purified Discs in tubes of 10. B. E. and T. R. (concentrated liquid) in 1-Cc. glass bulbs, each bulb containing 1 milli- gram of total dry tubercle solids. T. R. Dilute in cases of 6 bulbs of 1 Cc. each. B. F. in 1-Cc. hermetically sealed bulbs, 6 in a box. Tuberculin Old in 3^-Cc. glass bulbs, rubber- stoppered. Tuberculin Ointment for the Moro Test, in 2-gramme collapsible tubes. Tuberculin for the von Pirquet Test, three hermetically sealed glass tubes in one package. Section 9. ORGANOTHERAPY. During the last twenty -five years more and more interest Jias been manifested in the inves- tigation of the functions and diseases of the ductless glands. The importance of these structures has been more generally recognized, and our knowledge of their functions has been largely increased. We are beginning to learn that many dis- eases are due to the failure or perversion of normal chemical processes over which the ductless glands have an essential control. Ductless glands act on other tissues at a dis- tance by means of substances which we name "hormones," these hormones being conveyed by the blood stream to the cells for which they are destined. The cells of a gland have the property of forming one or more hormones, and each of these hormones has the power of exciting a definite chemical activity in those cells for which it has a special affinity. Substances may be formed which, instead of activating, control or inhibit chemical action. The nor- mal metabolism of the tissues in health is maintained and an adequate supply of hor- 151 152 ORGANOTHERAPY mones is assured by the proper functioning of the ductless glands. The complex and delicately balanced com- position of the blood shows how important this fluid is as a carrier of many vital bodies. We do not know in what form the hormones are conveyed through the blood stream; whether in solution or suspension in the blood plasma, or attached in some way to the red or white corpuscles. What we do know is that the normal blood carries these hormones effi- ciently. The most important ductless glands are the thyroid, parathyroid, pituitary, and suprare- nal. Other glands, such as the pancreas and the generative glands, supply both an external and an internal secretion, but in these the two forms of secretion are supplied by two sets of cells, and one set may fail while the other con- tinues active in function. THYROID. The effects of disease upon an internal secre- tion are best observable in the case of the thy- roid gland, in which the structure is simple and the secretion can be seen stored in the alveoli of the gland substance. If this gland atrophies, its secretion gradually fails and the symptoms of myxedema slowly develop. In case of failure of the thyroid gland in man we are able to supply the necessary hor- ORGANOTHERAPY 153 mones in an active state from one of the lower animals, and in a measure restore to normal health a person whose thyroid function has been more or less impaired. Disease is also the result of abnormal activ- ity of the thyroid gland. The secretory activ- ity does not always depend upon the size of the gland. A very great enlargement of the thyroid may take place in some forms of goitre without excessive secretion, whereas in Graves' disease but a slight increase in size may accom- pany symptoms of active hypersecretion. In Graves' disease certain vital organs are oper- ated at high pressure owing to the excessive thyroid supply, and the symptoms of the dis- ease are the outward expression of this glandu- lar hyperactivity. The respiratory inter- change of gases is increased 50 per cent. ; sugar toleration is reduced, and glycosuria may occur. Slight enlargement of the ductless glands may take place in response to special physio- logical requirements. Thus the pituitary gland enlarges during pregnancy, and the thy- roid gland at puberty and during menstrua- tion. We do not know in what manner the thyroid hormones produce the rapid rhythm of the heart which is so constant a symptom in Graves' disease. The tachycardia is produced in a healthy subject by giving large doses of 154 ORGANOTHERAPY thyroid extract, but this does not influence the ventricular rhythm directly. PARATHYROID. The true function of the parathyroid glands and their relation to the thyroid itself are little understood. They are generally regarded as separate organs with a special relation to the nervous system, which is shown by the development of tetany when they are removed. PITUITARY. The pituitary gland has a remarkable influ- ence upon metabolism. Disease may be due not only to lack of pitu- itary hormones, but also to a superabundant supply of these hormones. SUPRARENAL. In the suprarenal glands the medulla and cortex have separate functions. The medulla is characterized by the presence of chromatin and is supplying constantly an active hor- mone, adrenalin. So active is this hormone that one one-thousandth of a milligram per kilogram of body weight suflfices to produce a definite rise of blood-pressure; it stimulates the whole of the sympathetic system by its action on the myoneural junction. We possess in Adrenalin an agent of very great value as a hemostatic, useful also in the treatment of asthma, hay fever, shock and other conditions. OnOANOTHEBAPY 155 We fully recognize that the ductless glands have important relationships to each other, and that the secretion of one may stimulate or inhibit the activity of the others. THYREOIDECTIN. In the preparation of this substance the thy- roid gland is removed from the horse by oper- ation, and after a time, when the blood of the animal has become surcharged with the ele- ments normally held in check by the thyroid secretion, the animal is bled and the blood made into Thyreoidectin by desiccation. The theory underlying the use of this product in thyroidism is that the excess of thyroid secretion in the patient's blood will be neu- tralized by the Thyreoidectin and thus ren- dered harmless. Before this product was evolved, the milk from thyroidectomized cows and goats had been used in the treatment of exophthalmic goitre with some success. Therapeutics. Thyreoidectin is indicated in the treatment of pathological conditions attended by hypersecretion of the thyroid gland. Many cases have been reported in which it has controlled the symptoms of exophthalmic goitre in a marked manner. The treatment must be continued for long periods of time to obtain the most favorable results. 156 ORGANOTHERAPY Thyreoidectin is supplied in 5-grain cap- sules, 50 capsules in each bottle. THYROPROTEIN (BEEBE). A standardized proteid obtained by a pro- cess perfected by S. P. Beebe, Ph.D., M.D., of the Cornell University Medical School, and entrusted to Parke, Davis & Co. by Dr. Beebe, is offered to the medical profession under the name of Thyroprotein (Beebe). It consists of the pure proteids of normal thyroid glands, assayed and adjusted to a definite alkaloidal standard. Thyroprotein is standardized on the basis of its iodine content, and a uniform intelligible dosage is rendered possible thereby. For the standard we have selected the proteid obtained from normal human thyroid glands. The anal- yses of this proteid show that one gramme of the purified material contains 3.384 milligrams of iodine. After the purified proteid from the animal glands has been collected its iodine con- tent is determined, and, regardless of whether this proteid is richer or poorer in iodine than the standard, it is considered that each 3.384 milligrams of iodine represents one gramme of the active thyroid proteid. Therapeutics. Thyroprotein relieves certain disturbances of nutrition, as cretinism and myxedema, in which the thyroid gland is usu- ally found to be undeveloped or atrophied; it ORGANOTHERAPY 157 is employed with some success in excessive obesity, keloid, scleroderma, and psoriasis. It has proved of value in some cases of acute mania, melancholia, and puerperal mania, and has been recommended in the early symptoms of eclampsia. Thyroprotein is supplied in 2-grain tablets containing respectively 1, 2 and 5 per cent, of Thyroprotein. The tablets are put up in bot- tles of 50. We also market glasep tic ampoules of Thyroprotein, each ampoule containng 1/50 grain in 1 Cc. of physiologic salt soluton. The ampoules are put up in boxes of one dozen. THYROID GLANDS (DESICCATED). The fresh thyroid glands of healthy animals are utilized in the manufacture of this product. The investigations made into the physiological action of the thyroid gland seem to indicate that it stimulates the combustion of body-fat and increases the urinary flow; another impor- tant effect is the hastening of cell activity. It seems also to prevent the body utilizing all the fat-forming materials which may be ingested. Therapeutics. This preparation has been successfully used in the treatment of myxe- dema, and there are few drugs for which as much can be claimed as for thyroids in the relief of the symptoms of this disease. It is also used successfully in the treatment of cre- tinism, obesity, hemophilia, scleroderma, and 158 ORGANOTHERAPY simple goitre. There have been encouraging reports from its use in certain forms of insan- ity. Dr. J. F. Percy, of Galesburg, 111., has treated with thyroid glands (desiccated) cases of nephritis and also cases of nephritis com- plicated with diabetes mellitus (some thirty- five in all) ; he states that all the cases were benefited by the treatment, and that none died. Thyroid Glands (Desiccated) is supplied in powdered form in ounce vials; also in 2-grain capsules, in bottles of 100; and in 1/5-grain, 1 -grain and 2-grain tablets, in bottles of 100, 500 and 1000. THYMUS GLAND (DESICCATED). The fresh thymus glands of healthy animals are used in the manufacture of this product. The thymus gland has been prescribed quite extensively in certain diseases on the same principle as that governing the use of the thyroid, namely, that it possesses the function of internal secretion and will, therefore, bene- fit certain systemic conditions in persons in whom the thymus was atrophied too early in life. Therapeutics. This product has been used with benefit in the treatment of simple and exophthalmic goitre. It has also found use in the treatment of rickets, marasmus, andarthri- ORGANOTHERAPY 159 tis deformans. In some eases it acts well when thyroid substance has failed to produce results. It has an advantage over thyroid substance in that there is no risk of producing symptoms of thyroidism by its use. Dr. S. S. Cohen, of Philadelphia, writing of his experience in the treatment of Graves' dis- ease, says: "On the whole, thymus gland is the most useful of the ductless-gland prepara- tions in the largest number of cases of Graves' disorder. It must be given in sufficient quan- tity — ^from 0.5 to 3 grammes (8 to 45 grains) daily — ^for months together, with the alternate use of adrenalin." Thymus Glands (Desiccated) is supplied in powdered form, in ounce vials, also in 2-grain capsules in bottles of 100, and chocolate^ coated tablets in bottles of 100, 500 and 1000. ADRENALIN. "Adrenalin" is the name given by Dr. Jokichi Takamine to the astringent, blood- pressure-raising principle of the adrenals, or suprarenal glands, as first isolated by him and manufactured by Parke, Davis & Co. It is supposed that the chief function of the adre- nals is to supply an internal secretion which is responsible for the muscular contractility and preserves the tone of the cardiac and vas- cular walls, and even of the skeletal muscles. The activity of this secretion is evidently due 160 ORGANOTHERAPY to the principle, Adrenalin, which our chem- ists secure in the form of minute grayish-white crystals. The Kterature of Adrenalin has grown to such an extent since the discovery of the prod- uct in 1900, and its applications have become so general that justice cannot be done the sub- ject in a work of this kind. Every passing season adds to its wonderful achievements. Therapeutics. In view of the fact that Adrenalin is not employed (therapeutically) in the crystal form but usually in the form of Adrenalin Chloride Solution, it is understood that wherever the word "Adrenalin" appears (therapeutically speaking) without modifica- tion. Adrenalin Chloride Solution, 1:1000, is meant. Adrenalin is used as an astringent in the treatment of inflamed mucous membranes in any situation. In pathological conditions its use is so very extensive that we can but list the affections in which it has yielded brilliant results : Acne rosacea, angioneurotic edema, antral infection, ascites, asthma, bubonic plague, chloroform narcosis, collapse, conjunc- tivitis, coryza and rhinitis, dysentery, edema, epistaxis, esophagitis, eye wounds, gastric ulcer, glaucoma, hay fever, hematemesis, hematuria, hemophilia, hemoptysis, hemorrhoids, herpes zoster ophthalmicus, hypertrophied spleen, iri- tis, keratitis, laryngitis, myocardial insuffi- ORGANOTHERAPY 161 ciency, neuralgia, osteomalacia, otitis media, peritonitis, pertussis, opium poisoning, pruri- tus, purpura fulminans and purpura hemor- rhagica, snake-bite, spasmodic croup, stricture, tabes, tonsillitis and hypertrophied tonsils, typhoid fever, urethritis, uterine erosions, var- icocele, and vomiting of pregnancy. Also its use in combination with cocaine and novo- caine in minor surgery is familiar to every medical student and practitioner. We have prepared a brochure of 135 pages, entitled "Adrenalin, Descriptive and Clinical," con- taining descriptive matter and clinical reports, a complimentary copy of which will be sent to any physician upon request. The addition of Adrenalin to cocaine greatly increases the anesthetic effect of the latter. Thus a 0.5 per cent, cocaine and adrenalin solution produces the same anesthetic effect as a 2-per-cent. solution of cocaine alone. Certain advantages are obtained by com- bining Adrenalin with novocaine — a synthetic product, which is less toxic than cocaine. It is non -irritant, and possesses the added advantage that it may be repeatedly sterilized, by boiling, without injury. Adrenalin and novocaine combinations may be sterilized, if necessary, by boiling, but the heat should be applied only to as much as is required for immediate use. Parke, Davis & Co. offer several formulae of Adrenalin with cocaine, and its substitute 162 ORGANOTHERAPY novocaine, for the convenience of the profes- sion, and in such strengths and forms as are most likely to be required. To the solutions of Adrenalin with cocaine and novocaine is added a minute quantity of chloretone to pre- vent fungoid formation. Our list of Adrenalin preparations is as fol- lows : Adrenalin Crystals, Adrenalin Chloride Solution, Adrenalin Inhalant, Adrenalin Oint- ment, Adrenalin Suppositories, Adrenalin Tape (Sterilized), Adrenalin Tablets, Adren- alin Tablets No. 2, Adrenalin and Chloretone Ointment, Adrenalin and Chloretone Suppos- itories, Adrenalin Compound Suppositories, Adrenalin and Cocaine Tablets, Adrenalin and Cocaine Tablets "B," Adrenalin and Cocaine Tablets "C," Adrenalin and Cocaine Tablets "D," Codrenin "A," Codrenin "B," Codrenin "C," Eudrenin "B," Adrenalin and Eucaine Tablets "B," Adrenalin and Novocaine Tab- lets, Adrenalin and Novocaine Tablets "B," Adrenalin and Novocaine Tablets "C," Adren- lin and Novocaine Tablets "D," Novrenin, Anesthone Cream, Anesthone Inhalant, and Oral Astringent Lozenges. SUPRARENAL GLANDS (DESICCATED). Therapeutics. The results of the internal administration of Suprarenal Glands have been very encouraging in cardiac diseases marked by feeble or irregular pulse, also in Addison's ORGANOTHERAPY 163 disease, exophthalmic goitre, rachitis, and sim- ple anemia. Dose, 2 to 4 grains. Suprarenal Glands, Desiccated, is supplied in powdered form in ounce vials, and in cap- sules and tablets of 2 grains each, bottles of 100. SUPRARENAL LIQUID WITH CHLORETONE. This product is an aqueous extract of supra- renal glands which is physiologically standard- ized, and preserved with a small amount of chloretone. Therapeutics. It is intended for application to mucous surfaces, for its astringent and hem- ostatic effects. Suprarenal Liquid with Chloretone is sup- plied in ounce vials. PITUITRIN (PITUITARY EXTRACT). Pituitrin is made from the infundibular por- tion or posterior lobe of the hypophysis. It is standardized by its blood-pressure raising effect. It has a stimulating effect upon the arterial system, the rise of blood-pressure which follows its administration being more protracted than that produced by Adrenalin. It also stimulates unstriated muscle in atonic conditions of uterus, intestine and bladder. Its injection causes neither pain nor local reac- tion, and no toxic symptoms follow even maximum doses. 13 164 ORGANOTHERAPY Therapeutics. In obstetrics Pituitrin is ad- ministered in uterine inertia, postpartum hemorrhage, and after Caesarian section. It acts within a few minutes, soon attains its maximum effect, and ceases to act after an hour or two ; it produces rhythmical uterine con- tractions, and in the placental period of labor it seems to prevent atony. It is practically impossible to induce abortion or premature labor by means of this agent. In the first stage of labor it stimulates to renewed activity labor pains that have ceased, and it intensifies feeble pains, but its most pronounced action is in the second stage of labor or period of expulsion. Pituitrin should not be used until the os uteri is well dilated, and never in an obstructed labor. The post-operative use of Pituitrin is grow- ing in favor with surgeons; post-operative atony of the bladder has been overcome in a large number of gynecological cases by its intramuscular injection. In abdominal sur- gery the post-operative injection of Pituitrin incites intestinal peristaltic action within one hour, making the patient comfortable by pre- venting an accumulation of intestinal gases and abdominal distention. Its administration also prevents, in many cases, the post-opera- tive shock of major operations. Pituitrin has been used with variable success ORGANOTHERAPY 165 in the treatment of exophthalmic goitre and cerebral anemia. Good results have also been reported in the control of hemoptysis, epis- taxis, and post-operative nasal hemorrhage. Pituitrin (Pituitary Extract) is supplied in 1-Cc. ampoules, packed six in a box. CORPORA LUTEA (DESICCATED). That the generative glands exercise a dual function is generally recognized. The extract of the ovary has been studied clinically for many years and the accepted opinion seems to be that it has undoubted therapeutic value. The corpus luteum contains the principle (hor- mone) which produces the characteristic effects of ovarian extract, and that the remainder of the organ is of little value therapeutically can hardly be doubted. To meet the very evident demand for this material we supply the dried and powdered Corpora Lutea. In its preparation we sepa- rate the yellow granular material from beef ovaries and discard the remainder of the gland. This granular material is of very deli- cate structure, and must be handled with the utmost care. It is dried at a low temperature in order that the finished product may possess the maximum therapeutic activity. As the active principle of the gland has never been separated or identified, it is not possible to standardize the drug for medical 166 ORGANOTHERAPY purposes. Close investigation has been made by scientists to determine the difference, if any, in the size and chemical composition of the corpus luteum of ovulation and the corpus luteum of pregnancy. One of our investigators collected the ova- ries from 700 non -pregnant and 689 pregnant cows during the late autumn months, at which time cattle as a rule are in excellent health and all stages of pregnancy are in evidence. The total number of corpora lutea obtained from non-pregnant cows was 316, and from pregnant cows 692. In the pregnant cows one of the ovaries invariably showed a well developed corpus luteum, and less than half of the non-pregnant cows possessed corpora lutea. The color and shape of the two varie- ties are identical, and it is therefore impossible to make any classification by external appear- ance only. To determine the frequency of pregnancy in cattle in the packing-houses, an examination of the ovaries and uteri was made on forty cows appearing consecutively on the killing floors, but of two lots from different sections of the country. These cows were all within the calf-bearing period. Of these forty cows, thirty-five yielded ovaries containing corpora lutea of such size as permitted dissecting out. Of these thirty -five, twenty -nine, or 83 per cent. (72 per cent, of the whole) were pregnant. ORGANOTHERAPY 167 The corpora lutea from these pregnant cows were not uniformly large; many were identical in size and appearance with those from non- pregnant animals; others were so large as to occupy five-sixths of the entire ovary. Owing to the larger yield of corpus luteum from a pound unit of ovaries from pregnant cows than from the same unit of ovaries from non-pregnant cows, the material used in the preparation of Corpora Lutea, P. D. & Co., may run as high as 90 to 95 per cent, of corpus luteum verum. Therapeutics. Corpora Lutea is used princi- pally to control the symptoms following the removal of the ovaries, and for the relief of the nervous disturbances incidental to the natural menopause. It is also used successfully in dysmenorrhea, amenorrhea, hysteria and neur- asthenia. The usual dose is 5 grains, three times a day. Corpora Lutea is supplied in 5-grain cap- sules in bottles of 50 and 100, respectively. * * * Among the other animal derivatives which are in use to-day are Pepsin, Pancreatin, Ox- gall, and Rennin. We present these in many valuable forms and combinations. Our "pep- sin plant" is the largest in the world and our product the finest obtainable in any market. Section 10. PARKE, DAVIS & CO.'S BIOLOGICAL FARM. "From tiny acorns mighty oaks do grow." Twenty years ago Parke, Davis & Co. began the manufacture of biological products. A few rooms, a small stable, and a cinder track to exercise the horses answered the then needs of the Biological Department. The rapid advance into favor and importance of biological ther- apy cannot be more fully realized than by noting the demands made upon this special department in the matter of equipment. The biological farm, exceeding in area 700 acres, situated near Rochester, in Oakland County, Mich., U. S. A., 30 miles due north from Detroit, is ideal for the purpose to which it is put. The topography of the farm, now in its maturity, is gently undulating. It lies at an altitude of about 600 feet above the level of the Detroit River, and is rectangular in shape. Its extreme length from east to west is about one and one-half miles, and its width from north to south about three-quarters of a mile. Its east and west limits are dominated by hills which command to the eye a beautiful pano- 170 BIOLOGICAL FARM ramie view of the intervening valley. Hills likewise command both the northern and southern limits of the farm, thus enclosing it in a basin of undulating formation. On the southern border, flowing from west to east, is the Clinton River, and about the center of the basin, flowing from north to south and emptying into the Clinton River, is Stony Creek. These streams are fed by living springs, the water being clear and cold. The soil of the farm in the higher portions consists of a gravel loam mixed with clay, and the meadow or low land is of a sandy loam. The entire tract has been underdrained with tile, thereby insuring the best possible results, and preventing in the low spots standing pools and the breeding of mosquitoes. The slopes of the hilltops are wooded, with clumps of trees here and there along the windings of the creek and the clear-flowing river. The hills, clothed with wood to their crests, appear in abrupt outline from a distance, while the river, the brook, the trees scattered along their banks, and the undulating valley are a delight to behold. The visitor enters the woods, or ascends the higher ground where open vistas ! through the trees afford the eye many charm- ing views of the valley and the opposite hills. Altogether the farm affords a varied and beau- tiful prospect. Of necessity much work of a practical nature BIOLOGICAL FARM 171 has been done, much is now in the doing, and much yet remains to be accomphshed. Some cereal is produced, and some alfalfa grown, but the main provision of the farm is that of grazing. Here on sunny slopes and in quiet, sheltered nooks, the horses, cattle, sheep and other animals required for the production of the various sera, etc., roam at large under ideal hygienic conditions. The farm, of course, is subdivided by fencing. In each enclosure adequate shelter for the flocks and herds is provided, and in such meadows as are not con- tiguous to either river or creek the water sup- ply is had from natural springs flowing into solid concrete receptacles. On the heights, at the western end of the farm, are located the buildings for the clinical work. These constitute at present a group of seven buildings, all of wood and concrete construction, and include an operating build- ing in which the animals are inoculated and bled ; a building in which the smallpox vaccine is propagated; another in which the animals are dipped and made thoroughly aseptic pre- paratory to operative procedure; and three long stables to accommodate the several hun- dred horses required in this work, together with a building for the breeding and care of the guinea-pigs which are used for test purposes . This group of buildings constitutes an ideal veterinary institute for the housing of the ani- 172 BIOLOGICAL FARM mals and for the various operations incidental to the work. To cleanse the buildings, both walls and floors, an adequate supply of water under pressure is instantly available, while at intervals the entire group of buildings is dis- infected. Asepsis throughout the whole estab- lishment is rigidly maintained. The operators while on duty wear sterilized duck uniforms, and all instruments and materials are steril- ized prior to use. Located at this plant is a drilled well 300 feet deep which furnishes a sanitary water supply to the various buildings. Artificial heat and electric power are also supplied. A sani- tary reduction plant has been fitted up in which animal and vegetable refuse matter is first cooked and then ground for use on the farm as fertilizer. On the heights at the eastern end of the farm are located the stables for the care and treat- ment of horses used in the production of Thy- reoidectin, with a separate building for surgi- cal work. Here also, somewhat removed from the other buildings, are the detention stables where newly arrived horses are kept for at least two weeks under observation of the chief veterinarian before admission to the general stables. The entire farm is under the immediate charge of a fully qualified veterinarian, with competent assistants. No expense, no expen- RESEARCH LABORATORY 173 diture of energy or of time, has been spared, and no detail has been overlooked that mature judgment might foresee would insure ideal working conditions; in short, this farm and its appurtenances constitute a complete scien- tific equipment for this most important and responsible work. PARKE, DAVIS & CO.'S RESEARCH LABORATORY. Recognizing the importance and value of research investigation, Parke, Davis & Co. have built a fireproof building sixty feet wide by one hundred and sixty long, four floors and basement. The building faces directly upon the Detroit River. This building, as its name indicates, con- tains the departments engaged in the solution of new problems in chemistry, materia medica and therapeutics, including the special subject of organotherapy. Its investigations extend into the fields of the various sciences related to medicine, and its personnel includes special- ists in bacteriology, physiology and physio- logic chemistry, pharmacology, practical phar- macy, and analytical chemistry. These de- partments are subdivided into sections, each in charge of an expert in the subject assigned to that section. These include sections on bacteriologic research, physiologic chemistry, 174 RESEARCH LABORATORY serum research, histologic and pathologic re- search, chemical and pharmacologic research, the physiologic assay of drugs, and the study of plant bacteriology. There is also here a library numbering more than six thousand vol- umes pertaining to the sciences of biology, physiology, chemistry, pharmacy, hygiene, sanitation, and general medicine, together with complete files of all the leading periodi- cals of the world devoted to those sciences, numbering in all about 175 separate publica- tions. The Parke, Davis & Co. laboratories have received the approval of the Government of the United States, and after rigid official inspection were granted License No. 1 by the Secretary of the Treasury of the United States, under the provisions of the act approved June 1, 1002. As the document has a certain his- toric interest, we submit a photographic repro- duction of the original license. 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