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Thesis Example For Essay


Examination of tablets ofbismuth, opium and phenol, the journal a m a , july 25, 1908, thesis example for essay p 330 puckner, w a , and hilpert, w s. Tablets of bismuth, opiumand phenol, dec 17, 1910, p 2169, may 6, 1911, p 1344 unreliablepharmaceutical products, editorial, may 6, 1911, p 1335 308 puckner, w a , and warren, l e. Aromatic digestive tablets, the journal a m a , aug 20, 1910, p 710 another reason for doubting the accuracy of dosage, irrespective ofthe characteristics of the drugs composing the tablets, has been themanifest lack of care in their manufacture in 1914, kebler309reported the results of a far-reaching investigation of tabletcompounding in which he pointed out that tablets on the market werenot as uniform or accurate as was generally believed, the variationsbeing “unexpectedly large in numbers and amount ” during the past year, the connecticut agricultural experiment station310 undertook theexamination of tablets-- proprietary and nonproprietary-- taken from thestock of dispensing physicians the variations found in weights ofthe tablets were strikingly similar to those reported by kebler 309 kebler, l f. The tablet industry, jour am pharm assn , 1914, 3, 820, 937, 1062 310 bull 200, connecticut agricultural station, food and drugproducts, 1917, p 161 variation in weights of tablets kebler connecticut variation per cent per cent less than 10 per cent 43 44 more than 10 per cent 57 56 more than 12 per cent 44 35 more than 15 per cent 28 26 more than 20 per cent 9 10the determinations of the composition of the tablets when comparedwith that claimed for them showed wide variation-- from 54 per cent above to 70 5 per cent below. In almost two thirds of the tabletsexamined, the variation amounted to more than 10 per cent.

Milky liquid large quantities ofwhite deposit mixed with considerable black the deposit mixes fairlywell but the greater writing settles out after standing an hour or two collosol manganese, 2 5-1000. Clear reddish-brown liquid withoutdeposit of any kind is not opalescent or fluorescent collosol iodin, 1-500. Very pale straw colored liquid withoutdeposit has a slight opalescence collosol sulphur, 1-100. Liquid is opalescent there is essay depositof yellow writingicles a four ounce bottle was also submitted the liquidin this bottle is milky with considerable deposit of yellow crystalslike ordinary crystalline sulphur collosol cocain, 1-100. Transparent, colorless liquid with nodeposit chemical examination showed 0 4 per cent of what may havebeen cocain this residue gave alkaloidal tests collosol quinin, 1-100. Slightly opalescent, colorless liquid, withno deposit gives alkaloidal reactions -- from the journal a m a , june 7, 1919 pulvoids calcylates compound report of the council on pharmacy and chemistrythe council has authorized publication of the following report, notso much because the preparation with which it deals is of any greatimportance, but as a protest against the large number of similarirrational complex mixtures which are still offered to physicians w a puckner, secretary pulvoids calcylates compound the drug products co , inc are tabletseach of which is claimed to contain. “calcium and strontium disalicylate, 5 grs. Resin guaiac, 1/2 gr. Digitalis, 1/4 gr. Cochium colchicum?. seed, 1/4 gr. Squill, 1/4 gr. Cascarin, 1/16 gr with aromatics ”“pulvoids calcylates compound sugar coated orange color”is advertised medical times, january, 1919 as being“analgesic-antipyretic and diuretic, ” and is included in thepreparations designated by the advertiser as “approved remedies forlagrippe and ‘flu ’” the claim that “their tolerance is remarkable”refers not to the physicians who tolerate such products, but to thealleged fact that pulvoids calcylates are tolerated remarkably well the advertisement continues. “may be given persistently and continuously without gastric disturbances ” “they are uniformly efficient more certain in effect than the ordinary salicylates ”it would be difficult to find an advertisement of equal lengthcontaining a greater number of misleading or directly false statementsthan are found in this one the journal april 22, 1916, p 1307 hascalled attention to the lack of justification for this absurd mixtureof drugs and has discussed the preparation with especial reference toits use in acute rheumatism, in which the salicylates occupy a specialfield the advertisement just quoted mentions la grippe and “flu” orinfluenza as special fields of usefulness for this preparation this, apparently, is merely an attempt to spread the sail for any breeze salicylates have a field of usefulness in influenza in that theyoften afford relief from pain there is no reason to suppose that amixture containing calcium and strontium salicylates-- the “calcium andstrontium disalicylate” of pulvoids calcylates is probably a mixtureof calcium and strontium salicylate127-- has any greater salicyliceffect than an equal amount of sodium salicylate on the other hand, itis worse than useless to give colchicum, squill and digitalis for therelief of such pains 127 see report, the journal, sept 9, 1916, p 827 should cardiac dilatation develop, and digitalis medication berequired it would be impossible to adjust the dose of such a mixturewith special reference to the digitalis action, which alone would beindicated for that condition no educated physician at present wouldthink of giving resin of guaiac merely because his patient requireddigitalis, nor would he administer “cascarin, ” whatever that may be, infixed doses, every time he gave a dose of salicylate it is impossible to recognize the several effects induced by thistherapeutic omneity, and the medical profession should consider it aninsult to be offered mixtures such as pulvoids calcylates compound pulvoids calcylates compound is, per se, of no great importance.

Proprietary mixtures if they have originality or otherimportant qualities which, in the judgment of the council, entitle themto such place, and important, nonproprietary, unofficial articles the council recommends that when the latter are prescribed, theybe indicated by the abbreviation, “n n r , ” thus insuring to theprescriber the quality of these articles laid down in the book proprietary mixtures -- a mixture will be considered as proprietary, and therefore requiring consideration by the council for admissionto the book or appendix, if it contains any proprietary article. Ifit is marketed under a name which is in any way protected, or ifits manufacturer claims for it any unusual therapeutic qualities proprietary mixtures which are marketed in conformity with therules are listed in the appendix of the book under the names of therespective manufacturers such proprietary mixtures are not admittedto the body of the book, save in the exceptional paper cited in thepreceding paragraph nonproprietary mixtures of official substances -- since the ingredientsof such mixtures do not require consideration by the council, andsince the mixtures are not open to the proprietary abuses which callfor the work of the council, it is not necessary that they should beinvestigated by the council the physician must judge whether suchmixtures should be directed to be prepared by the pharmacist, orwhether he is justified in ordering a ready-made preparation if hedecides to use a ready-made, nonproprietary preparation, he must judgefor himself whether it is marketed in accordance with the rules itshould, however, be remembered that the application of a trade name toany substance makes it proprietary explanation of rule 1. Compositionsecrecy objectionable -- it is not only the right but also the duty ofthe physician to know the essential composition of what he prescribes;the council cannot compromise on this proposition vehicles and preservatives -- in the case of mixtures, not only thepotent ingredient, but also the general character of the vehicle, thepresence of alcohol, and the identity of preservatives, or of any othersubstance, whether added or present as an impurity, must be stated ifthese can under any circumstances affect the therapeutic action ofthe article this, as a rule, does not mean the publication of tradesecrets, such as flavors or the details of the working formula trade secrets -- furthermore, trade secrets will not be received asconfidential by the council, since it accepts information only withthe distinct understanding that this may be freely published, at itsdiscretion inspection of factories -- the council does not accept invitations toinspect factories. Its concern is with the finished products on the other hand, the council requires that the information becomplete and accurate as to medicinal ingredients unofficial constituents -- unofficial constituents of proprietarymixtures must be presented by the manufacturer in the regular way andmust be acted on by the council before the preparations containing themcan be accepted fraud -- when it appears that a manufacturer has made a deliberatelyfalse statement concerning a product, he is asked to furnish anexplanation. And if this is not satisfactory, the product will not beaccepted, even if the false statement is subsequently corrected oromitted testimonials -- the foregoing paragraph applies not only to statementsmade to the council, but also to statements furnished to physicians bythe manufacturer or his agents, even when these statements are in theguise of testimonials explanation of rule 2. Identificationin order to avoid errors in the case of chemical compounds, and toguard against adulterations, lack of potency or strength, and themistaking of one chemical for another, it is necessary to have at handsuitable tests tests, etc -- if these facts have appeared in the literature, orin standard textbooks, reference to them will be sufficient. Butwith new chemicals, especially synthetics, the manufacturer or hisrepresentatives will be required to supply such tests for publication, as will assure an intelligent opinion of these products physiologic standardization -- in paper in which chemical methods ofidentification are unknown or unreliable, physiologic standardizationshould be employed the council considers the phrase “physiologicallystandardized” or “assayed” as misleading unless the standard andmethod are published in sufficient detail to permit of their controlby independent investigators it is evident that when no standard ispublished, it is impossible to know whether the quality is high orlow, and the conscientious manufacturer who sets for himself a highstandard is placed on a level with the dishonest or careless one whoadopts a low standard again, if the process of standardization isnot published, it is impossible to learn, without actual trial, therelative value of one preparation as compared with that of anothermanufacturer, or to confirm or disprove the statements of themanufacturer as to the quality of his product standardization of disinfectants and germicides -- no disinfectant orgermicide of the phenol type will be accepted for new and nonofficialremedies whose phenol coefficient, determined according to the methodof the hygienic laboratory, u s p h s , is not stated on the labelof the preparation explanation of rule 3. Direct advertisinglay advertising -- the impossibility of controlling the irresponsibleclaims which are usually made in advertisements to the public, thewell-known dangers of suggesting by descriptions of symptoms to theminds of the people that they are suffering from the thesis diseasesdescribed, the dangers of the unconscious and innocent formation of adrug habit, and the evils of harmful self-medication, including thedangers of the spread of thesis infectious and contagious diseases whenhidden from the physician, and similar well-known considerations, arethe reasons for discouraging, in the interest, and for the safety, ofthe public, this reprehensible form of exploitation advertising inmedical journals, etc , distributed solely to physicians, does not comewithin the scope of this rule exceptions -- in the case of subjects on which the public should beinstructed, as the use of disinfectants, germicides, antiseptics andfoods, advertisements to the public, if not in objectionable forms, are considered admissible in no case shall such advertisementsinclude recommendations for use as curative agents, nor shall thenames of any diseases be mentioned in exploitation if the preparationis sufficiently toxic to require caution in its use to preventpoisoning, this fact shall be stated on the label on account of thedeplorable results which would follow any abuse of this privilege, theconscientious cooperation of manufacturers and their agents in adheringstrictly to the limitations laid down is asked.

Also, that patients had been treated first withhexamethylenamin under one name and later by the same substance underanother name the journal, jan 19, 1907, p 241 hexamethylenetetramin was admitted to the eighth revision of theu s pharmacopeia in writing because of this official recognitionand standardization and thesis example for essay in writing because the extravagant reports ofits virtues had been largely discounted, physicians have in generalprescribed the drug by its pharmacopeial name, with one notableexception. Urotropin one reason for this is that urotropin was thefirst proprietary brand of hexamethylenetetramin introduced, a secondreason is that through the extensive and persistent advertising ofthe proprietary name under which the substance was introduced, it hasbecome firmly fixed in the minds of thesis physicians the other is thatthe product was claimed to be of greater purity than the product soldunder the pharmacopeial or other name although no evidence confirmatoryof this claim has ever been published on the other hand, danielbase, as long ago as 1907, found that hexamethylenamin sold under itspharmacopeial name is just as pure as when sold under proprietarynames when, in 1907, urotropin was admitted to new and nonofficialremedies, the published description showed that it was manufacturedby the chemische fabrik auf aktien vorm e schering, berlin, andthat schering and glatz were the united states agents in 1919, thedescription was revised to show that schering and glatz were no longerselling the german product as it is the general practice to omit articles that are admitted tothe u s pharmacopeia for the reason that their quality is guaranteedunder the federal food and drugs act and because pharmacopeialnonproprietary articles are rarely advertised with claims that requirethe council control, yet, in the case of urotropin, it was retainedbecause it was sold under a name not recognized in the pharmacopeia andbecause special proprietary claims were made for it urotropin marketed under unwarranted therapeutic claimsthe period for which urotropin stood “accepted” expired with the closeof 1921 to determine its continued eligibility for new and nonofficialremedies, the council examined the labels and circular matter sent byschering and glatz for the purpose and also a booklet “urotropin, ”subsequently sent by the firm to physicians it was found that the pamphlet contained a number of unwarrantedstatements writingicularly objectionable are the claims made for the useof urotropin as an antiseptic in body fluids that are alkaline, such asthe cerebrospinal fluid, bile, aqueous humor of the eye, saliva, theexcretions caused by middle ear infection and other excretions of thenasal, bronchial, laryngeal and mucous membranes the lack of efficacyof hexamethylenamin in alkaline secretions is generally admitted andthe clinical references to the use of hexamethylenamin in the pamphletare obsolete in the introduction to the pamphlet, schering and glatzstate that they are well acquainted with the scientific research workdiscrediting the efficiency of hexamethylenamin in nonacid mediums, but that they feel that the accumulated evidence for its efficacy insuch conditions should not be “brushed aside ” however, the pamphletis not made up of quotations, but of unqualified statements with oneexception, all references to the antiseptic properties of the drug inalkaline mediums are previous to 1913, that is, before the importanceof reaction of the medium was fully appreciated to quote theseearlier articles without regard to the later work, which in most eyesdiscredited them, constitutes in effect an exploitation of this brandof hexamethylenamin under unwarranted therapeutic claims urotropin a brand of hexamethylenamine, u s p in consideration of the confusion which arises from the applicationof different names to an identical article, the rules of the councilprovide that when an article which has been accepted for new andnonofficial remedies is admitted to the u s pharmacopeia underanother name, it will be retained, provided the official name isgiven prominence on the label and in the advertising of such article neither the label nor the advertising for urotropin gives prominenceto the pharmacopeial name as a synonym nor indeed does it bring outthe fact that urotropin is a brand of hexamethylenamine, u s p schering and glatz, inc , was advised that urotropin could be retainedin new and nonofficial remedies only on condition that the objectionsto the therapeutic recommendations were removed and on agreement thatthe u s p name appear on the labels and circular matter the firmdid not offer to make the product eligible for continued recognition;accordingly the council directed the omission of urotropin because ofconflict with rule 6 unwarranted therapeutic claims and with rule8 objectionable names -- from reports of council on pharmacy andchemistry, 1921, p 71 styptysate not admitted to n n r report of the council on pharmacy and chemistrythe council has authorized publication of the following report, declaring styptysate ernst hischoff co , inc inadmissible to new andnonofficial remedies w a puckner, secretary styptysate, according to the advertisement of ernst bischoff co , inc , new york, is “obtained by dialysis from bursa pastoris sheppardsic!. purse ” it is claimed to be “the remedy for hemorrhages, ”to be “superior to ergot and hydrastis, ” “of writingicular advantagein menorrhagia and metrorrhagia” and to have been “found of greatvalue in vesical hemorrhages and hemorrhages from mucous membranes ingeneral ” the styptysate label bears the synonym “dialysate herba bursapastoris”. The statement that it contains “alcohol 11 per cent ” andthat it is “made in gerthesis ” no other statement of the composition orstrength of “styptysate” is furnished nor is the name of the germanmanufacturer disclosed in an advertising circular entitled “styptysate, a new reliablehemostatic, ” it is declared that in recent years the plant, shepherdpurse capsella bursa pastoris, “has been submitted to clinicaltests in the form of a concentrated dialysate, known as styptysate, by loewy, oppenheim, krummacher and others, and that their reportscoincide in regard to styptysate as a hemostatic par excellence, writingicularly in uterine hemorrhages, even in paper where ergot andhydrastis had failed to produce satisfactory results ” the circularalso reprints essay “short clinical reports” without reference to theirauthorship. One ascribed to krummacher and two ascribed to “b h m , kansas city, mo , ” and the following references. “a krummacher, m d , monthly review for obstetrics and gynecology, berlin, vol xlix, 4, and vol lii ” “h oppenheim, m d , medical clinic, berlin, 1920, 35 ”shepherd purse is a weed common in the united states and in europe like most other herbs, it has essay reputation as a folk medicine itis used by eclectics and homeopaths, being included in the homeopathicpharmacopeia of the united states shepherd purse receives noconsideration at the hands of the authors of standard works on materiamedica, pharmacology or therapeutics from an examination of recent german medical publications, it appearsthat the use of shepherd purse was proposed as a substitute forergot and hydrastis, when the latter drugs became scarce in gerthesis these publications, in the main, emanate from those in the employ ofpharmaceutical firms and deal with proprietary preparations or they arewritten by physicians who used these proprietary preparations at thesolicitation of the manufacturers for this reason the reported resultsmust be accepted with reserve one of the proprietary preparations discussed in the germanpublications is styptysate, manufactured by isalfabrik johannesbuerger, wernigerode it is said to be produced by submitting the juiceof fresh shepherd purse to dialysis and preserving the dialysateby the addition of alcohol there is no statement as to the drugstrength or the chemical or biological standards, if any, used inits manufacture. Hence, the preparation is essentially a secret one as first produced, the preparation seems to have been fortified bythe addition of cotarnin.

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Vi tag der freien vereinigung für mikrobiologie , berlin, 1912 ref münchen med wchnschr , 1912, p 659 the most important critique of eosin-selenium has been contributedby the subsequent investigations of one of wassermann originalcollaborators, f keysser 277 keysser publication contains a largenumber of very careful observations on the various forms of eosinsupplied by the german manufacturers, as well as on other matters whichcannot here be considered in detail he finally reached the conclusionthat the eosin furnished by the manufacturing house of sandoz wasthe most effective for his purposes, inasmuch as it combined thelowest grade of toxicity with the highest capacity for discoloringthe tissues the selenium he used in the form of selenio-vanadiumfurnished by clin of paris, which was the identical preparation usedby werner and szécsi in combination with borcholin the maximum doseof this selenio-vanadium is 0 06 c c for each gram of mouse eosin, 0 01 gm , dissolved in 0 5 c c of physiologic salt solution, is mixedwith 0 5 c c of the selenio-vanadium this mixture is then used thesis example for essay forintravenous injections the results produced by the injection of thismixture are to all intents and purposes similar to those obtained bywassermann, except that keysser induced cure in a larger proportion ofanimals, namely, from 6 to 8 per cent it is evident from his carefuldescription of his experiments that the treatment is extremely toxic tothe animals the therapeutic dose is considerably greater than one-halfthe toxic dose this accounts for the fact that an extremely largeproportion of the animals perish during the course of the treatment the tumors failed to be influenced unless the dose given fell verylittle short of the fatal amount moreover, in order to accomplish acomplete cure, at least eight to ten injections must be given, and inessay instances not less than fourteen 277 keysser, f. Ztschr f chemotherap , 1914, orig , ii, 188 keysser most important conclusions, however, were obtained byfollowing an altogether different line of procedure it has beenpointed out by carl lewin272 that the therapeutic results obtainedfrom subcutaneous mouse tumors, however encouraging, could not belogically applied to the treatment of human cancers the subcutaneoustransplanted tumors, as is well known, are as a rule limited by adistinct capsule and show no tendency to infiltrative growth in thiswritingicular they present a most striking difference when comparedwith human tumors on the other hand, the metastases of mouse tumorsin the internal organs present an infiltrative mode of growth andthus approximate very much more closely to the human type of tumors keysser, therefore, determined to test the therapeutic effectivenessof his compounds on tumors implanted in various organs he developed atechnic which enabled him to implant tumors in the liver, the spleen, the kidneys and other writings of the mouse by means of injection throughspecial needles, often without the assistance of a cutting operation the tumors so implanted grew rapidly, and within from two tothree weeks reached the size of cherry pits the growth wascharacteristically infiltrative animals with these tumors were thensubmitted to intravenous injection of the therapeutic agents in exactlythe same fashion as the animals carrying subcutaneous tumors theresults, however, were absolutely different whereas the subcutaneoustumors invariably showed a much more intense discoloration than theother tissues of the mouse, this feature was entirely lacking in thecase of the internal tumors softening and liquefaction, which almostinvariably follows on the third or fourth injection in the case ofsubcutaneous tumors, and which is the first symptom of cure, neverpresented itself in the case of the internal tumors their consistencythroughout the treatment was indistinguishable from that of the tumorsof control animals the treatment, in fact, appeared to exercise notthe slightest influence on internal tumors there was neither cessationnor retardation in growth, but the tumors continued their normal rateof destructive increase with the production of metastases, leadingeventually to the death of the animal either during the course of thetreatment or shortly thereafter microscopic changes, such as had beenobserved by hansemann in the case of subcutaneous tumors, were entirelylacking no matter in what organ the tumors were implanted, theseresults remained the same no matter what type of tumor was employed, whether carcinoma, adenocarcinoma or sarcoma, the therapeutic outcomewas regularly and consistently nil these results induced keysser to determine whether or noteosin-selenium could actually be shown to exercise a deleteriouseffect on cancer cells outside the body in order to do this he made asuspension of mouse tumor cells in salt solution and mixed this withthe eosin-selenium-vanadium, using the latter in amounts equivalent tothree times the fatal dose for a mouse after the mixture had stoodfrom one to three hours, it was injected either subcutaneously orintravenously into mice in order to test the vitality of the cells in every instance the injections resulted in the production of tumorswhich could be in no way distinguished from the tumors produced byuntreated cancer cells in other words, the therapeutic preparation hadabsolutely no effect on the tumor cells in the same way keysser carried out experiments along the linesinaugurated by neuberg, using a combination of glycocoll and copper he also tested the combination of borcholin with selenium-vanadiumused by werner and szécsi he was able to confirm the fact that bothof these substances produced an unmistakable therapeutic effect onsubcutaneous tumors on the other hand, they were absolutely withoutinfluence on the internal tumors in this respect, therefore, they wereentirely comparable with the eosin-selenium compound the theoreticalbasis constructed by neuberg, which rests on the assumption that themetallic compounds stimulate autolytic processes in the tumors, wasalso subjected by keysser to destructive criticism finally, keysser showed that none of these therapeutic agents wereeffective even in the case of subcutaneous tumors, unless the latterhad reached at least the size of cherry pits if a therapeuticinjection were made immediately after inoculation of the tumors, noeffect was observed the tumors grew exactly as in the control animals, and the injected animals died in about the same period of time as they all of these facts, which taken together constitute a very remarkableand convincing piece of scientific investigation, permit of butone conclusion it is quite clearly established that none of thepreparations of which the therapeutic effectiveness has hitherto beenproclaimed exercise any direct influence on the life or developmentof the tumor under certain very definite and restricted conditions, however, they do appear to produce certain changes in the tumors, and in a small proportion even cures these results, however, areobtained only in the case of tumors which are subcutaneous in locationand not smaller than a cherry pit in size keysser interpretationof the striking differences between tumors is of interest in thisconnection he believes that the constant palpation and examinationof the subcutaneous tumors, which is prompted by interest in theexperiment, produces circulatory changes with hyperemia and hemorrhage these circulatory changes are responsible for the increased tendencyof the injected substances to lodge in the tumors, thereby possiblyincreasing the tendency to autolysis which the circulatory changes haveinaugurated it is, of course, questionable whether this explanationcan be regarded as final in a series of experiments which i performedthesis years ago, i was able to show that sodium iodid when injectedintravenously accumulates in tumors in larger amounts than in any othertissue of the body in rats a similar observation has been recordedby wells, de witt and corper 278 in the same way i found thatvarious dyes, such as congo red, when injected intravenously, could bedemonstrated in tumors long after the rest of the body had recoveredits normal color. The liver alone vied with the tumors in this respect the dyestuff was invariably sharply localized in the necrotic portionsof the tumor the conclusion seemed obvious that, owing to circulatoryconditions or possibly even to chemical conditions, the dye wasretained longest in the necrotic writings of the tumor this effect wasunquestionably not due to handling, inasmuch as the animals in myexperiments were not palpated from the time of injection until death 278 wells, h g , de witt, and corper. Ztschr f chemotherap , 1914, orig , ii, 110 i have, however, had an even more striking demonstration of the samefact i have given intravenous injections of dyes to patients sufferingwith various forms of internal tumors, as, for example, cancer of thebreast, in the hope of favorably influencing the growths at operation, the picture presented by the tumor is striking in the extreme itpresents areas of various size which are intensely discolored by thedye these areas, both to the naked eye and under the microscope, are the necrotic writings of the tumor the actively growing areas oftumor tissue and all the normal tissues of the organ present theirnormal color all of these observations lead to the conclusion thatthe necrotic areas in tumors either possess a higher affinity forsodium iodid and for the dyes than do the normal tissues, or thatthese substances are more slowly absorbed from the necrotic areasowing to the circulatory deficiency whichever of these explanationsis accepted, it is quite reasonable to believe that necrotic areasmight well undergo liquefaction under the influence of the varioussubstances which have been used for therapeutic injection such aresult is, of course, without direct effect on the growth or vitalityof the living writing of the tumor this fact is quite clearly evidencedby the experimental data, which show that the internal portions of thetumor might undergo liquefaction and yet the tumors were not cured indeed, löhe, who made microscopic examinations of the tumors treatedby caspari and neuberg, states writingicularly, with reference to a tumorwhich had been subjected to treatment, that “the central portion ofthe tumor showed softening, while the external margin was composed ofactively growing cells ” the central portions of implanted tumors are, of course, those which first undergo spontaneous necrosis it still remains to explain the small percentage of cures achieved bywassermann and by keysser it does not appear to me that this problempresents any insuperable difficulties the fact must be emphasizedthat practically 95 per cent of the animals die under the treatment, which sufficiently indicates the toxic effects of the agent used wemust remember that transplanted tumors are under all circumstancesat a certain disadvantage as compared with the normal tissues of thebody after all, they are implanted on a foreign soil their bloodsupply is impoverished and imperfect they have a natural tendency toundergo necrosis, and in thesis paper spontaneous retrogression it isnot strange, therefore, that they should prove in slight degree moresusceptible to toxic effects than are the normal tissues of the body if we remember that the various therapeutic agents introduced in allprobability reach a essaywhat higher degree of concentration in thenecrotic areas of the tumor than in the normal tissues of the body, anassumption which is entirely in accord with the facts as observed inthe case of sodium iodid and of various dyes, we may be quite preparedto believe that this factor is sufficient to induce the destruction ofthe marginal healthy and living cells of the tumor the fact that smallsubcutaneous tumors were found by keysser to be entirely refractoryto the treatment is entirely in accord with this assumption, in viewof the fact that tumors of this size present practically no centralnecrosis the same explanation holds of the observation previouslycited from caspari that the primary spontaneous tumors of animalsdo not yield to the treatment indeed, he himself states that thetreatment is effective only in tumors in which autolysis takes placeduring life the word autolysis, however, in this connection is amisnomer and represents a gratuitous assumption. As an actual fact, one is entitled to say only that such tumors undergo central necrosis, in all probably owing to defective circulatory supply the process isexactly similar to the coagulation necrosis described in the case oftubercles by weigert if autolysis occurs, it is only secondary to thepreceding necrosis this explanation, however, is confronted by the fact that the internaltumors produced by keysser showed no tendency to effect a localizationof the dyes, and correspondingly no tendency to be affected by thetherapeutic agents one might be permitted to inquire whether theseinternal tumors had undergone any necrosis keysser unfortunately makesno mention of this matter it is certainly true that the infiltrativemode of growth of the internal tumors, which is entirely differentfrom that of the subcutaneous implantations, is associated with amuch better blood supply and a lessened tendency to undergo necrosis that such tumors can undergo necrosis, however, is evidenced bycertain illustrations given by carl lewin in his paper on internaltumors but such changes usually occur only in advanced stages tojudge from his plates, keysser worked with relatively small tumors, an assumption which is rendered even more likely by the fact that hisinjections were undertaken in a fairly early stage of their growth inthis connection i may quote certain experiments of my own on internaltumors 279 the implantations made in my experiments were produced byintravenous injections of a tumor suspension into the jugular vein ofrats such injections resulted almost invariably in the production ofa large number of tumors in the lungs, which, as is well shown in thefigures accompanying the original article, differed very markedly insize the smaller of these tumors are composed throughout of activelygrowing cells, while the large tumors present an area of centralnecrosis exactly as do the subcutaneous tumors if such an animal begiven an intravenous injection of a dye such as congo red, it will befound that the larger tumors present an area of central discolorationcorresponding to the area of previous necrosis, while the smallertumors, like normal tissues, are not colored thus, it is clear thatthe internal tumors implanted in animals are subject to the same lawsconcerning the distribution of dyes and, of course, other substances asare the subcutaneous tumors as i have stated previously, an exactlyanalogous observation has been made in a human breast tumor in theabsence of any contradictory evidence, therefore, i think that it isperfectly justifiable to assume that keysser failed to achieve a resultin the internal growths simply owing to the fact that those growthspresented practically no areas of necrosis at the time of his injection 279 j m research, 1913, p 497 another theoretical question which bears closely on the recenttherapeutic investigations in human beings concerns the rôle ofcolloids, as such, in the procedure it is quite clear from what hasalready been said that all experiments with animal tumors have beenlargely influenced by the belief that metals in the colloidal formexercise a peculiar and characteristic influence on the destructionof tumors even when the therapeutic agents have been introducedin crystalline form, as by neuberg and caspari, the authors findthemselves compelled to assume that the metals are reduced to colloidalform within the tumors for the latter assumption there is absolutelyno evidence.