Review Article Drugs 13: 124-136 (1977) © ADIS Press 1977

Anthelmintics M.Katz Faculty of Medic ine, Division of Tropical Medicine, Columbia University School of Public Health, New York

Summary

This article describes the drugs used in helminthic infections and their therapeutic indications, mode of action, toxicity and other details of each of the recommended drugs, and discusses the nature and treatment of infection by helminths important in human medicine. Infestation due to the roundworms Enterobius vermicularis, Ascaris lumbricoides and the hookworms, Ancylostoma duodenale and Necator americanus can all be treated effectively with pyrantel pamoate. For Enterobius vermicularis , however, a newer drug, mebendazole, is equally as effective. The advantage of these drugs in the indicated circumstances is that they can be administered in a single dose. Unfortunately, pyrantel pamoate is not a panacea and in the case of Necator it is not as effective as in the other roundworms . In that situation the use of tetrachlorethylene is preferable. For treatment of Strongyloides stercoralis, an important human parasite, because it can become disseminated and lead to fatal infections in immunoin competent hosts, the only effective drug is thiabendazole. In treatment ofTrichuris trichiura infection , mebendazole, administered over a period of 3 days, is the most effective available drug. For the roundworms inhabiting tissues - either as aberrant infections of man or as the normal part of their life cycle in man - therapy tends to be largely non-specific. For example, in visceral larva migrans , caused by the dog roundworm Toxocara canis. only palliative therapy with systemic anti-inflammatory agents and corticosteroids may be helpful. Cutaneous larva migrans, caused by the dog hookworms Ancylostoma brasiliensis and Ancylostoma caninum, is also treated primarily with symptomatic measures, but there is a suggestion that thiabendazole may kill the larvae and thus be effective. Trichinella spiralis may cause severe, even fatal infections in man , but only symptomatic therapy can be offered. Therapy for filar ial infections is regrettably complicated and not completely effective. Diethylcarbamazine remains the best available drug, but in some ofthese infections local surgical excision may also be used. It is important to bear in mind that release of antigens from dying or dead worms may cause systemic inflammatory and allergic reactions that may require therapy with corticosteroids. Therapy for Cestodes is achieved most effectively with niclosamide, but the antimicrobial agent paromomycin has also been effective. For the aberrant cestode infections of man , such as echinococcal cysts or Taenia solium cycticerci, treatment is surgical if the affected areas are accessible. Treatment of schistosoma I infections is quite toxic and, therefore, it is mandatory to determine viability of the worms before recommending therapy. If therapy is required, then

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Schistosoma mansoni infections are treated with stibophen and S. japonicum with antimony potassium tartrate , taking care in both of these instances to watch for the early signs of antimony toxicity; therapy of S , haematobium inf ections is based on admin istration of niridazole . Infections with other flukes tend to be less portentous than those due to the schistosomes. Fasciolopsis buski can be treated effectively with tetrachlorethylene. Fasciola hepatica with bithionol, as is Paragonimus westermani. Clonorchis sinensis cannot be usually eradicated , although chloroquine phosphate or emetine has led to a transient reduction in the egg output of the worm. A table provides details of drug dosage, but familiarity with side-effects and indications for therapy is a major requirement for success.

Anthelmintics are a group of drugs joined together only by their pharmacological effects on worm infections; Neither the chemical composition nor the mode of action of any of these drugs is necessarily related to the therapeutic properties of any other drugs. Throughout the history of man's combat against parasitic worm infections many drugs have been introduced, used , and discarded . Some have been harmless and others quite toxic; some have been effective and others useless. Most of the drugs - or at least the first examples of the particular classes of compounds - have been discovered through serendipidty, rather than through a coherent and logical planned approach. Moreover, many of the anthelmintics long in use in veterinary medicine have ultimately been 'discovered ' by physicians and adapted to treatment of man . Since helminthic infections are among the most common human diseases (Katz, 1975; Stoll, I 94 7)~ and since the therapy of most is relatively straightforward, it behooves the practicing physician to be as familiar with the anthelmintic drugs as they are with antimicrobial agents, digitalis, and insulin. This article will discuss only the anthelmintics now in common use, those still in use, but likely to be replaced by newer better drugs, and those still considered experimental, but likely to become approved for human use in the near future. The drugs, their mode of action (to the extent that it is known) and toxic side-effects will be described first (section I), followed by a discussion of specific helminthic infec-

tions, indications for therapy, and drug use (section 2; table I, II).

J. The Drugs 1.1 Pyrantel Pamoate (Aubry, et al., 1970)

ModeofAction: Depolarisation of myoneural junction ; inhibition of cholinesterase, with resultant spastic paralysis of the worm . Absorption: Essentially non-absorbable. Excretion: 90 % excreted in faeces; 10% in urine. Toxicity: Excessive doses cause neuromuscular blockade in experimental animals . Dysmorphogenic effects have not been evaluated. Therapeutic Effects: Excellent drug against Ascaris and Enterobius; effective in a single dose. Good drug against the hookworms. Drug of choice against Ascaris and Enterobius.

1.2 Mebendazole (Magbool et al., 1975)

Mode of Action: Irreversibly inhibits glucose uptake .

Absorption: Essentially non-absorbable. Excretion: 90 % excreted in faeces; 10% in urine. Toxicity: None discovered in man . Possibly dysmorphogenic in experimental animals.

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Therapeutic Effects: Excellent drug against Enterobius ; effective in a single dose. Very good drug against Ascaris, Trichuris, or the hookworm ;

1.5 Bephenium Hydroxynaphthoate (Copp et al., 1958)

effective in multiple doses. Drug of choice for

Mode of Action: Unknown. Absorption: Apparently not absorbed. Excretion: Excreted in faeces. Toxicity : Rarely causes nausea, vomiting and diar-

Trichuris .

1.3 Piperazine (Swartzwelder et aI., 1955) Mode of Action: Blocks response to acetylcholine

and causes flaccid paralysis of the worm. Absorption: Readily absorbed from the small intestine. Excretion: Approximately 25 % is metabolised; the remainder is excreted in urine. Toxicity : No evidence of serious toxicity in man; no evidence of dysmorphogenicity in man , but no critical study has been conducted. Therapeutic Effect: Good drug against Ascaris; may be drug of choice in intestinal odstruction due to Ascaris; adequate drug against Ent erobius .

1.4 Thiabendazole (Brown et al., 196 J) Mode of Action Unknown. Kills various nematode larvae in vitro; kills approximately 60 % of encysted Trichinella spira lis larvae in experimentally infected pigs and rodents. Absorption: Rapidly absorbed from the small intestine. Excretion: Approximately 10% is excreted in faeces; the remainder in urine . Toxicity : Frequently causes anorexia and nausea. Occasionally causes dizziness and vomiting. Rarely causes diarrhoea, pruritus, and headache. Liver toxicity. demonstrable by transient SGOT elevation. has been rarely observed. Probably is contraindicated in severe liver disease, but no guidelines in this regard are available. Therapeutic Effects: Very good against Strongyloides stercoralis. Good drug against cutaneous larva migrans . Drug of choice for Strongyloides stercoralis infection and for cutaneous larva migrans .

rhoea . Therapeutic Effects: Excellent drug against Ancylostoma duodena Ie. Good drug against Necator americanus. Drug of choice for Ancylostoma duodenale infection.

1.6 Tetrachlorethylene (Lamson et al., 1932) Mode of Action: Reversibly paralyses the worms . Releases Iyosomal enzymes and may thus interfere with intracellular digestive processes of the worm. Absorption: Readily absorbed from the small intestine. Excretion : Metabolised by the liver. Toxicity : Occasional nausea and vomiting; rarely intoxication and loss of consciousness. (This drug causes Ascaris to migrate aberrantly and therefore should not be administered until effective therapy against Ascaris has been completed). Therapeutic Effects: Very good drug against Necator american us. Drug of choice for N. americanus infection.

1.7 Niclosamide (Keeling, 1968) Mode of Action: Interferes with respiration and blocks glucose uptake. Absorption: Not absorbed. Excretion: Excreted in faeces. Toxicity : None known. Therapeutic Effects: Excellent drug against all intestinal tapeworms. Drug of choice for Taenia saginata, T. solium, Diphylobothrium latum and Hymenelopis nana infections.

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Table I. A summary of the diagnosis of helminthic infections Parasite

Examination of specimen

Notes Collect first thing in the morning

Enterobius vermicularis (pinworm)

Cellulose tape for ova

Ascaris lumbricoidis

Stool for ova

Toxocara (visceral larva migrans)

Differential white cell count for eosinophilia; isohaemagglutinin titres ; IgG level; precipitin test ; liver biopsy

Necator americanus or Ancylostoma duodenale (hookworm)

Stool for ova

Strongyloides stercoralis

Stool for larvae

Trichuris trichiura (whipworm)

Stool for ova

Trichinella spiralis

Skin test ; serological tests; muscle biopsy (rarely)

Diagnosis difficult to establish; often remains presumptive

Immunosuppressed host especially susceptible to this infection

Filariae

Blood; biopsy of subcutaneous tissue

Taenia saginata. T. solium, Diphyllobothrium letum, Hymenolepis nana

Stool for proglottides or ova

Echinococcus granulosus

Skin test ; serological tests

Sch istosoma mansoni or S .japonicum

Stool and rectal biopsy for ova; determ ine viability of ova

Eggs may be scarce; collect several specimens; concentrate specimen

S . hematobium

Urine for ova; biopsy of bladder _ mucosa, or polyp; determine viability of ova

Eggs may be scarce; collect several specimens; concentrate specimen

Fasciolopsis buski

Stool for ova

Usually casual finding

Clonorchis sinesis

Stool for ova

Fasciola hepatica

Stool for ova

Eggs may represent those ingested in infected sheep liver

Paragonimus westermani

Sputum for ova

In stool if sputum swallowed

1.8 The Antimonials (Bueding and Schiller, 1968) The antimonials include antimony potassium tartrate (tartar emetic) and stibophen. Mode of Action : Inhibit phosphofructokinase. Absorption : Used parenterally only. Excretion : Renal. Toxicity : Commonly cause vomiting, renal tubular damage, arthralgia, bone marrow depression, bradycardia; rarely causes hepatitis and haemolytic anaemia .

Except D. medinensis (see text)

Therapeutic Effects: Very good drugs against the schistosomes. Stibophen is the drug of choice for Schistosoma mansoni, antimony potassium tartrate is the drug of choice for S. japonicum.

1.9 Niridazole (Symposium , 1969) Mode of Action : Inhibits uptake of exogenous glucose. Absorption : Entirely absorbed from small intestine.

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Table II. A summary of the treatment of helminthic infections Parasite

Drug

Dose

Notes

Enterobius vermicularis

Pyrantel pamoate

11mg/kg as single oral dose l00mg single oral dose for adults and children

Treat all infected children in household. Retreat all individuals after 2 weeks

(pinworm)

Mebendazole

Ascaris lumbricoides

Pyrantel pamoate Mebendazole

As above 200mg daily for 3 days

Toxocara (visceral larva migrans)

Anti -inflammatory agents

Systemic

Necator americanus

Tetrachlorethylene Mebendazole Pyrantel pamoate

0.012ml/kg up to 5ml max as single oral dose 200mg daily for 3 days As above

Ancylostoma duodenale

Bephenium hydroxynaphthoate Mebendazole Pyrantel pamoate

1 day 200mg daily for 3 days As above

Ancylostoma braziliene: A . caninum (cutaneous

Ethyl chloride Ant iprurit ics

Spray System ic

Strongyloides stercoralis Trichuris trichuria Trichinella spiralis

Thiabendazole

50mg /kg/24h in 2 divided doses for 2 days

Filariae

Diethylcarbamazine

6mg /kg/24h orally in 3 divided doses for 3 weeks

Use anti-inflammatory " gents or antipyretics for filarial antigen- induced fever

Onchocerca volvulus

Diethylcarbamazine

25mg /24h for 3 days; 50mg/24h 5 days; l00mg/24h 12 days

Gradually increasing dose to minimise ocular effects

D. medinensis

Niridazole

25mg /kg/24h (max 1.5g) orally for 1 week

All tapeworms

Niclosamide

2g orally as single dose after a light meal 19 orally q6h for 4 doses

(hookworm)

(hookworm)

larva migrans)

Mebendazole Anti-inflammatory agents

Paramomycin

Patient may become dizzy (rest for 1 hour)

Retreat in 2 to 4 weeks if failure (rare)

200mg daily for 3 days Systemic

Cysticerosis, echinococcosis

Surgery in conjunction with scolicidal solutions

Schistosoma hematobium

Niridazole

25mg /kg/24h (max 1.5g) as single oral dose for 5 days

S . mansoni

Stibophen (8.5mg /mll

1M over 2 to 3 weeks to total dose 80m !. (Initial dose 1.5ml; 3.5ml after 2 days, then 5ml every other day).

S .japonicum

Antimony potassium tartrate (0.5 %)

IV on alternate days to total of 360m!. (Init ial dose 3ml; increased by 4ml increments to 28mI which is cont inued every other day for course).

Fasciolopsis buski Clonorchis sinensis Fasciola hepatica

Tetrachlororethylene No satisfactory treatment

As for N . americanus

Bithionol

40mg /kg/24h for 10 doses on altemate days

Paragonimus westermani

Bithionol

As above

Chew niciosamide tablets thoroughly. Several courses of niciosamide or paromomycin may be required

Gradual dose increase to avoid toxic side-effects. Injections are painful

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Ex cretion: Rapidly metabolised in the liver; metabolites excreted by the kidney and in faeces (after re-entry into the gut with bile.) Toxicity: Common flattening or inversion of T wave on the ECG (but no clinical cardiac toxicity); occasional confusion. hallucinations ; rarely convulsions. Causes haemolysis in G-6-PD deficient individuals. Therapeutic Effects : Very good drug against S. haematobium and Dracunculus medinensis . Good drug against S. mansoni and S. japonicum. Drug of choice for S. haematobium and D. medinensis.

1.10 Diethylcarbamazine (Harned et al., 1948) Mode of Action: Largely unknown; affects microfilariae so as to render them susceptible to phagocytosis by the fixed monocyte system (but not by circulating phagocytes), May also kill some adult worms. Absorption: Readily absorbed from the small intestine. Excretion: Renal. Toxicity: Commonly causes headaches, myalgia, arthralgia. anorexia, nausea, and vomiting. (Allergic reactions to antigens from killed filariae may develop .) Therapeutic Effects: Very good drug against all filarial worms, except D. medinensis. Drug of choice for treatment of all filariae worms, except D. medinensis .

1.11 Paromomycin (Salem and AI Allaf, 1967; Wolfe. 1963) Mode of Action: Unknown (when it is used as an anthelmintic). Absorption: Minimal. Excretion : Excreted in faeces, partly degraded, partly unchanged. Toxicity: When used orally occasionally produces diarrhoea.

Therapeutic Effects: Good drug for all tapeworm infections.

1.12 Pyrvinium [Viprynium] Pamoate (Sawitz and Karpinski, 1956) Mode of Action: Inhibits oxygen uptake and interferes with absorption of exogenous glucose. Absorption: Not absorbed. Excretion: Excreted with faeces. Toxicity: Frequent nausea and vomiting, when the drug is taken in liquid suspension; rare, if it is taken in tablet form. Therapeutic Effects: Adequate drug for E. vermicularis infections.

2. The Helminthiases 2.1 Round Worms 2.1.1 Enterobius vermicularis This ubiquitous worm inhabits the rectum and causes perianal pruritus as the female crawls out and lays eggs. It seems that only a minority of infected persons are symptomatic, although no appropriate study has been reported. Certainly there is a great variability in host response, or at least in host complaints about these infections. The cycleis maintained by swallowing of the ova, easily picked up by the scratching fingers. A contributing factor in the spread of this infection is the relative lightness of the eggs, which are readily conveyed through the air, inhaled and swallowed. Thus intrafamilial spread and cross infection in schools contribute to the maintenance of the infection in most human societies. The cycle, from the ingestion of the ovum to the appearance of an adult worm in the rectum is approximately 2 weeks. It takes another 2 weeks for these new adults to begin laying eggs. Hence there is periodicity of clinical symptoms of I month to six weeks. Therapy must aim at the eradication of the worm and should be given to all infected children in the

Anthelmintics

household. Adults usually do not maintain the anooral transmi ssion through fingers and perhaps need not be treated. It is important to bear in mind that none of the available drugs kills the ova. Hence one must re-treat each individual 2 weeks after the original drug administration in order to destroy the new crop of adult worms that have developed from ova ingested at the time of the original therapy . Two drugs are equally useful in treating this infection . Pyrantel pamoate is administered as a single dose of II mg/kg, to both adults and children, and mebendazole is also administered once, at a dose of I OOmg, for both adults and children. The older drug, piperazine has the disadvantage requirement of daily administration for I week. Pyrvinium pamoate, given for 2 days, as a single daily dose of 5mg/kg/24h (maximum 250mg), has the disadvantage of causing nausea and vomiting . Since the drug is bright red in colour, the vomitus tends to stain whatever clothing it touches. Neither of these two drugs has any advantage over the first two.. 2 .1.2 Ascaris lumbricoides This round worm inhabits the small intestine and usually causes no symptoms. The patient becomes aware of the infection either because of vomiting of the worm , or through passing one in the stool. The physician can diagnose an asymptomatic infection by finding the characteristic ova in a microscopic examination of the stool. Rarely, Ascaris causes problems by migrating aberrantly through the intestinal wall into the peritoneum and causing peritonitis, or into the bile ducts or the vermiform appendix, causing an obstruction. In very heavy infection the worms may become entwined and cause intestinal obstruction . The infection is perpetuated in a community by ingestion of ova from the soil, where they must incubate from 3 to 4 weeks before becoming infectious. Thus there is no danger of a direct man to man spread. The best therapy for Ascaris infection is pyrantel pamoate, given as for Enterobius. Mebendazole is quite effective(Chavarria et al., 1973), but it

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must be given for 3 days, at a daily dose of 200mg , for both children and adults . The advantage of the single dose therapy with pyrantel pamoate is obvious. Piperazine given for 2 days at a single daily dose of 75mg/kg/24h (maximum Jg), is also quite effective. Because of its mode of action that leads to muscle relaxation of the worms , piperazine may have a specific advantage in the treatment of intestinal obstruction by the Ascaris . 2 .1.3 Visceral Larva Migrans This systemic infection is caused by an abnormal migration of larvae of Toxocara canis and perhaps also T. catti - round worms of the dog and cat respectively. The protean symptoms of a multisystem disease are well described in standard pediatric textbooks. The diagnosis is indirect, because no ova are shed in the stool. Hypergammaglobulinaemia a useful clue to the diagnosis. Although a claim has been made for the effectiveness of thiabendazole (for dosage schedules see section on Strongyloides) it has not been demonstrated (Campbell, 1971; Campbell and Cuckler, 1964). Symptomatic relief can be achieved with anti-inflammatory agents; in severely affected patients corticosteroids may be life saving. 2 .1.4 The Hookworms The so-called old world hookworm, Ancylostoma duodenale and the new world hookworm Necator american us, live in the small intestine and are responsible for continual blood loss. A . duodenale can cause loss of O.2ml of blood per worm, per day and N. american us O.02ml. Most individuals with light infection are asymptomatic . Those poorly nourished and heavily infected develop anaemia and hypoproteinaemia. Diagnosis is made readily by identifIcation of the ova in the stool. Although the ova of the two hookworms can not be distinguished from one another, the worms themselves can be readily told apart . The geographic origin of the infection gives a reasonable clue to the species of the worm. Ancylostoma is treated best with bephenium hydroxynaphthoate given in two doses of 5g each for one day. Necator does not respond nearly so well to

Anthelmintics

bephenium and therefore this drug is not recommended for it. Instead, Necator should be treated with a single dose of tetrachlorethylene of 0.0 12ml/kg up to a 5ml maximum. Either infection can be satisfactorily treated with mebendazole, 200mg/24h for 3 days. The requirement of a 3 day therapy is a disadvantage with this drug . Pyrantel pamoate is equally as effective for both infections. Its dose is II mg/kg (maximum Ig) given as a single dose. 2 .1.5 Cutaneous Larva Migrans This is a superficial skin infection caused by larvae of dog hookworms Ancylostoma brazilienze and A. caninum . It is characterised by an intense itching and has been treated traditionally by local application of ethyl chloride spray and systemic administration of antipruritic drugs . Thiabendazole (see section on Strongyloides for dose) may be effective in killing the larvae and thus shortening the symptomatic period. 2 .1.6 Strongyloides stercoralis This worm lives in the small intestine and usually causes no symptoms. Its major direct effect, when it does cause disease, is intractable diarrhoea . The infection is diagnosed by finding larvae in the stool. People become infected through exposure of skin to the larvae in moist soil. Since the larvae deposited in the soil must incubate for several days before moulting to become ineffective larvae, man to man spread does not ordinarily occur. The extraordinary circumstance when it may occur and, more important, when autoinfection can take place results from moulting of the noninfective larvae to the infective ones within the patient. The basis for this change is not fully understood, but it is related to an alteration of the immune status of the host. immunQsuppression, . whether through a disease, or one deliberately induced by physicians, can be responsible for the development of the autoinfectious cycle (Purtillo et al., 1974). In such a form this nematode, in contrast to the others, actually increases in numbers in the patient who is not reinfected from exogenous sources. Since the worm can persist for decades, a severe infection may follow after a prolonged period of asymptomatic carriage of

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the worm (Brown and Perna, 1958). Autoinfection, in addition to causing an increase in the numbers of the worms and consequent diarrhoea, can also be a cause of sepsis with enteric organisms carried by the migrating larvae from the intestine to the blood stream . Therapy with thiabendazole administered in two divided doses of 50mg/kg/24 hours, given for 2 days, is quite effective. Retreatment in 2 weeks to a month in case of a rare failure is recommended. All immunosuppressed patients should have their stool examined for presence of Strongyloides larvae; those infected should be treated promptly. 2 .1.7 Trichuris trichuria This nematode lives in the colon. Light infections can be asymptomatic . Heavy infections cause colitis and diarrhoea that can be so severe as to result in rectal prolapse. Diagnosis is made by identification of the characteristic ova in the stool. In addition stools of Trichuris-infected patients may contain CharcotLeyden crystals, hexagonal structures representing degenerative products of eosinophils. Infection is acquired by ingestion of ova in the soil where they must incubate for a month to become infective. Thus direct man to man spread is not possible. Therapy with mebendazole is effective in nearly 100% of cases (Magbool et al., 1975). Neither thiabendazole nor hexylresorcinol enema, each of which is partially effective, has any place in therapy of Trichuris . 2 .1.8 Trichinella spiralis This causes disease primarily during the migratory phase. The infection is acquired through eating infected meat - mainly pork , but also bear meat and ground meat sold as beef but adulterated with pork . The ingested larvae liberated from intramuscular cysts moult, become adults , mature sexually and bear live larvae in the host's small intestine. These larvae penetrate intestinal mucosa, reach the blood stream and with it invade virtually every tissue in the body. The invasion provokes an inflammatory reaction and the larvae are ultimately destroyed, except for those

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that invade striated muscles. In the muscles the larvae enter individual cells (muscle fibres) and convert them into units supporting metabolism of the larvae (Despommier , 1975). Gradually the larvae coil within the cell, eventually encyst and ultimately calcify. An identical life cycle takes place within the pig and other animals , the flesh of which is consumed, giving rise to new infections. Man, obviously, is a 'blind end' of this infection. The earliest manifestation of clinical disease often not recognised as trichinosis - is diarrhoea. It is contemporaneous with the intestinal phase of the infection and can begin as early as 24 hours after ingestion of the infected meat; it can last for I week. The migratory phase gives rise to protean symptoms of a multisystem inflammatory disease. There can be fever, myalgia, facial oedema and, depending on the organ infected, myositis, encephalitis, arthritis, and pneumonitis. Elevation of leucocyte count and oesinophilia are characteristic. The symptoms and signs of trichinosis may last for several days to as long as I month . Their severity is directly proportional to the number of invading larvae, which in turn depends on the number of larvae originally ingested. In many cases this number is small and thus most infections are asymptomatic or characterised by minor symptoms, rarely recognised for what they are. Diagnosis depends on clinical suspicion, good history , and immunological tests. An intradermal injection of Trichinella antigen gives rise to an immediate hypersensitivity reaction. This test can become positive as early as the I Ith day and almost invariably by day 17 following the infection. Unfortunately, the patient can be responsive to it for 5 years or so, and therefore the test may be misleading. Moreover, not all of the available antigen preparations are considered reliable (Lamb et al., 1964). Serological tests, bentonite flocculation (Vogel et al., 1957) and counterelectrophoresis, (Despommier et al., 1974) are better indices of the disease, with the latter having great sensitivity and specificity. Rarely , muscle biopsy may be required to confirm the diagnosis. There is no specific therapy for trichinosis. Although claims have been made that thiabendazole

is effective (Campbell, 1971), there is little evidence for it. In experimental infection the drug does kill the adults in the intestine, but is less effective against the migratory or encysted larvae. Palliation of symptoms with anti-inflammatory agents and corticosteroids is the only useful measure in management of this infection.

2.2 Filarial Worms These round worms are tissue parasites inhabiting the lymphatics, blood, muscles, connective. tissues, the eyes, and serous cavities. The ersulting disease depends on the species of the parasite and its location within the host. Wuchereria bancrofti and Brugya malayi adults live in the lymphatics where they produce blockage. After a decade, or more, dependent lymphoedema (elephantiasis) results. Larvae (microfilariae, produced viviparously, appear in the blood during the nocturnal hours, although the circadian periodicity is not absolute in B. malayi. Onchocerca volvulus adults inhabit subcutaneous tissues, surrounded by encapsulated fibrous tumors. Microfilariae are found in the subcutaneous tissues and the eyes. In the latter, these larvae can invade all chambers and cause inflammation that may lead to blindness. Loa loa adults also live in subcutaneous tissues, but the microfilariae are found in the blood during the daytime hours. No serious symptoms are associated with this infection; connective tissue swellings (Calabar swellings) are its major manifestation. Dracunculus medinensis adults live in the skin, or subcutaneous tissue, where they may attain the length of approximately Im. Its cephalic end ultimately moves close to the surface and forms a cutaneous papule, which ruptures and discharges larvae when the skin is exposed to fresh water . All filariae are transmitted by arthropods. W. bancrofti and B. malayi , by mosquitoes, which ingest the microfilariae, support their development into infective forms, and inoculate them into the new hosts, in whom these larvae migrate to the lymphatics and develop into adults. O. volvulus is similarly spread by

Anthelmintics

the black fly of the genus Simulium and L. loa by the Chrysops flies. D. medinensis infection takes place through ingestion - usually in drinking water - of a minute crustacean, Cyclops. which has become infected by ingestion of the larvae discharged into water . These larvae penetrate the host's intestinal wall and ultimately migrate into the subcutaneous tissues. Diagnosis of filarial infections except D. medinesis - depends on finding the microfilariae in the blood, or in a biopsy of subcutaneous tissue, depending on the species. D. medinensis must be recognised on the basis of physical signs, presence of a papule, skin ulcer, or observation of the discharge of larvae. Most filarial infections are treated with diethylcarbamazine, at a dose of 6mg/kg/24 hours given in 3 divided doses for 3 weeks. O. volvulus is also treated with diethylcarbamazine, but it is given at a gradually increasing dose in order to prevent or reduce ophthalmic reaction. Beginning with 25mg daily for 3 days and followed with 50mg daily for 5 days, IOOmg daily for 3 days and, finally 150mg daily for 12 days. In the case of O. volvulus drug therapy is a supplement to surgical excision of the subcutaneous nodules. A febrile illness during diethylcarbamazine therapy is the result of the release of filarial antigens from the killed worms . This reaction responds to nonspecific palliation with anti-inflammatory and antipyretic drugs and, in severe cases, corticosteroids. D. medinensis responds best to niridazole, at 25mg/kg/24 hours, not to exceed 1.5g for I week.

2.3 The Cestodes (Tapeworm) All the adult tapeworms infecting man inhabit the small intestine, where they are attached to the mucosa by the anterior end, or scolex, which has hooklets, suckers or grooves. The scolex is followed by the neck region, from which new segments, the proglottides, arise. The length of an entire worm varies with species and spans a range between 3mm and 10m.

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Regardless of the total number of the proglottides, it is the scolex that is most important, because it alone can generate new proglottides and will do so even if the rest of the worm has broken off and left the host. There are five species of tapeworms for which man is the definitive host: Taenia saginata , T. solium, Diphyllobothrium latum, Hymenolepis diminuta and H. nana. Man becomes infected by the ingestion of an encysted scolex in the case of the first four, and the ovum in the case of the last. T. saginata parasitises cattle, T. solium , pigs and D. latum, fresh water fish. When poorly cooked flesh of these animals is eaten, its component cysts are digested, the liberated scolex attaches itself to the mucosa of the small intestine and becomes the progenitor of the long tapeworm . In general, these worms cause little morbidity - what they do cause is the result of their bulk and some movement - and most patients become aware of the infection by spotting proglottides and large segments of the worm in their stools. In addition, D. latum has caused megaloblastic anaemia, because of its great affinity for vitamin B11 which it extracts from the host's ingested diet. In the case of H. diminuta, the larval fleas and adult mealworm beetle are intermediate hosts and ingestion of these insects causes infection. H. nana requires no intermediate host; its ova, excreted in human stool, may be ingested in contaminated food or as a result of direct close human contact. Moreover, the worms can parasitise mice and rats and the excreta of these rodents may be the source of human infection. Autoinfection is common , either by ingestion of the excreted ova by the patient - analogously to what occurs in pinworm (enterobiosis) infections - or by the development of infectious ova without their leaving the intestine. Diagnosis of the infection is made by the identification in the stool of the characteristic proglottides or ova; ova of T. saginata and T. solium cannot be distinguished morphologically from each other. In addition to this form of tapeworm infection, wherein man is the definitive host and carries the adult worm in the intestine, man may become an 'abnormal' host for the intermediate form of the worms.

Anthelmintics

Ova of T. solium, but not T. saginata, can undergo development in man according to the pattern in the intermediate host. This may lead to the formation of cysts (cysticerci) in various organs and tissues , notably brain or bones. These cysts act as space occupying lesions. It has been suspected that proglottides of T. solium are regurgitated into the stomach and that the ova they contain become liberated and begin their development. It is also possible, however, that this form of T. solium infection results from ingestion of food contaminated with the ova. A tapeworm of dog, Echinococcus granutosus, whose intermediate host is sheep, can give rise to cysts in man , if man ingests the ova shed in dog faeces. Echinococcal cysts can involve virtuall y every organ and tissue and, unlike T. solium cysts, can replicate within man . If they are ruptured, they can form metastatic cysts. In addition, the released cyst fluid may provoke anaphylaxis . Diagnosis depends on the identification of the cysts as space occupying lesions through X-rays, scans with radioactive tracers , or exploratory surgery. Presence of a cyst in a patient whose stools contain T. solium proglottides or ova points to the specific diagnosis. A skin test (Casoni) and serological tests for echinococcosis are helpful in identification of the infection. Treatment of the intestinal infection consists of the administration of niclosamide (Zg), taken as tablets, which must be chewed thoroughly. The drug is given as a single dose, admin istered after a light meal. Paromomycin, given orally at a dose of 19, every 4 hours for a total of 4 doses, is also effective. Either treatment is quite satisfactory for T. saginata, T. solium, D. tatum and H. diminuta, but less so for H. nana infection, because autoinfection makes eradication of the worm difficult. Several courses of treatment may be required . Cysticerosis and echinococcosis must be treated by surgery ; removal of echinococcal cysts is a delicate procedure, because rupture must be prevented at all costs. Use of scolicidal solutions, such as hypertonic salt, alcohol, or formalin is recommended . Cryosurgery has also been effective (Said and Nazarian, 1971).

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2.4 The Flukes S chistosomes. From the standpoint of human disease, the schistosomes are the most important fluke pathogens. The adult worms of Schist osoma haemat obium live in the pelvic veins and the adults of S. mansoni and S. jap onicum in the portal veins. The eggs they lay are carried by the bloodstream and deposited in the ur inary bladder, in the case of S. haemat obium and the intestinal mucosa, the liver, the lungs, and other tissues, in the case of S. mansoni and S. jap onicum. The pathogenic process depends on the host immune response to the deposited eggs, which leads to the development of a granuloma (Warren, 1972). In the bladder this results in the formation of pseudotubercules and eventually carcinoma; in the case of S. mansoni and S. japonicum, the granulomata lead to portal obstruction and hypertension and the consequent formation of oesophageal varices; fibrosis of the liver - the so-called pipestem cirrhosis develops. Fibrosis of the lungs often leads to the development of cor pulmonale . Occasionally eggs find their way to the spinal cord and may cause inflammation and transverse myelitis. Diagnosis depends on the identification of the character istic eggs in the urine (for S. haematobium) and stool for (S. mansoni and S. japonicum .) It may be necessary to sediment large quantitie s of stool obtained by purgation , to find the eggs. If this fails, but the diagnosis is strongly suspected on clinical grounds, one may have to resort to a rectal biopsy. Most important in the diagnosis is the determination of viability of the eggs. Since drug therapy is toxic, it is important to establish that there is an active infection . Eggs seen in the stool may represent oviposition that took place months, or even years earlier, with the worm s themselves no longer alive. Live eggs have characteristically active flame cells, easily seen under the microscope. Therapy for S. haematobium is niridazole, at a dose of 25mg/kg/24 hours (not to exceed 1.5g/24 hours) , given once daily for 5 days. This therapy is also quite effective for the other two schistosomes, but antimonial compounds are considered better,

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although no concurrent comparative study of the two forms of therapy has yet been conducted. The drug of choice for S. mansoni is stibophen . It is available in a solution containing 8.5mg of antimony/ml and is administered intramuscularly over a period of 2 to 3 weeks to an accumulated dose of 80ml. The initial dose of 1.5ml is followed 2 days later by 3.5ml and then 5ml every other day. This gradual administration is recommended in order to identify any toxic side-effects. The injections are painful and the patient must be provided with sufficient information about the consequence of untreated schistosomal infection and be given much encouragement and sympathy to continue the therapy. S. japonicum is treated with antimony potassium tartrate. The drug is available as a 0.5 % solution and is given intravenously on alternate days to a total of 360ml. The initial dose is 3ml and subsequent doses are increased by increments of 4ml until the dose of 28ml is reached; this dose is then continued every other day for the balance of the therapy.

Fasciolopsis buski: This flatworm usually lives in the small intestine, although it has also been found in the stomach and colon. It causes little morbidity and the symptoms, if they do develop, mimic those of a mild gastroenteritis. Infection of man depends on the ingestion of encysted larvae, which repose on fresh water plants. The entire cycle involves also a snail as the first intermediate host, infected by larvae hatching from eggs deposited in water contaminated by human excreta. Diagnosis is made by finding the characteristic eggs in the stool, but it usually is a casual finding, in view of the limited symptoms. The drug of choice is tetrachlorethylene, at the same dose as for Necator americanus therapy . Clonorchis sinensis parasitises human bile ducts. There is no evidence that the infection causes any symptoms (Strauss, 1962), although many different ones have been attributed to it. These include epigastric discomfort and diarrhoea. Infection is acquired by ingestion of raw or insufficiently cooked fresh water fish, which contains encysted larvae of

Clonorchis. The snail is the first intermediate host, infected by larvae that hatch from eggs passed in human stool and deposited in water. Finding of characteristic eggs in the stool establishes the diagnosis. There is no satisfactory treatment. Chloroquine phosphate or emetine has been used in therapy, but the most that they have accomplished is transient reduction of the egg output of the worms. Fasciola hepatica. a parasite of sheep, occasionally also infects man, in whom it invades bile ducts within the liver. Biliary obstruction has been attributed to it. Fasciola infection results from ingestion of encysted larvae on plants; snail is the first intermediate host infected by larvae hatching from eggs deposited in fresh water. The diagnosis is made by finding eggs in the stool, but these may represent merely ingested eggs in infected sheep liver. Treatment is with bithionol. 40mg/kg/24h given for 10 doses administered on alternate days. Paragonimus westermani is a lung fluke, which forms cysts surrounded by inflammatory reaction. Symptoms produced by this worm include cough, production of blood-tinged sputum, chest pain and low grade fever. They are nonspecific and may be confused for pneumonia or pulmonary tuberculosis . Man acquires this infection by eating encysted larvae in raw or insufficiently cooked fresh water crabs and crayfish, themselves infected by larvae from snails, which are the intermediate hosts, subject to infection by larvae hatching from eggs deposited in water in human excreta. Diagnosis is made by identification of the eggs in the sputum and - if sputum is swallowed - also in the stool. This infection is treated with bithionol, as listed under Fasciola.

References Aubry. M.L.; Cowell. P.; Davey. M.J. et aI.: Aspects of the pharmacology of a new anthelmintic pyrantel, British Journal of Pharmacology 38: 332-344 (I 970).

Anthelmintics

Brown. H.L. and Perna. V .P.: An overwhelming strongyloides infection . Journal of the American Medical Association 168: 1648-1651 (I 958). Brown. H.D.; Matzuk, A.R. ; lives . I.R . et al.. Antiparasitic drugs IV 2.(4 ·-Thiazolyl) - benzimidazole. a new anthelmintic. Journal of the American Chemical Society 83: 1764-1765 (I 961). Bueding, E. and Schiller . E.: Mechanism of action of antischistosomal drugs ; in Rodrigues Da Silva and Ferreira (Eds) Mode of Action of Antiparasitic Drugs. p.81-86 (KPergamon. Oxford 1968). Campbell. W .C; Thiabendazole effects in visceral larva migrans. Journal of the American Medical Association 217 : 342-343 (J 971). Campbell. W .C. and Cuckler, A.: Thiabendazole in the treatment and control of parasitic infection in man . Texas Reports on Biology and Medicine 27: 665-692 (J964). Chavarria. A.P.; Schwartzwelder, J.e. ; Villarejos . V .M. et al .: Mebendazole, an effective broad spectrum anthelmintic. American Journal of Trooical Medicine and Hygiene 22: 592-595 (J 973) . CoPP . F.e.; Standen. D.O.; Scarnell, J. et a!.: A new series of mintics. Nature 181: 183 (I 958) . Despommier, D.O. : Adaptive changes in muscle fibers infected with Trichinella spiralis . American Journal of Pathology 78: 477-484 (I 975) . Despommier. D.; Muller. M.; Jenks. B. et aI.: Imrnunodiagnosis human trichinosis using counterelectrophoresis and agar gel diffusion techniques. American Journal of Tropical Medicine and Hygiene 23: 41-44 (I 974). Harned. B.K.; Cunningham. R.W.; Halliday. S. et aI.: Studies on the chemotherapy of filariasis. VI some pharmacodynamic properties of l -diethylcarbamyl-4-methylpiperazine hydrochloride . hetrazan . Journal of Laboratory and Clinical Medicine 33: 216-235 (J 948) . Katz. M.: Parasitic infections. Journal of Pediatrics 87: 165-178 (J 975) . Keeling. J.E.D .: The chemotherapy of cestode infections. Ad vances in Chemotherapy 3: 109-152 (I 968) . Lamb. G .A.; Kagan . I.G .; Scholten s, R. et a!.: Evaluation of intradermal and serologic tests in a large outbreak of trichuriasis. American Journal of Hygiene 80: 235-241 (J 964). Lamson. P.O.; Brown. H.W. and Ward. e.B.: Anthelmintics. some therapeutic and practical considerations of their use.

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Journal of the American Medical Association 99: 292-295 (I932). Magbool , S.; Lawrence. D. and Katz. M.: Treatment of trichuriasis with a new drug mebendazole. Journal of Pediatrics 86: 463 -465 (I 975) . Purtillo. D.T.; Myers . W .M. and Connor. D.H .: Fatal strongyloidiasis in immunosuppressed patients. American Journal of Medicine 56: 488-493 (J 974) . Said. F. and Nazarian. I.: Surg ical treatment of hydatid cysts by freezing of cyst's wall and instillation of 0.5 percent of silver nitrate solution. New England Journal of Medicine 284 : 1346-1350 (J 971). Salem. H .H. and AI Allaf, G .: Paromomycin and Taenia saginata , Lancet 2: 1360 (I 967). Sawitz, W .G . and Karpinski . F.E. : Treatment of oxyuriasis with ayrrovpxchloride (Poquil) , American Journal of Tropical Medicine and Hygiene 5: 538-543 (J 956) . Stoll. N .R .: Th is wormy world . Journal of Parasitology 33: 1-18 (I 947) . Strauss. W .G .: Clinical man ifestations of chlonorchiasis; a controlled study of 105 cases . American Journal of Tropical Medicine and Hygiene 11: 625-630 (I 962) . Swartzwelder. J .C.; Miller. J .H. and Sappenfield. R.W.: The treatment of cases of ascariasis with piperaz inine citrate . With observations of the effect of the drug on other helminthiases. American Journal of Tropical Medicine and Hygiene 4: 353-358 (I 955). Symposium on the pharmacological and therapeutic effects of niridazole and other antischi stosomal compounds. Annals of the New York Academy of Sciences 160: 423-946 (I 969). Vogel . H.; Widelock, and Fuers , HT.: A microflocculation test for trichinosis. Journal of Infectious Diseases 100: 40-47 (J 957). Warren. K.S.: The immunopathogenesis of schistosomiasis: A multid isciplinary approach . Transactions of the Royal Society of Tropical Medicine and Hygiene 66: 417-421 (I 972) . Wolfe. G .: Chemotherapy of amebiasis; in Schnitzer and Hawking (Eds) Experimental Chemotherapy. Vol I p.355-433 (Academic Press. New York 1963).

Author's address: Prof. Michael Katz. Facult y of Medicine. Division of Tropical Medicine. Columbia Un iversity School of Public Health . 630 West 168th Street. New York . NY 10032 {USA).