Stroiifrvli's ill liorsrs: tctr:irlili)ii'tlivK'iio for iM'rtaiii slircp p.-ira- 

 sites; and other troatnicnts. 



The method devised li.v Hall has since been widely adopted 

 and employed by nnini'rous iiivestiRatois in establishing the 

 value of many other anthelmiTitics. 



Except in the rase of eondenmed eriniinals who will volun- 

 tarily submit to tist, till' nu'thod of eritieal testing cannot be 

 used in man. t)ther metliods have necessarily been adopted for 

 evaluating the ei^cacy of anthelmintics for nematode infections 

 in this host. One of these, the use of a so-called standard 

 treatment, was based on the administration of the test drug, 

 the screening of the stools an<l the recovery of worms, followed 

 witliin a suitable period by the administration of the standard 

 treatment, the relative efTicacy of which was known. Worms 

 passed following this treatment were collected and counted and 

 a comparison between .the results obtained with botli treatments 

 enabled the investigator to arrive at sonu' evaluation of the 

 efficac.v of the test drug. While the method necessarily had its 

 limitations, its use led to findings of value particularly when 

 applied to relatively large numbers of persons to obviate the 

 margin of error in individual differences. Under these con- 

 ditions, the standard treatment method was used effectively by 

 Caius and Mliaskar in their extensive investigations in connec- 

 tion with the hookwtirm in.jury in the Madr'as Presidency and 

 similarly by Darling, Rarlicr, Hackett, Smillie and other physi 

 cians on the staff of the International Health Board in their 

 far-flung search for the most effective treatment for hookworm 

 disease. 



Following the discovery by Stoll in 1!)2.3 and Stoll and 

 Hausheer in lS)2(i of a method of counting nematode ova in 

 feces with some degree of accuracy, the Stoll count has been 

 used extensively in evaluating anthelmintic treatments in man. 

 With due regard for the limitations imposed upon it by the 

 varying factors involved, the method has been of marked value 

 in gauging the efflciency of certain anthelmintics particularly 

 those designed for the treatment of Asearin and hookworm in 

 fections in man. Because of its greater reliability and its ease 

 of application, this method has replaced largely the use of the 

 standaid treatment method. Hall and .\ugustiiie in 1920 sup- 

 plemented the Stoll count with a count of worms passed fol 

 lowing treatment in evaluating certain anthelmintic treatments 

 for man. 



At times it is protit.-ible to employ several different methods 

 of research. Lamson and his associates used in vitro testing, 

 critical testing and the Stoll egg-counting method in their ex- 

 tensive investigations into the anthelmintic value of the alkyl 

 h.vdroxy benzenes and related compounds. In this case, com- 

 parable in vitro tests on Jscaris linnbriroides with large num 

 bcrs of compounds gave leads which could be developed further 

 by the employment of other methods. 



Mode of Action 



Little information is available concerning the manner in 

 which anthelmintics act on worms. An extensive use of in i'i(ro 

 tests in this field of investigation may yield some data but, 

 since it is difficult, if not impossible, to simulate in vitro the 

 environmental conditions of the parasite in its natural host, re- 

 sults obtained in this manner must be used with great caution. 

 The physiology of nematodes in itself is an almost totallj' un- 

 explored field. In the absence of precise knowledge concerning 

 the life processes of a parasite, it is not likely that we shall 

 know in what manner toxins act on the organism. The meager 

 information which is available throws little light on the prob- 

 lem in hand. 



According to their mode of action, anthelmintics may be 

 divided roughly into the following groups: 



1. Narcotizing or paralyzing agents. 



2. Compounds exhibiting a destructive action on protein. 



•S. Compounds containing enzymes capable of digesting nem- 

 atode tissues. 

 4. Anthelmintics of unknow^n action. 



The first group contains such well known anthelmintics as 

 santonin and the chlorinated hydrocarbons. Worms eliminated 

 following the administration of these anthelmintics may ex 

 hibit more or less movement. This characteristic is so marked 

 with santonin that earlier authors were led to describe this 

 drug as a vermifuge, a term which originally designated an 

 anthelmintic that irritated the parasites and drove them into 

 the colon where they might be removed with a brisk purge. 

 (Trendelenburg, 191.T.) However, as Lo Monaco demonstrated 

 in ISilfi and as Chopra and Chandler (1928) have pointed out, 

 santonin is highly toxic to ascarids in vitro if the test solutions 

 are properly prepared. If santonin is partially dissolved in 

 suitable quantities of normal liexane, a chemical which in it- 

 self is innocuous, the drug causes in vitro successive stages of 



sliiiiiil.-ition and profound paralysis. Therefore, it is now con- 

 sidered that .santonin |iarlially paralyzes the jiarasites, which 

 in that condition are unable to maintain their position in the 

 alimentary canal. The prompt elimination of the parasites by 

 the action of a pnrgalivi- may increase the efficacy of santonin 

 as shown by Morris and Martin (li):U) and by others. 



The chlorinated hydrocarbons contain several well known 

 compounds which exert an anesthetic action on worms. In vitro 

 the parasites gradually lose their motility and, if exposure to 

 the drug is continued after iinmotility sets in, the parasite may 

 be killed. However, if removed from the solution promptly, 

 it may recover. The authors have observed hookworms and 

 a.scarids moving feebly when removed from dogs with drugs 

 belonging to this series. 



On the other hand, oil of chenopodium belonging in the 

 first group apparently has a paralyzing action on the mus- 

 culature, an effect which almost always results in the death of 

 the nematode. 



The largi' group of hydroxy benzenes are examples of those 

 aiithelinintics in the second group. If solutions of egg albumin 

 are treated with these compounds, the iiroteins are promptly 

 precipitated. With the more water soluble coniponnds of this 

 series, such as phenol, the preeijiitation is relatively com- 

 plete; with comjiounds such as thymol and hexylresorcinol, the 

 precipitation is partial; while the extremely" insoluble com- 

 pounds precipitate only small quantities of the protein. In 

 vitro, he.xylresorcinol exerts a searing effect on the cuticle of 

 A.'icaris liimbricoidef!. resulting in the destruction of tissue; if 

 the exposure is closely controlled, blisters may be formed. In 

 solutions of hydro-xy benzenes which are not quickly fatal, 

 Ascaris exhibits a marked stimulation of activity greater than 

 that observed in solutions of santonin or of the halogenated 

 hydrocarbons. Since Lamson and Ward (1932) have described 

 a blistered condition of the cuticle of ascarids removed from 

 patients treated with hexylresorcinol, tin. mode of action in 

 VIVO may be identical with the action observed in vitro. 



In connection with the third group, Robbins (1930) has 

 shown that the anthelmintic activity of leche de higueron, the 

 sap of the Central and South American fig tree, Ficiis laiiri- 

 folia, is correlated with the presence of a proteolytic enzyme, 

 which he has named "ficiii." Asenjo (1940) has shown re- 

 cently that the destructive effect of fresh pineapple .juice on 

 Ascnris liimbriroi/lrx in vitro is probably associated with the 

 action of the proteolytic enzyme, bromelin. However, there is 

 no evidence as yet that the above-mentioned .jiiice has any an- 

 thelmintic value. 



The fourth group probably includes the ma.jority of anthel- 

 mintics. Any comments regarding the mode of action of these 

 drugs would be speculative for the most part. For instance, 

 we do not know how trivalent antimony compounds act on 

 somatic nematode parasites, although in the case of "Fouadiu" 

 the action of the drug is cumulative on iJirofilaria immitis and 

 the adult worms succumb very gradually. Some observations 

 of the senior author seemed to indicate that sterilization of the 

 adult female worms is due to fatty degeneration and necrosis 

 of the reproductive cells of the ovary and perhaps the drug 

 acts similarly on the somatoplasm. 



Little is known concerning the nature of the anthelmintic 

 activity of various dyes. Gentian violet stains the tissue of 

 such nematodes as Strong/iloidcs and Enterobinx. against which 

 it is effective. In Enterobiii.i passed following treatment, the 

 cuticle is usually slightly stained, the digestive tract more so, 

 and the reproductive organs, particularly in the female, are 

 intensely stained. The dye no doubt has a cumulative action 

 since some stained gravid female pinworms will migrate in 

 the early stages of treatment. Furthermore, the prolonged 

 course of treatment necessary to eradicate infections with both 

 of these nematodes supports the view that the anthelmintic is 

 not one of the contact type. 



Similarly, worms eliminated following the administration 

 of phenothiazine are stained reddish, but there is little reason 

 for thinking that the action of this drug is in anyway cumula- 

 tive, as prolonged treatment seems to be relatively less effective 

 than a single large dose. Many worms eliminated following 

 treatment with this drug are alive and move feebly, a circum- 

 stance which suggests that phenothiazine should be classed 

 with the narcotics and para].yzants. 



The manner in which anthelmintics reach the tissues of the 

 parasite is as little known as is the action of drugs on these 

 tissues. One assumption has been that nematode parasites with 

 their well developed digestive tract ingest the anthelmintic in 

 solution with the food and absorption therefore takes place 

 from the oesophagus or through the cells lining the wall of 

 the intestine. However, evidence for such a hypothesis is not 

 convincing. For instance. Well's (1931) striking demonstra- 

 tion of the blood sucking proclivities of the dog hookworm has 

 shown that the parasite may take up as much as 0.S4 cc. of the 



333 



