host's blood in 24 hours. The blood passes rapidly through the 

 digestive tract and apparently is not subjected to any material 

 amount of digestion. Consequently, the worm probably uses 

 as food diffusible substances in the plasma. In spite of the 

 marked diffusibility of carbon tetrachloride, the drug has 

 little or no action on hookworms when injected intravenously. 

 Wright and Underwood (1934) cite work with Bozicevieh in 

 which repeated intravenous injections of carbon tetrachloride 

 failed to have any effect on the microfilariae or adults of 

 Dirofilaria immiiis. While it is probable that this parasite 

 takes only a limited amount of nourishment orally because of 

 the atrophied digestive tract, yet it is bathed continuously in 

 the blood plasma. Even under these conditions of intimate 

 contact, the anthelmintic had no effect. 



The studies of Mueller (1929) indicated that carbon tetra- 

 chloride penetrated the cuticle of Ascaris and was not taken in 

 through the digestive tract. Mueller believed that fat soluble 

 compounds such as chloroform and carbon tetrachloride exert 

 an anthelmintic effect by reason of their action on the fat 

 content of the muscle cells. 



Brown (1937) has reported the results of some ingenious 

 experiments designed to ascertain the manner in which certain 

 anthelmintics reach the tissues of Ascaris lumbricoidcs. While 

 the results were in part inconclusive because of the difficulty 

 of handling worms without injuring them traumatically, the 

 evidence seemed to indicate that oil of chenopodium and car- 

 bon tetrachloride in solution are absorbed through the body 

 wall. Brown was able to show that Ascaris will ingest solutions 

 of carbon tetrachloride in mineral oil but will refuse to ingest 

 dilute solutions of chenopodium. Brown did not believe that 

 the drugs tested acted directly on the nervous system of the 

 parasite even when injected in the region of the nerve ring. 



The experiments of Strong (1918), Lambert (1923), Hall 

 and Sliillinger (192.")) and Fernan-Nihiez (1927) may be cited 

 as bearing on this problem. Strong injected oil of chenopo- 

 dium intramuscularly for the removal of whipworms without 

 success. Lambert was equally unsuccessful with intramuscular 

 injections in two eases in man but obtained better results in a 

 third case. However, when used intravenously, the drug had 

 a marked vennicidal action again.st Trichiiris, little action on 

 Ascaris and none on hookworms. Hall and Shillinger obtained 

 very indift'erent results on dogs but Fernan Nunez reported 

 marked success against Trichiiris in man with intramuscular 

 and intravenous injections. The manner in which whipworms 

 derive their nourishment is still a deliatable point although 

 Garin (1913) was able to demonstrate lilood in th^> intestinal 

 contents and Schwartz (1921) reported a hemolysin from Tri- 

 chiiris viilpis. The evidence from the above-mentioned experi- 

 ments would seem to indicate, however, that the drug was 

 possibly absorbed through the digestive tract in view of the 

 little likelihood that under these conditions it would have been 

 in adjacent tissues in sufficient concentrations to have been 

 absorbed through the cuticle. Recently Trum (1938) found 

 that oil of chenopodium injected intravenously was very toxic 

 for horses, but had very little effect on the blood sucking 

 strongyles present in these animals. 



Correlation Between Chemical Structure and 

 Anthelmintic Efficacy 



Compounds comprising the group of cft'ective anthelmintics 

 and those for which some anthelmintic efficacy has been re- 

 ported are associated with such widely divergent chemical 

 groups that no general correlations can be drawn between aii- 

 thelmic efficacy and chemical composition. As a rule, anthel 

 mintics are very specific in their action, exhibiting their opti- 

 mum efficacy against one species of parasite or at best against 

 closely allied species of parasites. Drugs specific for the re- 

 moval of nematodes are seldom effective for the removal of 

 cestodes. The one glaring exception to this rule is carbon tet- 

 rachloride which is a fairly effective treatment for Taenia and 

 Diphyllobnthriiim lafiim infections of man although of little or 

 no value against other cestodes. On the contrary, there is no 

 taeniafuge which is effective for the removal of nematode 

 parasites. 



The specificity of anthelmintics is conditioned not only by 

 the anatomy and physiology of the parasite but also in part by 

 the anatomy and physiology of the host. In this connection, 

 drugs effective for the removal of strongylid parasites from 

 carnivores fail to a great extent when employed against simi- 

 lar parasites of ruminants. Such drugs are frequently held 

 in the rumen with a resultant dissipation of their action long 

 before they reach the object of their attack farther down in 

 the complicated digestive tract. On the other hand, the 

 anthelmintic value of copper sulphate solution against Hacmon- 

 chus contorUis in ruminants is associated with the peculiar 

 stimulus which the drug exerts in bringing about the closure 



of the oesophageal groove thus permitting the solution to be 

 diverted directly into the abomasum. 



The optimum action of two effective drugs is often lost or 

 markedly reduced when such drugs are combined in a single 

 dose. Frequent efforts have been made to develop a single 

 method of treatment which would be effective against both in- 

 testinal nematodes and cestodes. These efforts have nearly 

 always resulted in failure. In such cases, drugs -which are 

 effective against nematodes and cestodes, respectively, lose 

 much of their efficacy when combined. Fnder these varied cir- 

 cumstances, attempts to correlate anthelmintic efficacy and 

 chemical structure must be made on the basis of a selection of 

 closely related compounds on a single species of parasite. 



Hall and Wigdor (192(i) were apparently the first to carry 

 out studies of this sort. Their work was carried on in 19lV 

 and 1918 but was interrupted by military service. Their lim- 

 ited study was made with terpenes and certain other aromatic 

 hydrocarbons. Unfortunately, the study provided little infor- 

 mation of value partly because of the divergent structure of 

 the compounds tested and partly because of tlie feeble anthel- 

 mintic activity of many of them. 



Cains and Mhaskar's extensive investigation into the value 

 of hookworm remedies was a thorough piece of work. How- 

 ever, here again too many compounds (70 in all) of too di- 

 vergent a character were employed. In the summary and 

 conclusions of their work, Cains and Mhaskar (1923) stated 

 that the effective hookworm treatments studied by them dif- 

 fered so much in molecular composition and structure that no 

 general correlations could be said to exist between anthelmintic 

 properties and chemical composition. They concluded that 

 anthelmintic action on hookworms is specific. 



Wright and Sehaffer (1932) selected a series of chlorinated 

 alkyl hydrocarbons, a feiv of which had been .studied by Hall 

 and his associates. The previousl.v unstudied compounds were 

 tested critically for their anthelmintic efficacy against hook- 

 worms and general correlations were drawn l>etween anthel- 

 mintic efficacy, chemical structure and physical properties. 



In the homologous series, there was a rise in anthelmintic 

 efficacy against Anciilostoma caniiniiii with an increase in the 

 length of the hydrocarbon chain from the low member of each 

 group to the next higher member. In each case, there was an 

 accomjianying decrease in solubility from above the optimum 

 solubility range to a solubility within that range. In one 

 homologous series (normal monochlor compounds) a iieak of 

 anthelmintic efficacy was teached. It was pointed out that in 

 a similar way other homologous series would no doubt each 

 have a peak of anthelmintic efficacy, for the reason that a 

 point will be reached Avhere the solubility of a higher member 

 will be so slight as to result in little or no anthelmintic effi- 

 cacy. It was concluded that although the addition of — CH2 — 

 groups to the hydrocarlion chain results in a progressive change 

 in solubility from one member to the next in homologous series, 

 a progressive change in anthelmintic efficacy does not neces- 

 sarily follow. 



An increase in anthelmintic efficacy against A. canininn did 

 not always result with an increase in the number of chlorine 

 atoms in the molecule or with an increase in the relative per- 

 centage weight of chlorine in the molecule. In those cases 

 where a high degree of anthelmintic efficacy was associated 

 with increase in the chlorine content, the resulting compounds 

 without exception possessed a solubility within the optimum 

 range. Further, the siireading of the chlorine atoms in the 

 hydrocarbon molecule did not invariabl.v result in an increase 

 or decrease in anthelmintic efficacy. 



Differences in position of the chlorine atom in the molecule 

 resulted in changes in anthelmintic efficacy and the accompany- 

 ing change in water solubilitj' was an important factor in 

 determining anthelmintic efficac.v. Even among comjiounds 

 with the same number of carbon, hydrogen and chlorine atoms, 

 changes in the position of the chlorine atom resulted in com- 

 pounds showing marked differences in anthelmintic efficacy for 

 hookworms. In addition, differences in iinthelmintic efficacy 

 were exhiljited when the methyl radical was introduced in dif- 

 ferent positions in the clilorinated liydrocarlicju molecule. 



Wright and Sehaffer concluded that antlu'lmintic efficacy of 

 chlorinated alkyl hydrocarlions against A. ciiniinnii is intimately 

 linked with water solubility which varies with the chemical 

 structure of the molecule and that the anthelmintic efficacy is 

 not solely dependent on the halogen concentration or on the 

 position of the chlorine atom or atoms in the molecule. With a 

 single exception those compounds having water solubilities be- 

 tween 1:1250 and 1:.5300 showed a high degree of anthelmintic 

 efficacy for hookworms in the dog regardless of the halogen 

 concentration or the position of the diloiine atom or atoms in 

 the molecule. Water solubility is, therefore, the factor most 

 definitely correlated with the anthelmintic efficacy of chlori- 

 nated alkyl hydrocarbons for hookworms. 



334 



