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Progress and Prospects in the Chemotherapy of of Man and Other Animals ]

W. C. CAMPBELL z extraintestinal worms, regardless of whether Key words: pest management, symposium. tile host be man, sheep, cattle, horse, swine, or (Table 1). The results are quite re- Having worked with and markable. The first three compounds are antinematodal drugs for some time, I wel- common to both lists, and they are, by come the opportunity to gain a new per- any standard, drugs of major consequence. spective on the subject by exchanging view- points with those who work on the chemi- It is commonly held that intestinal cal control of quite different categories of nematodes are easy to destroy because a nar- nematode. Some of you work with free- cotic or immobilizing effect will result in living nematodes and I should tell you their expulsion, whereas extraintestinal that, as a parasitologist, I regard worms parasites are trapped in their various niches without hosts as somehow underprivileged. and can recover from nonlethal effects and Many among you work with nematodes resume their parasitic activity. The classic that parasitize plants; such worms have "intestinal" example (popularized by H. L. shown a laudable degree of upward mo- Gordon) is to be found in the treatment bility. This paper concerns worms with of Ascaris . Consider an Ascaris higher, or at least hotter, hosts; i.e., nema- worm in the small intestine of a pig given todes that parasitize man and domestic . The worm becomes stuporous; animals. The important thing, however, is and by the time it recovers, the pig has that we have in common not only nema- gone. One of the attractions of this view- todes but nematode ecology. Worms must point is that drugs against intestinal he studied in relation to their environment, worms do not need to be absorbed from the gut and therefore offer advantages in regardless of whether that environment be animal, vegetable, or mineral. I begin with terms of safety and tissue residues. But the a brief summary of the major current drugs situation is, for once, simpler than it seems. and their uses, followed by a cursory review It is probably a mistake to think of in- of the modes of action of those drugs. At- testinal nematodes as creatures sloshing tention is then directed to the question around in gut contents (perhaps the pin- of whether we can reasonably ask for bet- worm is an exception). The worms and ter drugs, and, if the answer be yes, to the their hosts are on intimate terms, and in question of how we should go about get- most, if not all, cases, the worms are po- ting them. tentially vulnerable to both absorbed and nonabsorbed drugs. Nonabsorbed drugs do have certain advantages; but the spectrum DRUGS AND THEIR USES of activity of current nonabsorbed drugs My initial response to the invitation to is either narrow (e.g., ) or (as consider the distinction between intestinal in the case of ) not so wide as that and extraintestinal nematodes was to sketch of absorbed drugs. This is important be- out tables of drugs active against worms of cause, in most situations, the advantage either kind, in various host species. It conferred by nonabsorption is outweighted quickly became evident that the most re- by that conferred by breadth of spectrum. vealing approach lay in a simple listing of It should be noted that among the "intes- major drugs active against intestinal or tinal only" compounds in Table I, many have a spectrum that is narrow even within Received for publication 28 Seutember 1982. the context of the gut; whereas those with 1Presented in a symposium to the Society of Nematolo- broad intestinal spectrum generally have gists, July 1982. Knoxville. Tennessee. :Merck Institute for Therapeutic Re,arch, P.O. Box activity against extra.intestinal nematodes 2000, Rahway, NJ 07065. tOO. The author is grateful to Ms. L. S. Blair and Dr. R. M. Weppelman for constrtlctive review of the manuscript and Extra-intestinal worms, too, may be af- to Dr. Robert S. Rew for assistance in reviewing the modes of action of drugs. fected by temporary immobilization. This 608 Chemotherapy of Nematode Infections: Campbell 609 Table 1. Drugs of current significance in the For most, if not all, of these drugs, ex- treatment of nematode infections. perimental attempts have been made to discover their antinematodal mechanism. Nematode dwelling site These studies may readily be found in the Gastro-intestinal Extra-intestinal scientific literature, and the findings have been reviewed (5). For the present purpose * benzimidazoles* it will suffice to merely recapitulate the levamisole modes of action that have been postulated ivermectin (Table 9). As might be expected, the phenothiazine suramiu organo-phosphates arsenicals weight of evidence varies from drug to piperazine drug; in any case, a proper Popperian pru- pyrantel/ pyrvinium Tahle 2. Biochemical actions which are likely to account for, or contribute to, the antinematodal bephenium effect of drugs.*

*Including the pro-drugs, thiophanate and Drug Action febantel. benzimidazoles Inhibition of poly- is exemplified in trematode infection by the merization; inhibition of failure of schistosomes to regain the mesen- fumarate reductase teric veins one they have been swept into levamisole, pyrantel, Depolarization of nerve-cell the liver by the action of certain drugs. morantel, membranes, through cho- The same may be true of in methyridine linergic agonist action ruminants and heartworm in , al- bephenium, Depolarization of nerve-cell though the situation is by no means clear rhenium mcmbranes, through cho- and probably varies from drug to drug. line- binding Of the drugs listed in Table 1 as effec- organo-phosphates Depolarization of nerve-cell tive against extra-intestinal worms, three membranes, through inhi- (, organo-arsenic, and diethylcar- bition of acetylcholineste- bamazine) are used for such worms only; rase yet even within that narrow context, those piperazine Hyperpolarization of muscle- drugs have limited applicability. They are cell membranes used almost exclusively for worms of the Potentiation of GABA re- order Filaroidea. It seems to me, therefore, lease and binding, at synapse that in general we should avoid thinking dithiazanine Inhibition of glucose or oxy- of parasites as intestinal or extra-intestinal. gen uptake, depending on Drug susceptibility undoubtedly depends target species upon habitat and feeding habit, but hab- st yrylpyridinium, Inhibition of glucose uptake itats should not be categorized simply as pyrvinium intestinal or extra-intestinal. Subtle differ- Inhibition of ences among a wide range of microhabi- organo-arsenic tats, and subtle metabolic differences im- diethylcarbamazine Opsonization of nematodes posed by phylogenetic heritage are likely 2,4 dinitrophenol Uncoupling of electron-trans- to be more important determinants of drug port-associated phosphory- susceptibility. lation suramin Inhibition of dihydrofolate MODES OF ACTION reductase It was afterwards . . . when the remedies nitroscanate None known had already been discovered, that men bitoscanate None known began to discuss the reason for them: None known therapy was not a discovery following letrachlorethylene upon reasoning, but after the discovery phen°thiazine None known of the remedy, the reason for it was sought out (Celsus, 30 A. D.) *Compiled in collaboration with Dr. R. S. Rew. 610 Journal o/Nematology, Volume 15, No 4, October 1983 dence compels one to point out that the to act by inhibition of parasite dihydrofo- proposed modes of action represent not late reductase. Other compounds with anti- hypotheses that have been proven correct, nematodal action include methyridine, a hut merely hypotheses that have not been cholinergic agonist; diethylcarbamazine, proven wrong. which may make nematodes more vulner- Benzimidazoles have been shown to in- able to host immune responses; organo- hibit fumarate reductase, and some of them arsenic, which may inhibit glycolysis; and have been shown to inhibit glucose uptake bitoscanate, nitroscanate, tetrachlorethyl- in vitro; both actions have been proposed ene, and phenothiazine, for which mechan- as primary mechanisms. Many isms have not been proposed. workers, however, now favor the thesis that the antinematodal, , and CURRENT NEEDS antitumor effects of benzimidazoles reside in their inhibition of tubulin polymeriza- No matter how broad the spectrum of tion and consequent disruption of micro- efficacy, or how safe the drug, there is al- tubule assembly. ways room for improvement. But modern Levamisole, too, is an inhibitor of [u- antinematodal drugs are so impressive in marate reductase, but at a much higher these two respects that it seems more use- in vitro concentration. The drug induces ful to look for other, more specific, weak- contractions of nematodes in vitro, and nesses and opportunities. there is evidence that it acts as a cholinergic Potency: The progressive development ganglionic agonist. of potency in drugs is represented in sim- Ivermectin (one of the avermectins) is plified form in Table 3. The current zenith believed to act through the mediation of is represented by the avermectins, with the neurotransmitter gamma-aminobutyric Bla being active in vitro against acid (GABA). Experiments conducted on dngiostrongylus cantonensis and Meta- Ascaris and lobster suggest that the aver- strongylus elongatus at 3.6 × lO-~SM (6) mectins stimulate presynaptic release of and ivermectin being fully active against GABA in the inhibitory neuron and en- preadult Dirofilaria imrnitis in dogs when hance the postsynaptic binding of GABA given as a single oral dose at 0.003 mg/kg to its receptor. These effects cause the (4). Since this was the lowest dosage tested, chloride-ion channels to remain open, it remains to be determined how closely thereby maintaining the postsynaptic cell Table 3. Increasing potency in the evolution of in a negatively charged resting state and modern broad-spectrum . A simpli- preventing the induction of electric poten- fication based on the approximate dosage required tials across the cell membrance. In the case to give optimum efficacy (for that drug) when given to sheep as a single oral dose. of Ascaris, the action is believed to operate at the synapse between interneuron and motorneuron; in the case of the lobster Time of major market Compound Dosage walking leg, it appears to act at the synapse introduction or class (mg/kg) between motorneuron and nerve cell. Other antinematodal drugs that cause Early 1940s phenothiazine 600 paralysis by interference with neuromuscu- Late 1950s organophosphates 50-100 lar transmission are the organophosphates, Early 1960s thiabendazole 4.5 which inhibit acetylcholinsterase in nema- Mid 1960s pyrantel 25 todes; bephenium and thenium, which are l.ate 1960s tetramisole 15 Early 1970s morantel 10 cholinomimetics; pyrantel and morantel, Early 1970s levamisole 7.5 which are cholinergic ganglionic agonists; Mid 1970s new benzimidazo!es* 5-10 and piperazine, which hyperpolarizes mus- Early 1980s ivermectin 0.2 cle cell membranes. The narrow-spectrum compounds dithi- *Includes , , mebenda- azine, pyrvinium, and styrylpyridinium in- zole, , and pro-drugs. Benzimidazoles of intermediate potency hibit glucose uptake; 2,4-dinitrophenol is (cambendazole, parbendazole) were introduced be- thought to act as an uncoupler of oxidative tween the introduction of thiabendazole and the phosphorylation, while suramin appears new benzimidazoles. Chemotherapy of Nematode Infections: Campbell 611 one can approximate the point of having grounds of safety, economics, and conven- efficacy against D. immitis in dogs without ience, this is a very unsatisfactory treat- giving any drug at allt ment. In man, adult Onchocerca volvulus Extreme potency is not necessarily ad- can be killed by multiple intravenous in- vantageous to a patient, a livestock owner, jections of suramin; but on the same a salesman, or a manufacturer. For all of grounds, the treatment is highly unsatisfac- them, a pill with a large amount of some tory. Treatment of the preadult and micro. active ingredient may be more (or less) at- filarial stages of these worms is currently tractive than a pill with a smaller amount unsatisfactory, but recent studies with of some other drug. The potential payoff ivermectin, , and, to some ex- of potency lies in the realm of special tent, levamisole are very promising. methods of drug delivery. Drugs are also needed for other filariases Drug resistance: Resistance has been a of man, since the current treatment of relatively minor problem in the control bancroftian and brugian filariasis is far of nematode infections in domestic ani- from satisfactory. The primary need right mals and is not known to be a problem now is for efficacy against the lymph-dwell- at all in the treatment of nematode infec- ing adult worms. As with all filarial infec- tions in man. Nevertheless, there are (in tions in man, chemoprophylaxis remains domestic animals) nematode strains that a goal for the future. are resistant to benzimidazoles, levamisole, Delivery systems: Probably the best op- and pyrantel/morantel. It is almost im- portunity for the future, with respect to possible to assess the seriousness of the antinematodal drugs, lies in the area of problem in terms of livestock productivity, delivery devices. Almost all anthelmintic but it is a recognized, if regional and spo- treatments are given orally or by intramus- radic, problem in anthelmintic commerce. cular or subcutaneous injection, but we also We lack a sound knowledge of the mechan- have drugs that can be absorbed when isms of resistance; therefore, stratagems to applied to a patch of skin and so exert an minimize tile emergence of drug resistance effect on endoparasitic nematodes. Prac- cannot readily be devised. tical use of this method is currently limited Specific parasites: Anthelmintics are to levamisole, but organophosphates are available that are highly effective against commonly used in this way to provide sys- virtually all of the important nematodes temic efficacy against ectoparasites. It can of sheep, cattle, swine, and horses. The be expected that other drugs will be used same cannot be said for man and dog. In in this way in the future. human trichinosis, mebendazole appears to Sophisticated delivery systems generally be as satisfactory as one could expect a will require great potency, because the trichinosis drug to be; in addition, that physical constraints of the system will gen- drug and pyrantel are excellent for the erally require the use of very small quan- common intestinal nematodes of man. But tities of drug. Nowhere is this more evi- a good treatment is sorely needed for the dent than in the case of controlled-release invasive form of Strongyloides stercoralis. systems, where the objective is to provide A new drug is needed for Dracunculus in- prolonged or repeated treatment with only fection in man, although it is hoped that a single administration of drug to the host. the current "International Water Supply Tim desirability of such a delivery system and Sanitation Decade" will minimize that may arise from the cost, inconvenience, or need. Good treatments are needed for cer- impracticability of multiple drug admin- tain relatively rare diseases, such as those istrations to a group of beasts or people. caused by tissue stages of Angiostrongylus The approach is exemplified by the recent and Toxocara. introduction of morantel in the form of In both dog and man, it is the filarial a slow-release bolus for the control of group of nematodes that represent the gastrointestinal nematodes in cattle (1). An greatest need for better drugs. In the dog, example still in the experimental stage treatment for adult heartworm (Dirofilaria may be found in studies with ivermectin immitis) usually consists of multiple intra- in cattle (3). Further increases in anthel- vaneous injections of organo-arsenic. On mintic potency may make it possible to 612 Journal of Nematology, Volume 15, No 4, October 1983 use parenteral controlled-release devices. • Totality. The argument deals with Regardless of anatomical location, devices the probability of meeting the total objec- could conceivably be designed to release tive (i.e., the discovery of a drug that will drug in either a continuous or pulsatile be clinical and/or commercially successful) manner. not just the discovery of new active com- While controlled-release devices appear pounds. to offer a major opportunity for the future, The probability of success for a partic- they also constitute one of the greatest ular method of new drug discovery cannot areas of concern. Subjecting parasites to a be measured, but we have the historical sustained, and sometimes suboptimal, drug record to guide us. All successful classes of level may exacerbate the problem of drug anthelmintic, antibacterial, and antiproto- resistance. A minor problem could be made zoal drugs, with the possible exception of major, and our current inability to predict ethopabate, seem to have been discovered such consequences only emphasizes the need as the result of empirical testing or chance for research on the mechanisms of drug re- observation. None was discovered as the sistance in nematodes. result of biochemical studies on the para- site. Drugs currently under development NEW DRUG DISCOVERY may change that picture, but the generali- zation appears to be true at this writing. I am indeed so disgusted with learned Empirically discovered drugs or modes of quackery, that I take some interest in action have been rationally exploited in honest, humane and strong-minded em- the development of superior members of piricism . . . (Benjamin Waterhouse, a particular drug class, but that point is 1825) tangential to the present argument. It seems An argument renewed: I have on an- to me that an appeal to precedent is not other occasion taken a stand in favor of unscientific. the empirical approach to the discovery Once discovered, a new drug has a low of new drugs for infectious diseases (2). probability of reaching the medical or agri- The paucity and misdirection of opposing cultural marketplace. Of all the factors con- argmnents prompt me to recapitulate my tributing to the nonintroduction of a new viewpoint and to comment on statements drug, failure to find an active lead com- by others on the subject. pound is only one; matters such as safety, The argument is made within a very stability, registration costs, and manufac- specific context, indicated by the key words turing costs add up to an obstacle much probability, inlection, and totality (PIT). more formidable than that posed by the • Probability. A fundamental objective need to find an active compound. That is of drug discovery programs is the adoption wily we must look at the total probability of an approach that has a high probability of success. That is why it is important to of success. A low-probability approach discover new leads as quickly and cheaply might pay off handsomely, giving its spon- as possible. Newly discovered leads are sors cause for celebration, but not entitling abandoned frequently and routinely in a them to congratulations on intellectual big screening program. It is, however, grounds. A scientific attitude usually de- no easy matter to abandon a lead produced mands adoption of the method with the as the result of a long and costly piece of highest perceived probability of success. basic research. • Infection. The argument applies only The rational approach, in simplified to infectious diseases. The situation with terms, is predicated on the discovery, in a respect to the discovery of new drugs for parasite, of a biochemical pathway or event metabolic disorders is probably quite dif- that might be blocked without harm to the ferent. It may also be different with respect host. The host may escape harm because of to agents for free-living nematode and quantitative or qualitative differences from arthropod pests, although the intimate re- the parasite with respect to the biochemi- lationship between pest and microhabitat cal mechanism in question. The term "ra- provides some similarity to the situation tional" has been retained here because it under present consideration. has become a nsefnl convention and accu- Chemotherapy of Nematode Infections: Campbell 613 rately describes the concept of the biochem- to discover new drugs (as dis- ical or other nonempirical approach. The tinct from the perfectly understandable ob- actual use of such an approach in a given jective of impressing our peers with how situation may or may not be rational (i.e., brilliantly we look for them), then we intelligent), and we should not imply that should worry more about probability and the choice of the empirical approach in a less about rationality. given situation is irrational. There is a One would like to think that it might fairly good chance of finding or devising a be taken as axiomatic that a large target chemical structure that will block any bio- is easier to hit than a small one. Yet this chemical mechanism that has been dis- seems to be the most overlooked aspect of covered in a parasite and selected as a the empirical vs. rational controversy. The target. But what is the probability that the testing of compounds against a whole para- chemical will do all the other good things site means aiming at a target consisting of (in terms of stability, absorption, degra- thousands upon thousands of known and dation, excretion, etc.) and none of the bad unknown biochemical processes. The ra- things (in such matters as mutagenicity, le- tionalist wants to select one or two. The thality, illegality, staining, and stinking)? justification is that in so doing he will Surely it is intellectually arrogant to sup- achieve differential toxicity; i.e., specificity pose that in the foreseeable future we will of action against the parasite. And so he he able to predict all biochemical conse- may--but he will have greatly reduced the quences of a hitherto unknown chemical. size of the target. As mentioned above, For the rational approach, as for the em- hitting the target in the sense of finding an pirical, the probability of success cannot active compound, even one with differen- be measured. tial toxicity, does not usually lead to the There has always been a spectrum of development of a successful drug. We rationality in scientific research as there should therefore strive for as many hits as is a spectrum of creativity in the arts. A possible and so should not aim at small photograph may be created almost entirely targets. by mechanical operations and chance A colleague recently devised a biochemi- events. The artistic component of a photo- cal anthelmintic assay based on the mode graph is a function of the degree of control of action of one of the leading anthelmintic exercised by the photographer (sensu latu). compounds, on the ground that he was Where there is little or no control, the seeking a new anthelmintic agent with a photograph, no matter how beautiful it is unique mode of action. His assay may yield thought to be, is not a work of art; where compoumls with desirable properties of the degree of control is high, the photo- one kind or another, but it will virtually graph is art no matter how ugly it may be preclude the discovery of compounds with perceived to be. Similarly the "scientific" a unique mode of action. This points up component of a new drug discovery de- another weakness of the biochemical as op- pends upon the control exercised by the posed to the empirical approach. Since we discoverer. In the initial discovery of an have learned more about parasites from active compound, the element of chance drugs than vice versa, there is an under- may be large (as in random screening) or standable tendency to base I)iochemical medium (as in the semirational approach, assays on known modes of action. Such the "enlightened empiricism" of Hitchings) assays may yield hetter drugs, but those or small (as in the yet-to-be-attained design drugs are likely to have much in common of an antiparasitic drug with all of the at- with existing drugs, and the assays are un- tributes of success). However, the selection likely to yield breakthrough treatments. or creation of an empirical screen is not a It does not follow that we should always matter of chance, and the subsequent proc- select the largest possible target. One could ess of bringing a drug to the point of prac- seek agents for control of liver fluke by tical utility involves both chance and de- seeking flukes in animals that had been sign. The end result is a genuine scientific treated in the preinoculation and post- achievement, and its empirical components inoculation phases. In such as assay, active need no apology. If our objective is truly compounds would include those that had 614 Journal of Nematology, Volume 15, No 4, October 1983 blocked excystment of the metacerciae in proach is certainly high, both in money and the host gut. But if one sought only com- in time, but I do not see how it can be com- pounds with that sort of action, then one pared to the cost incurred by the rational might want to conduct random screening approach until such time as useful drugs for compounds that would block excyst- are discovered by the rational approach. ment in vitro. In this particular case, the The elucidation of biochemical targets natural target event takes place in what is can be of value in providing an understand- biologically the "outside" of the host; i.e., ing of the mode of action of drugs, in pro- the lumen of the gut. Similarly, one might moting the most effective use of drugs, and want to screen against molting or mating especially in making possible the semira- or site selection in nematodes, or cell-wall tional process by which empirical observa- synthesis in bacteria, or any number of tions are transformed, embellished, and relatively narrow targets. The point here exploited to yield useful drugs. In the long is that an understanding of the biochemical run, the proposed strategy might even pro- processes of excystment, molting, etc., may vide totally new and successful rationally help in devising a screen, but such an un- designed drugs--so I am not suggesting derstanding is not essential. If at all possi- that such work should not be done. What ble, the screen should be based on the the strategy will almost certainly not do, is whole event of excystment, molting, etc., yield useful new drugs inexpensively or not on one biochemical component of it. quickly; nor can it be relied upon to There is another aspect of empirical shorten the time between discovery and screening that tends to be overlooked for to the less than 5 years that reasons of professional unpalatability Cohen considers expeditious. rather than philosophical unsoundness. There is in fact a telling argument Ideally there should be no preselection of against continued reliance on the empirical the compounds being tested. In practice approach. It is sometimes said that empiri- it is usually impossible to test all the com- cal screening was all very well in its day, pounds available, so some selection must but it is played out--the supply of untested be made. Such selection tends to be made compounds has dwindled to the point at on the basis of the perceived likelihood which there is low probability of success. that a given structure will he active and There is nmch force in that argument, but safe. Medicinal chemists are highly skilled it applies more forcibly to some infections in this regard, but it is important that they than to others. In the case of poultry cocci- use this skill judiciously and only rarely diosis, where vast numbers of compounds exclude compounds from an assay on the have been tested directly in the target spe- grounds of predictable unsuitability. The cies, empirical screening may have reached objective of the preselection process should the point of diminishing returns. In the not be to pick likely winners, but to ensure case of nematodes, hundreds of thousands diversity of chemical structure. of compounds have been tested in vitro, Proponents of the rational approach with truly breathtaking lack of success, and abound, and while they are quick enough to similar huge numbers have been tested in disparage empiricism, they rarely meet the vivo--but not in the target hosts and not issue head on. It is not enough, for example, against certain important nematode groups to point out biochemical differences be- such as the filariids. For any given infec- tween parasite and host and to allege that tion, however, the question is not whether the differences would be suitable targets the empirical method is as good as it was-- for chemotherapeutic attack. What is the question is whether there is anything needed is evidence, or argument on theo- better. With respect to parasitic nematodes, reical grounds, that hitting those targets I see no evidence that there is. would lead to a useful new drug. It has, too, L'ENVOI been alleged that the rational approach would be less costly and less wasteful than We have excellent drugs for most nema- the empirical approach, and would provide tode infections of man and his domestic new drugs more quickly. The cost of dis- animals. The exceptions are few but im- covering new drugs by the empirical ap- portant. There is a need for better drugs Insecticides, their design and evaIuation: Hummel 615 for use against certain nematode species, two directions. We can allocate our re- especially those species responsible for illa- sources equally or unequally, but the riasis in its various forms. There is an op- choice must still be made. portunity, if not a need, for new and im- The trouble with the empirical ap- proved drugs to complement or replace proach is that it is intellectually humiliat- those in current use. The greatest oppor- ing no matter how successful. The trouble tunity for improvement probably lies in with the rational approach is that it is the area of drug delivery systems. intellectually irresistable no matter how The discovery of new antiparasitic drugs un fruitful. is generally approached from either the point of view of empirical screening or of biochemical ("rational") design. Each ap- IATERATURE CITED proach has protagonists who have faith in I. Armour, J., K. Bairden, J. L. Duncan, R. M. its future success, with empiricists being Jones, and D. H. Bliss. 1981. Veterinary record. June able to boast of past success. Those who 20, 532-535. actually face the task of discovering new 2. Campbell, W. C. 1977. Control of parasites: drugs know that it serves no purpose to the role of drugs. Proc. Helm. Soc. Wash, 44:17-28. espouse the middle ground, important 3. Drummond, R. 1)., "F. M, Whetstone. and J. A. Miller. 1981. CoJltrol of ticks systemically with though semirational approaches might be. Merck MK-933, an avermectin. J. Econ. Entomol. Nor is it very daring or helpful to say that 74:432-436. we should have both approaches~for who 4. McCall, J. w., B. E. Lintlemann, and C. A. does not wish to hedge a bet? Who does Porter. 1981, Prophylactic activity of avermectins against Dirofilaria immitis. Pp. 126-130 in G. Otto, not applaud good basic research regardless ed. Proceedings of the Heartworm Symposium, Dal- of its short-term applicability to everyday las, Texas, January 1980. affairs? Who would deny the possibility 5. Rew, R. S. 1978. Mode of action of common of valuable but unpredictable spinoff from anthelmintics. J. Vet. PhalTnacol. Therap. 1:183- such basic studies? It is easy to say we need 198. 6. Sano, M., M. Terada, A. I. Ishii, and H. Kino. both empirical and biochemical approaches. 1981. Effects of avermectin Baa on the motility of But we cannot apply maximum effort in various helminths. Experientia 37:844-846.

Insecticides and Their Design'

HANS E. HUMMEL ~ creasingly competed with man's best efforts Key words: chemical control, insecticides, tle- velopment, screening, mode of action. in food, fiber, and timber production; ur- banization accentuated the need for public Pesticides and drugs originated from the health efforts, and animal husbandry neces- need for controlling man's external and sitated advances in parasite control. Man internal environment. Since the advent of responded to these challenges with pesti- agriculture, pests in the widest sense in- cides and drugs. The chemical weapons used in this fight are part of the history Received for publication 24 January 1983. of insect toxicology, pharmacology, and 1Presented in a symposium at the 1982 Annual Meeting hematology. of the Society of Nematologists, Knoxville, Tennessee, July 1982. At first, nature was man's best teacher 2Department of Entomology, University of Illinois, Ur- bana, IL 61801. and exclusive supplier of pesticides. ~Vith Drs. R. L. Metcalf and T. A. Miller kindly called my the increasing independence from nature attention to relevant references in tile older and newest literature, respectively. Dr. Po-yung Lu, Toxicology Data came the push for synthetic substances, for Bank of the Oak Ridge National Laboratory, Oak Ridge, procedures to make them, and for theories Tennessee, and Dr. E. Davis and her staff of the Biology Library of the University of Illinois, Urbana, provided hard to understand their modes of action. copies of some lesser accessible references. Dr. G. Eger- The interaction of man with pests is not Hummel, Marburg, supported the preparation of this manuscript. static: it is highly dependent on natural