CHAPTER IX 



ANTHELMINTIC MEDICATION FOR NEMIC 

 DISEASE OF DOMESTIC ANIMALS AND MAN 



WILLARD H. WRIGHT, Washington, D. C. 



and 



PAUL D. HARWOOD, Ashland, Ohio 



History 



The use of remedies for the removal of worms dates far 

 back into aiiticiuity. As primitive man became aware of his 

 intestinal parasites by observing the passage of such a large 

 nematode as Ascaris or the proglottids of large cestodes such 

 as Taenia saginata or Taenia solium, he no doubt sought from 

 his limited armamentarium weapons for the removal of these 

 undesirable boarders. Since most of his medicines were de- 

 rived from the plants found in his circumscribed environment, 

 he turned to them for his worm treatments. He chose so well 

 that derivatives of some of these plants in one form or another 

 are still in use as anthelmintics. Thus male fern, a frequently 

 employed taeniafuge, was known to the early Greek physicians, 

 if not before them; Jerusalem Oak, Chcnopoditim anthdininti- 

 cuin, was used as a worm remedy by the North American In 

 dians; and a decoction of the leaves of Mallotus pliilippinrnsis. 

 from which the taeniafuge kamala is obtained, was employed 

 by the early Ethiopians. 



Developments in anthelmintic medication have been divided 

 aptly into three epochs: The first, comprising centuries of un- 

 critical empiricism; the second, comprising several decades of 

 critical empiricism; and the third and last, comprising a rela- 

 tively few years of critical experimentation. 



The first epoch marked the period of primitive groping and 

 the centuries of acceptance of its empirical findings without 

 any marked advance being registered in the field. 



The second epoch followed the discovery of the Old World 

 hookworm, Ancitlostoma duodenale, by Dubiui in 1843, and the 

 gradual uufoldment of knowledge regarding the importance of 

 the parasite and the recognition of ancylostomiasis as a disease 

 entity. Gricsingcr's association of the hookworm with Egyp- 

 tian chlorosis, Wucherer's work which showed its relation to 

 tropical anemia in Brazil and Perroncito's discovery of hook- 

 worm as the cause of the St. Gothard tunnel disease stimulated 

 interest in the hookworm problem. These discoveries, followed 

 by Sonsino's classical observations, demonstrated the need for 

 specific therapeusis and prepared the way for the development 

 of a number of anthelmintics which, if not thoroughly efficient, 

 provided useful treatments; these held their place for a period 

 of four decades and until the epoch of critical testing provided 

 more specific and more effective drugs. The year 1881 marked 

 Perroncito's proposal of male fern as a hookworm treatni/nt. 

 the introduction by Bozzolo of thymol, and Baumler's unfavor- 

 able report on oil of chenopodium for this purpose. Male fern 

 had only limited use as a hookworm treatment but thymol 

 proved to have considerable efficacy and enjoyed a long vogue. 

 In fact, the latter drug was used more extensively than any 

 other until Schiiffner and Verwoort reintroduced oil of cheno- 

 podium in 1913 and showed that Baumler's conclusions, which 

 were apparently based on the treatment of only one ease, were 

 erroneous. In the meantime, Bentley in 1904 reported his 

 findings with betanaphthol and advocated its use In hookworm 

 disease. 



In 1905 Herman introduced a mixture of chloroform, eucalyp- 

 tus and castor oil as a treatment for ancylostomiasis in miners 

 at Mons, Belgium. The mixture was later modified by Phillips 

 and others and was subsequently employed extensively in the 

 treatment of hookworm disease in many parts of the world. 

 Schultz later found chloroform to be the active ingredient of 

 Herman's Mixture and reported the drug to be effective against 

 hookworms in the dog. 



In the meantime progress was being made also in the field of 

 anthelmintics for veterinary use. As early as 1894 Perroncito 

 and Bosso discovered the efficacy of carbon disulphide for the 

 removal of bots, Gasternphihis spp., from the horse. In fact, 

 the first critical testing of anthelmintics was actually carried 

 out by Grassi and Calandruccio in 1884 and 188.5 and by Per- 

 roncito in 1885 and 1886 in establishing the value of male fern 

 for the destruction of liver flukes in sheep by post-mortem 

 examination of treated animals. However, this method of test- 

 ing found no further advocates for a quarter of a century. 



A work of far reaching economic importance was the dis- 

 covery by Hutcheon in South Africa in 1891 of the efficacy of 

 copper sulphate solution for the removal of the common sheep 



stonuich worm. Hai iiioiicJius niniui-lus. The wireworm remedy 

 of copper sulphate and sodium arseuite worked out by Theiler 

 in 1912 and Veglia in 1920 has also been used extensively in 

 South Africa and was an important contribution to anthel- 

 mintic therapy. In the United States, Lewis and Guberlet 

 added a tobacco infusion to the copper sulphate solution ; Lam- 

 son introduced nicotine sulphate solution; and Curtice com- 

 bined copper sulphate and nicotine sulphate into the "Cu-Nic" 

 solutiou with an increase in efficacy against the common stom- 

 ach worm and some other gastrointestinal parasites of rumi- 

 nants. In general, however, it may be said that the four dec- 

 ades of critical empiricism produced less progress in the de- 

 velopment of veterinary anthelmintics than in anthelmintics 

 for human use. It was not until 1915 that substantial progres."; 

 was achieved in the former field. 



The year 1915 marked the practical beginning of the epoch 

 of the critical testing of anthelmintics. Hall laid down the 

 basic principles of this method and together with his associates, 

 including Foster, .\very, Snead, Wolf, Wilson, Wigdor and 

 Shillinger, checked critically the efficacy of empirical anthel- 

 mintics and developed new compounds of far reaching and 

 fundamental importance in both human and veterinary medi 

 cine. 



The method which Hall adopted was to administer known 

 doses of drugs to test animals of various species, collect all 

 worms passed in the feces for a given period of time, identify 

 and count these worms, sacrifice the test animals and make 

 thorough post-morten examinations with the recovery, the iden- 

 tification and the counting of all worms remaining. This 

 method gave specific information concerning the number of 

 worms present, the number removed and the number left after 

 treatment and provided an accurate index concerning the effi- 

 cac.v of the drug tested. The method was relatively ponderous 

 and time consuming compared to the favored process of drop 

 ping ascarids or some other easily collected invertebrate into 

 solutions of drugs and calculating the anthelmintic efficacy of 

 the drug by observing the ultimate fate of the animal in the 

 solution. However, critical testing developed precise informa- 

 tion whereas in vitro tests were often entirel.v valueless. 



The method of critical testing was of particular value in 

 veterinary medicine. It enabled an accurate assay of drugs 

 whose value was often more traditional than real, and its use 

 confirmed in many cases the efficacy- of empirically selected 

 anthelmintics and enabled dependable information to be ob- 

 tained concerning their therapeutic dose rate, their margin of 

 safety, the contraindications for their use and the type and 

 mode of purgation most suitable to promote the efficacy of the 

 drug and to protect the patient. 



Many of the tests, especiall.v those on dogs, provided results 

 which were applicable with but slight modification to human 

 medicine. The outstanding discovery in this connection was 

 that by Hall in 1921 of the value of carbou tetrachloride for 

 the removal of hookworms from the dog. Hal! immediately 

 suggested the use of the drug in the treatment of hnmai] hoo!< 

 worm disease, a suggestion which was forthwith adopted by 

 a number of investigators particularly Laml)ert and other 

 physicians on the staff of the International Health Board. It 

 was soon found that the efficacy of carbon tetrachloride ex- 

 ceeded that of all other drugs in this condition and it was 

 adopted practicall.y as a standard treatment and used in mil- 

 lions of cases in various parts of the world. Another discovery 

 less spectacular but actually of greater importance was that 

 of Hall and Shillinger in 1925 of the value of tetrachlorethy- 

 lene for the removal of hookworms. Because of its greater 

 safety and the fact that it produces little or no hepatic or 

 renal damage, tetrachloreth.vlene is replacing carbou tetra- 

 chloride in human ancylostomiasis and for many parasitic in- 

 fections of domesticated animals. 



Using the method of critical testing, Hall and his coworkers 

 established or confirmed the value of many anthelmintics in- 

 cluding copper sulphate for Ilaenwiiclnis contortus, oil of 

 chenopodium for ascarids in dogs and swine and for strongyles, 

 cyclicostomes, and pinworms in horses; carbon disulphide for 

 bots and ascarids in equines; carbon tetrachloride for stomach 

 worms and other worms in sheep and for a-scarids and 



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