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Home , Clefamide, Dichloroacetamide, Etofamide, Flubendazole, Intestinal capillariasis, Teclozan

CHEMOTHERAPY OF INTESTINAL PARASITES IN SOUTHEAST ASIA

DANAI BUNNAG and TRANAKCHIT HARINASUTA Department of Clinical Tropical Medicine and Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

INTRODUCTION mgjday for five days. In another study Levi et al., (1977) used and tinida­ The common intestinal parasites in the zole for 7 days and obtained cure rates of 80% Southeast Asian countries are as follows: and 97% respectively. The side effects were mild gastrointestinal disturbances. Protozoa: Giardia Iamblia Entamoeba histolytica Asymptomatic amoebiasis or cyst passers is Helminths: commonly encountered, but the prevalences varied widely. The prevalent rate in children in Indonesia were 21% in West Flores and Enterobius vermicularis 31% on Alor Island (Partono and Soewata, 1980; Carney et al., 1974), whereas the Strongyloides stercolaris prevalence on children in a Bangkok; Or­ Capillaria philippinensis phanage was 18%, in school children from provincial towns of Chumporn and Nakhon , Nayoki, Thailand were 0.8% and 0.6% buski respectively (Chongsuphajaisiddhi et al., 1978). Other intestinal flukes. derivatives are sparingly The treatment of these parasitoses are absorbed from the intestines. These are white variable. or yellowish powders, insoluble in water and tasteless. Four compounds are in use but only Giardiasis diloxamide furoate is effective; 500 mg three Giardiasis is most common in children times daily for 10 days gave a high cure rate especially in orphanages and other institu­ of 96% (Woodruff and Bell, 1960). The mode tions·, and is manifested by recurrent episodes of action is not known. of watery or bulky motions and diarrhoea. Symptomatic intestinal amoebiasis is re­ An effective drug has been , 100 mg latively mild and very few cases of fulminating three times daily for five days yielded a 100% amoebic dysentery with the passage of cure, but the drug is no longer marketed. intestinal casts are encountered. Dichloroace­ Nittoimidazole derivatives are also effective; tamide and derivatives are , metronidazole and o~nidazole in commonly used. The former group includes: a Single dose of 2 gm gave cure rates of 86 %, 52% and 96 %, respectively (Sabcharoen N-(B-oxyethy 1)-N-(p-phenoxy-) et al., 1980) while Kavousi (1979) obtained a 4-nitro)-benzyl) dichloroaceta­ 100% response using metronidazole 15-25 mide (250 mg tab)

422 Vol. 12 No. 3 September 1981 CHEMOTHERAPY OF INTESTINAL pARASITES

Etofamide closely related to clefamide Prophylactic treatment of intestinal amoe­ (200 mg tab) biasis is often practised using dichloroaceta­ mide derivatives, the efficacy of which has not dichloroacetyl-ethyl- amino­ been evaluated. ethyl-benzene, (100 mg tab) Amoebic liver abscess is the most common The nitroimidazole derivatives are com­ form of extraintestinal amoebiasis. In Thai­ pletely absorbed from the intestines and kill land we have recorded about 1,000 cases the trophozoites; the amoebic cyst however during the past 30 years and has been routinely resists these compounds at low dose, (Chong­ treated this condition with tissue amoebicides suphajaisiddhi, 1971). Metronidazole has and aspiration of pus. During the last 14 been used since 1959 for Trichomonas vagina­ years metronidazole was used with varying lis and in 1965-1966 it was prescribed for dosages and for the last 10 years tinidazole amoebiasis. Side effects occur in 20-30% has been used in the Hospital for Tropical and include metallic taste, upper gastroin­ Diseases. So far, there has been no relapses testinal symptoms. The nervous system is less or treatment failures. frequently affected, producing headache, dizziness and numbness oflimbs. The dosage Metronidazole 400 mg three times daily used in symptomatic amoebiasis is 600 mg for 10 day yielded a 100% cure with 6 months three times daily for 5-10 days. follow up (Harinasuta et al., 1975). Tinidazole has similar properties to metro­ Tinidazole 800 mg three times a day for 5 nidazole but the blood level at 24 hour after days yielded the same result in 8 patients administration was higher (Sawyer et al., (Bunnag and Harinasuta, 1973). A single 1976). It is excreted unchanged. Disulfiram­ day dose of 2.4 gm and 1.2 gm were studied like reactions with alcohol are observed as in in 12 and 5 patients respectively, obtaining metronidazole and are characterised by excellent results (Bunnag and Harinasuta, confusion, flushing, headache, drowsiness, 1974). Since then a single dose of 1.2 gm nausea, vomiting and hypotension. The has been given to 34 patients, the clinical optimal dosage is 2 gm daily for 2-3 days response and the healing of the abscess cavity which is a shorter course than that of metroni­ have been satisfactory. Occasional~y very dazole. large abscesses, with a diameter of 15 em and over are encountered, then 2.4 gm dose is similar to tinidazole and for five days was used. A patient with an metronidazole and the manufacture claims a abscess of 31 em vertical diameter was high plasma concentration in 1-2 hours, no sucessfully treated with 2.4 gm daily for five incompatibility with alcohol, little neurotoxi­ days and 28 aspirations of 5.53 litres of city, no teratogenicity and no carcinogenicity. pus. It has been recommended in symptomatic intestinal amoebiasis at 500 mg twice daily Occasionally amoebic liver abscess is for 5-10 days (Gruneberg et a!., 1970; complicated with Escherichia coli infection Schweitzer, 1976). and a dose or two of diluted with 20 ml of distilled water is introduced and hydrochlo­ into the cavity after aspiration. The aspirates ride are less frequently used nowadays. from subsequent attempts are cultured to Tetracycline 1 gm daily for 10 days in monitor the presence of bacteria. Aspiration symptomatic amoebiasis yielded a high cure should be performed daily or on alternate rate of 97% (Powell et a!., 1965). days until the pus is sterile or when there

Vol. 12 No. 3 September 1981 423 SouTHEAST AsiAN J. TRoP. MilD. Pus. HLTH. is no faecal odour. Systemic antibiotics are each year of life for a maximum number recommended in severely ill patients. of 25 fruits (Harinasuta, 1962). The fruits are pounded and the juice collected by strain­ The cavity of an abscess in the liver can be ing and 15-30 ml of lime water or coconut visualised roentgenologically by injection of milk added. The cure rate was 30-80% radio opaque medium (5 ml of 40% iodised (Migasena et a!., 1974; Unhanand et al., oil) and 50-100 ml of air; P.A and lateral 1978). About one million people was treated films are then takien. By measurement of the in mass campaign against intestinal parasites vertical and horizontal and anteroposterior in 1977-1979, however optic atrophy was diameters, the size of the cavity is estimated reported in 8 patients who had taken the (Harinasuta and Harinasuta, 1966). juice kept over-night (Limpaphayom et al., The study of the rate of healing was carried 1977). This might be due to the oxidative out by taking X-rays at intervals (both P-A process during storage and some had taken and lateral films). When the cavity was an over dose. The substance could be toxic obliterated, the oil was seen as collection of to the retina and optic nerve. droplets. If there was recrudescence i.e. pamoate, a tetrahydropyrimidine the cavity being formed again, the opaque is a crystalline powder, insoluble in water medium would spread and line the bottom of the cavity. A medium size abscess cavity and slightly absorbed. It inhibits neuromuscu­ (7.0-8.0 em in diameter) in our series took lar transmission producing spastic paralysis about 4-6 weeks to heal (Harinasuta and of the worms. The drug is given at 10-20 Bunnag, 1970). mg/kgjday for two-three consecutive days with cure rate of 63 %-83 %. The side effects The healing process of amoebic liver are mild and transient including nausea, abscess was also studied in 125 patients. vomiting, diarrhoea and abdominal cramps It was noted that the abscess cavity healed from the central towards the peripheral (Bhaibulaya et al., 1975; Migasena et a!., part of the liver (Harinasuta and Bunnag, 1978). 1970). , a derivative, Surgical drainage should be avoided as is a white, yellowish powder, very slightly secondary infection is very common and soluble in water and tasteless. It inhibits leakage of pus into the pleural cavity is often the glucose uptake leading to glycogen unavoidable; antibiotics are needed in large depletion and death of the worms. When amount for these patients. the drug is used at 100 mg twice daily for three days, it yielded a 90% cure rate. The side effects are mild and transient (Bunnag et al., 1976; Migasena et al., 1978). Severe hookworm disease is not common however hookworm infection is a common Flubendazole, is a paraflouro analoque of soil-transmitted helminthic infection in mebendazole and when given in two doses of Southeast Asia. Various drugs have been 300 mg at 24 hour intervals yielded a 81% used. Ma-klua (Diospyros mollis), fruits from cure rate by egg count method, the mean an indigenous plant used to dye cloth black percentage of egg reduction was 96. The side has been used in treatment of human hook­ effects weee mild and transient. It has the worm (Sadun and Vajrasthira, 1954). The same efficacy as mebendazole (Bunnag dose is calculated by age, one fruit for eta/., 1980c).

424 Vol. 12 No. 3 September 1981 CHEMOTHERAPY OF INTESTINAL pARASITES

Tetrachloroethylene given at 0.1 ml per kg, considerable choice of anthelminthics in the the maximum dose of 4-5 ml in gelatine treatment of infection. A single capsule. The drug has to be swallowed whole dose of 10 mg/kg body weight of pyrantel on an empty stomach and fat free diet to pamoate or a single dose of 100 mg of prevent absorption of tetrachloroethylene. mebendazole are effective. Since it is a family The cure rate was 77% (Magasena et a!., group infection problem, all members of the 1978). This drug should be given with care family should be treated. and should be avoided when Ascaris infection is present. It is kinown to cause Ascaris Trichiuriasis lumbricoides to be erratic. Side effects are usually mild and transient, however transient Trichuris trichiura infection in Southeast acute brain syndrome was reported in 4 Asia is rather mild except in certain parts patients (Jaroonvesma et a!., 1972). of Malaysia where prolapsed rectum is a common presentation. Flubendazole and Iron supplementation is also required in pamoate are effective. Oxantel patients with anaemia. pamoate is trans-1, 4, 5, 6-tetrahydro-2-(3- hydroxstyry 1)-1-methy I hydrochlo­ ride and has similar action as pyrantel pamo­ Occasionally ascariasis can cause intestinal ate but acts on T. trichiura only. The side obstruction but in mild infection the use of effects are mild and transient. The recom­ pyrantel pamoate, mebendazole or flubenda­ mended dose is 10-15 mg/kg/day for 2-3 days. zole in conventional doses is effective (Bunnag A combination of pyrantel pamoate and eta/., 1976, 1980). The drug of choice however oxantel pamoate has been recommended as is in a single dose of 150 mg. a broad spectrum anthelminthic for Ascaris Tetramisole and levamisole are two addi­ lumbricoides, hookiworm, Enterobius ver­ tional which are readily micularis and Trichuris trichiura infections absorbed and act on the neuromuscular (Margono et a!., 1980). system producing paralysis of the worms. Flubendazole is the para:fluoro ana1oque Agranulocytosis is kinown to occur after of mebendazole, the parent compound of a prolonged use of these drugs, however, the large series of benzimidazole derivatives and side effects are minimal and rare. Mebenda­ has proved effective against zole is well-kinown to cause erratic worms. especially T. trichiura infection (Janssen Pyranel pamoate at 10 mg/kig single dose Pharrri.) when given in two doses of 300 mg gave a 87% cure rate (Abidin et a!., 1978) orally at 24 hour interval gave promising while with smaller doses of pyrantel pamoate results (Bunnag et al., 1980c). 2.5 mg, 5 mg and 7.5 mg/kig. Hsieh and Chen (1971) reported cure rates of 68 %, 80% and 97% respectively. Strongyloides infection is more common in in a standard dose of 165 mg/kig adults than in young children and is prevalent and maximal dose of 4 gm is still commonly in mental hospitals and crowded prisons. used in weekily dose for 2 weeks. Infection otherwise well tolerated may by internal autoinfection become severe in Enterobiasis patients receiving steroid therapy for other Enterobiasis is common among school diseases. Thiabendazole 50 mg/kg body children and families in slum areas. There is weight for 2-3 successive days is effective in

Vol. 12 No. 3 September 1981 425 SOUTHEAST ASIAN J. TROP. MED. PUB. HLTH. the treatment of strongyloidiasis. (Campbell casionally encountered. The treatment is and Cuckler, 1969). Mebendazole is effective the same as for Taenia saginata infection at 100 mg bid for 3 days but with a lower but for H. nana a longer course of 5-6 days is cure rate. needed.

Capillariasis Fasciolopsis buski Intestinal was found to be This species of intestinal fluke is prevalent endemic in Northern Luzon, Philippines since in the central plain of Thailand. 1963. Mebendazole, 400 mg daily for 20-30 and tetrachloroethylene are quite effective. days yielded a 91-100% cure.· Clinical Niclosamide at 2 gm given daily for 3-5 days improvement was obtained in nearly all produce a high cure rate. Tetrachloroethylene patients (Singson et a/., 1975). at a single dose 0.1 ml/kg, (maximun 4-5 ml) yielded almost a 100% cure (Suntharasamai In Thailand, Bhaibulaya et a/., (1980 pers. eta/., 1974). c.mm) have treated 12 patients with 400 mebendazole daily for 3-4 weeks with a 100% Other intestinal flukes cure rate. The gastrointestinal symptoms improved in 3-4 days. Many species of small intestinal flukes including Prosthodendrium molenkampi and Phaneropsolus bonnei, Hap/orchis taichui and H. yokogawai are common intestinal flukes In man Taenia saginata infection is more in Northeast Thailand. at a common than T. solium infection but in dosage of 40 mg per kg body weight IS meat at slaughter houses Cysticercus cellu­ effective in expelling these worms. losae is more prevalent than Cysticercus bovis. Cysticercus cellulosae in man including Cysticercus racemosus and Cysticercus cere­ bra/is is often encountered. Human opisthorchiasis in Thailand is caused by Opisthorchis viverrini. It has been Nidosamide inhibits the oxidative phos­ estimated that some 6 million people of the phorylation process in the mitochondria Northeast and the North of Thailand har­ which releases the parasites from the in­ boured this fluke. From 1960 to 1978 various testinal mucosa. It is not absorbed therefore drugs had been studied, the results were no side effects are produced. A 2 gm dose of unsatisfactory except for cloxyle (Hetol) niclosamide, chewed and swallowed with (Bunnag eta/., 1970) but it was later found to liquid, preferably on an empty stomach be nephrotoxic and neurotoxic in dogs thus will produce cure in most patients. the drug was withdrawn from clinical use. Charoenlarp et a/., (1977) carried out the Praziquantel is an isochinolin-pyrazine trial of Thai herbal medicine in taeniasis derivative of a new acylated heterocyclic com­ usil)g 5 gm, of aqueous extract of Artocarpus pound. It is a colourless, crystalline powder, lakoocha (Puag Haad). Segments of tape with a bitter taste and slightly soluble in water. worm were expelled from .29 of 32 patients It is readily absorbed and reaches maximal ir~aied and 26 (24 T.saginata and 2 T.solium) plasma level in 2 hour, the half life is 4 hours. scolices were recovered. The mode of action is not yet fully known but Other tapeworm ··infections including Hy­ the integument of the fluke balloons at various meno/'epsis ntma, Railietina siriraji are oc- points and finally ruptures. This effect was

426. Vol. 12 · No. 3 September 1981 CHEMOTHERAPY OF INTESTINAL PARASITES observed using scanning electron microscopy The patients were carefully studied both by Mehlhorn eta!., (1980), when Clonorchis clinically and by laboratory testing before sinensis was incubated with praziquantel at treatment and 30 and 60 days after treatment. concentrations of 1-1000 !!g/ml. One hundred per cent cure rates were ac­ hieved by regimen I and regimen II, while in Praziquantel was used in treating 155 regimen Ill, IV and V cure rates were 89 %, patients with Opisthorchiasis viverrini at 44% and 91% respectively. Egg output varying dosages viz: ceased within 10 days of starting treatment. Worms were expelled and were recovered in Regimen: I 25 mgjkg body weight tds stools. There was no correlation between pc for 2 days. the egg output per gramme of faeces and the number of flukes recovered in the stools. II 25 mgjk;g body weight tds A total of 2,822 worms were collected from pc for 1 days. one patient. III 25 mgjk;g body weight bd Side effects including abdominal pain, pc for 1 day. vomiting, diarrhoea, lassitude, myalgia, IV 25 mgjkg body weight single headache, dizziness, tachycardia, insomnia, dose after meal. drowsiness and sweating, were mild and transient, and more frequent with the higher V 40 mgjk;g body weight single doses. No laboratory evidence of toxicity dose after meal. was observed.

Table 1 Efficacy of praziquantel in opisthorchiasis.

Pre-treatment Day60 Dosage No. of patients Cure rate% Regimen EPGmean No. neg*/ mgjkg body wt treated (range GM-EPG) No. exam.

I 6 X 25 29 10,833 26/26 100 (1932-93,211)

II 3 X 25 29 11,676 23/23 100 (1282-57,322)

III 2 X 25 30 15,504 23/26 88.5 (679-77,573)

IV 1 X 25 12 13,510 4/9 44.4 (1184-43,468)

v 1 X 40 55 12,858 40/44 90.9 (929-97,380)

*By faecal concentration'method. EPG =Eggs per gramme of faeces, GM =Geometric Mean.

Vol. 12 No. 3 September 1981 427 SoUTHEAST AsiAN J. TROP. MEo. PuB. HLTH.

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