Anthelmintics

ANTHELMINTICS, Anthelminthica, substances used for removing parasitic worms from the human or animal body (in dead or living form), or killing helminths when their elimination from the body is impossible (e.g., when worms are localized in the blood, in muscular or connective tissues, etc.). The use of anthelmintics has a long history: such preparations as wormseed, male fern rhizome, areca nut, etc., were already used in ancient times. In addition to anthelmintics that have passed into modern medicine, many substances whose use was based only on prejudices and old folk traditions (for example, pig or human urine, mouse feces for internal use, wolf bile as an external remedy, etc.) were also used until the beginning of the 19th century. The scientific study of anthelmintics began only in the second half of the 19th century and became especially productive in the second and third decades of the current century. At present, the arsenal of anthelmintics is very large and includes the most diverse chemical substances, partly inorganic, but mainly organic compounds. Among attempts to systematize anthelmintics, we note the division into Vermicida (i.e., "worm-killing", acting lethally on helminths) and Vermifuga (i.e., vermifuges, expelling them in living form). Such a subdivision does not have sufficient justification, as the same substance can at the same time be both. The division into Vermifuga (substances acting on nematodes) and Taeniafuga (acting on cestodes) also does not withstand criticism. Such a classification, which is completely incorrect nomenclaturally, does not provide for other groups of worms (trematodes, acanthocephalans) and is essentially incorrect, since there are substances that act on some cestodes but not on others, other substances act on cestodes and some nematodes, etc. In recent times, an attempt at classification of anthelmintics was made by Lamson and Ward (1932), dividing them according to the mechanism of action on helminths into the following groups: 1) causing in worms a state of narcosis (or paralysis), but not necessarily leading to death, 2) causing in worms narcosis or paralysis after which they do not recover, 3) killing worms by affecting the cuticle, 4) causing digestion of worms, 5) the mechanism of action of which is unknown. This classification is still far from perfect [insufficiently clear distinction between groups 1 and 2, the presence of a large (5th) group of substances whose position in this system remains unclear], but its imperfection is due mainly to the insufficient study of the question itself, while the principle laid at its base undoubtedly deserves attention. The main requirements for anthelmintic agents are: complete effectiveness against worms and sufficient safety for the patient and hence the possibility of mass deworming. As further requirements, such as low cost, convenience of administration, possibility of repeated treatments, the smallest number of contraindications for the given drug, and finally the simplicity of preparatory procedures and subsequent care are put forward. We do not yet have drugs that fully satisfy these requirements. It is especially difficult to find a substance that simultaneously satisfies the first two requirements, since substances that are poisonous, even for lower organisms, such as parasitic worms, are to some extent toxic to the hosts as well. However, research in recent years gives very encouraging results in this direction. They show that in a number of cases, when changing in a certain direction the chemical structure, the helminthicidal activity increases with decreasing toxicity to the patient. For example, if we take a series of resorcinol compounds with alkyl groups: propyl-, butyl-, pentyl-, hexyl-, heptyl-, and octylresorcinol, then we have a definite increase in helminthicidal power (and decrease in toxicity) with the most favorable combination of qualities in hexylresorcinol (and partly in heptylresorcinol) and a further decrease in parasiticidal activity from octylresorcinol and beyond; here, therefore, the increase in helminthicidal activity and decrease in general toxicity are associated with the lengthening of the alkyl chain, but only up to a certain limit. In other cases, we have an increase in parasiticidal activity with the introduction of another hydroxyl group into the main nucleus, for example, benzyl-phenol, naphthalene-beta-naphthol, para-cymene-thymol. Further observations show that in some groups of substances, it is possible to obtain more active preparations (and at the same time less toxic) from less active ones by introducing halogens, in particular chlorine; for example, carvacrol is more toxic and less effective than chlorocarvacrol; the inclusion of chlorine in the hydrocarbon chain of propane, butane, pentane, hexane gives substances active against helminths: n-chloropropane, n-chlorobutane, n-chloropentane, n-chlorohexane; these substances are arranged in decreasing order of activity against ascarids. In a whole series of cases, a dependence can be traced between the degree of activity of a substance and the number of chlorine atoms in it: dichloromethane (CH₂Cl₂) is less effective against intestinal helminths than chloroform (CHCl₃), and the latter is less effective than carbon tetrachloride (CCl₄), while tetrachloroethylene (C₂Cl₄) is even more active than the previous drug. However, the effectiveness of this series of substances is determined not only and far from always by the relative chlorine content: the position of chlorine in the molecule is also of great importance. For example, 2-chloropentane (CH₃.CH₂.CH₂.CHCl.CH₃) is more effective than n-chloropentane (CH₃.CH₂.CH₂.CH₂.CH₂Cl).

The effectiveness of anthelmintics may depend to a certain extent on the physical properties of the preparation; in particular, the degree of solubility is of great importance, with a decrease in which in many cases increases effectiveness; however, this is only true up to a certain limit, beyond which effectiveness decreases again. For example, in a series of CHCl₃, CCl₄, C₂Cl₄, effectiveness against intestinal nematodes increases with decreasing solubility in water, which for these substances is determined by the following figures respectively: 1:161; 1:1,250; 1:10,000, but further with hexachloroethane (C₂Cl₆) we already have a sharp decrease in effectiveness: its solubility is still much less than that of tetrachloroethylene (C₂Cl₄). Wright and Schaffer (1932) established with respect to chloro-substituted alkyls that with respect to ascarids the greatest activity is shown by substances with a degree of water solubility from 1:350 to 1:1,350. However, in this same series of substances, the limits of 'optimal' solubility for achieving the best effectiveness somewhat shift when tested on other helminths; thus, for the dog hookworm (Ancylostoma caninum), the optimal solubility figures will be in the range from 1:1,250 to 1:5,300. Finally, it should be noted that the nature of the solvent with which anthelmintics are tested or applied is also of great importance. For example, hexylresorcinol is significantly less effective in alkaline aqueous or oily solutions than in a solution of pure water. For therapeutic intervention, the localization of the worm is by no means indifferent: whether it inhabits the esophagus, stomach, small or large intestine; whether it lies freely in the lumen of the digestive tract or partially (in some cases completely) sits in the tissues; whether it is fixed in the wall of the digestive tract, as is fixed, etc. If worms located in the upper part of the large intestine and cecum are less accessible to treatment than those in the stomach and small intestine, it is even more difficult to affect liver and lung helminths or those in the bloodstream; and on such helminths as trichinae, cysticerci, etc., localized in muscle and connective tissues, we practically still cannot affect them with medicinal substances. - In addition to the localization of worms, the belonging to one or another zoological group, class, family, genus, etc., is of course also of great importance when affecting them with anthelmintic preparations. Different worms, located next to each other in one organ, may react quite differently to the effects of anthelmintics: santonin in the small intestine selectively affects almost exclusively ascarids, without affecting nearby hookworms or cestodes, but rather more than the latter, it acts on pinworms and whipworms in the large intestine and lower part of the small intestine; on the contrary, male fern extract mainly affects cestodes, and among nematodes much more hookworms than ascarids, and at the same time kills fasciolae in the bile ducts of the liver, without affecting the nearby Dicrocoelium lanceatum. At the same time, however, we know from experience that zoologically more or less close forms usually react similarly to anthelmintic substances; this fact is of great importance for research work, as it makes it possible to orient oneself in the large number of helminth species with which we deal in medicine and veterinary medicine. - Some authors note different resistance in male and female individuals of the same species to anthelmintics and point to significantly greater resistance of young forms compared to older ones. As a rule, we, based on knowledge of the anthelmintic effect of a particular preparation on a given helminth species in some animal, have grounds for a preliminary judgment on the effectiveness we can obtain when applied to another animal species. This rule (which also has its exceptions) enables us to subject anthelmintic preparations to preliminary experimental study on laboratory animals for subsequent transfer to humans or farm animals. -- The effectiveness of a medicinal substance when affecting helminths may depend on the methods of administration of the preparations. The most common method is the administration of the medicinal substance (after some preparation of the patient) in the form of liquid or solid preparations orally (naturally or through a gastric or duodenal tube) or with the help of an enema. In other cases, parenteral methods of treatment are used, mainly by subcutaneous or intravenous, sometimes intraperitoneal injections, for example, the treatment of schistosomiasis, filariasis in humans, etc. (with antimony preparations, emetine, etc.). In veterinary practice, when worms are localized in the respiratory tract, as is the case, for example, in dictyocaulosis of sheep, metastrongylosis of pigs, etc., it is possible to achieve a certain success by the method of intratracheal injections of helminthicidal substances or by the method of inhalations. Parenteral administration of anthelmintics can also be used to treat helminthiases of the digestive tract. (Treatment of cestodiasis by subcutaneous administration of arecoline, ascariasis by subcutaneous administration of sodium santoninate, etc.) The most commonly used anthelmintics at present include: santonin, chenopodium oil, thymol, carbon tetrachloride, tetrachloroethylene, arsphenamine, male fern rhizome, kamala, arecoline (see also Kusso, Helminal, Pomegranate tree, Butolari). Recently, a number of new substances have been introduced into practice, mainly derivatives of fatty and aromatic hydrocarbons, among which hexylresorcinol deserves special attention. It is impossible to give any general pharmacological characterization of anthelmintics, as they belong to the most diverse substances, acting quite differently on both the patient's body and the worms. For most of them, toxicity is characteristic, therefore almost all anthelmintics require very careful application. For greater effectiveness of anthelmintic treatment, preparation of the patient (some kind of diet) is usually required (for gastrointestinal helminthiases), and after administration of the anthelmintic - the prescription of a laxative, aimed at the possible faster elimination of killed or stunned helminths and unabsorbed residues of the drug from the body. The effectiveness of the use of anthelmintics is assessed by the excretion of parasites collected by various methods, and by control helminthological examinations. In mass use of anthelmintics, effectiveness can be determined by the number of patients completely cured in relation to the total number undergoing treatment ('extensive effectiveness'), or by the degree of reduction in invasion, i.e., the degree of decrease in the number of parasites in the body ('intensive effectiveness'); the most correct reflection is given by the combined application of both accounting methods (see also Deworming and individual helminthiases).