Studies on Endemic Hookworm: 2. Comparison of the Efficacy of Anthelmintics in Taiwan and Liberia

CJap. J. Parasit., Vol. 19, No. 5, 523-536, 1970]

Studies on endemic hookworm: 2. Comparison of the efficacy of anthelmintics in Taiwan and Liberia

Hsien-Chen HSIEH

Department of Parasitology, Kaohsiung Medical College, Taiwan

Republic of China

(Received for publication ; August 18, 1970)

Along with development of vaccination and Octylchloresorcinol (70 parts) and Octylreso- improvement of sanitation, searches for safe, rcinol (30 parts)] by Yamasaki et al. (1954). effective and cheap anti-hookworm drugs Since 1959, in Taiwan, the author and his have remained an important part of research co-wrorkers have evaluated the anthelmintic on endemic hookworm. activity of l-bromo-2-naphthol (Hsieh et al., Following experimental work by Perroncito 1960 a; Hsieh & Chen, 1965), piperazine (1879-1880) and clinical trials by Bozzolo & compounds (Brown et al., 1959 ; Hsieh et al., Pagliani (1880) in Italy, thymol, a phenolic 1961c, 1965), tetrachlorethylene (Hsieh et al., compound obtained from the aromatic oils 1960 a; Brown et al., 1959; Hsieh et al., of Thymus vulgaris, was found to be useful 1961c; Hsieh & Chen, 1965), bephenium against hookworm. It wras, however, unplea hydroxynaphthoate (Hsieh, 1959 ; Hsieh et sant to take and rather toxic. As indicated al., 1960b, 1961 be; Hsieh & Chen, 1965), in the Bibliography of Hookworm Disease stilbazium iodide (Hsieh et al., 1963 a), tri- published by the Rockefeller Foundation in chlorophenol piperazine (Hsieh et al., 1963 b), 1922 and the Bibliography of Hookworm thiabendazole (Hsieh, 1963) and phenylene- Disease (Ancylostomiasis) published by the diisothiocyanate (Hsieh et al., 1970), dithia- World Health Organization in 1965, the zanine iodide (Brown et al., 1959), ascaridol therapeutic efficacy of more than 50 drugs (Brown et al., 1959), and pyrvinium pamoate against hookworm had been tested by 1962. (Hsieh et al., 1963 b), combination of santonin Among them were oil of chenopodium (Ve- and kainic acid (Hsieh et al., 1961c), and rvoort, 1913), carbon tetrachloride (Hall, 1921 hetol (Lee et al., 1969). ab), tetrachlorethylene (Hall & Shillinger, This paper compares the therapeutic efficacy 1925), /3-naphthol (Caius & Mhasker, 1921) of the first 8 anthelmintics in the author's and hexylresorcinol (Maplestone & Mukerji, series which were confirmed to be effective 1932). Komyia (1958) reported that /3-naph drugs against hookworm ; with special refe thol and carbon tetrachloride are more toxic rence to unpublished data of evaluation on than thymol, oil of chenopodium, tetrachlo thiabendazole in Taiwan, and on bephenium rethylene, hexylresorcinol, l-bromo-2-naphthol hydroxynaphthoate, tetrachlorethylene, their and O-R 30. In Japan, l-bromo-2-naphthol combination, piperazine citrate, and phenyl- was introduced against hookworm by Miura enediisothiocyanate in Liberia, West Africa. et al. (1953) and O-R 30 [combination of The structural formula of these anthelmintics A study supported partly by U. S. Public Health is as follows : Services Research Grant No. A1-05775 from the National Institutes of Health and The Sino- Materials and Methods American Joint Commission on Rural Reco nstruction (JCRR) in Taipei, Republic of China. The anthelmintics and their dosage regi-

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Br Clx __ /Cl -OH cK ~~ xci

1 - Bromo- 2- Naphthol Tetrachlorethylene

OH O(CH2)2N(CH3)2 • Cl COOH

Bephenium hydroxynaphthoate

CH2 -CH2 HN< 2C1~ OH

(Piperazine, salt with 2F. Wt 2,4,5- trichlorophenol. 17.8% piperazine; 82.2% 2,4,5 trichlorophenol)

Trichlorophenol piperazine

CH2—CH2 = CH ^ CH2—CH2

Stilbazium iodide

h2c ~coo;

2 HOC -COOl XH20 0 I I 0;: 3 lH2C -( N S V

Piperazine citrate Thiabendazole

Phenylene-diisothiocyanate— (1, 4) mens tested by the author and his co-workers in Taiwan in 1963 was supplied by the Merck in the earlier evaluations were described in Sharp and Dohme Research Laboratories in the published papers (Hsieh, 1959 ; Browh et New York. For the investigation in Liberia al., 1959; Hsieh et al., 1960 ab, 1961 be, 1963 in 1969, bephenium hydroxynaphthoate (ma abc). nufactured by Burroughs Wellcome & Co., Thiabendazole used for the investigation London), tetrachlorethylene (manufactured by

( 88) Speke, Liverpool), piperazine citrate (manufa C. People treated : ctured by Halewood Chemical, LTD., Staines, All people in the study groups were the Middlesex, England) were purchased from native inhabitant living in the highly endemic drug stores in Liberia. Phenylene-diisothio- area of N. americanus and A. duodenale in cyanate was produced and supplied by Fa- Taiwan or Liberia. The Liberian group was rbwerke Hoechst AG., Frankfurt, Federal examined monthly by the author before Republic of Germany. medication, and never received any anthel A. The dosage regimens for the unpubl mintics during the observation period. ished evaluation were as follows : D. The methods for evaluation : 1. Thiabendazole (oral suspension) For most of the investigations on anthel Fifty mg/kg weight once or 25 mg/kg mintics made by the author, the Stoll's twice a day for 2 or 3 days. dilution egg counting method (Stoll, 1962) 2. Phenylene-diisothiocyanate (50 mg in was employed to determine the egg reduction. each capsule) Either the modified test-tube filter-paper cul For adults : 3 doses of 100 mg (or ap tivation (MTFC) method (Hsieh, 1970) or proximately 6 mg/kg weight simple test-tube culture (Hsieh, 1963) were divided in 3 doses) at 12 employed for all investigations to determine hour interval. the hookworm species. The "cure" rates For children : 2 doses of 100 mg (or were determined by the negative finding of approximately 6 mg/kg wei the Stoll and MTFC methods. The post- ght divided in 2 doses) at treatment stool examination was made 4 12 hour interval. wreeks after therapy. 3. Bephenium hydroxynaphthoate (2.5 gm It should be noted that the MTFC method base in the form of granules) (Hsieh, 1970) was primarily aimed at the A single dese of 1.25 gm or 2.5 gm collection of the infective larvae from both the filterpaper and the water in the test-tube base, given with or without combina tion of tetrachlorethylene. culture for specific identification of A. duo denale and N. americanus as the filariform 4. Tetrachlorethylene (0.2 ml in capsule) larvae of N. americanus have a greater A single dose of approximately 0.07- tendency to stay on the filter-paper in the 0.11 ml/kg weight, but not more than MTFC culture than those of A. duodenale. 5 ml, given with bephenium hydro The author employed the MTFC method xynaphthoate. along with the Stoll dilution egg counting 5. Piperazine citrate (0.5 gm tablet) method for estimation of the relative burden A single dose of approximately 63-199 of A. duodenale and N. americanus in an mk/kg weight. individual or group of people in Liberia B. Administration of the drug for the where the two hookworms were endemic. unpublished evaluation was as follows : Combined application of the two methods Each dose of phenylene-diisothiocyanate to was found to possess special value for compa be given after substantial meals at 12 hour ring the therapeutic efficacy of an antyel- anthelmintics, except for thiabendazole, to be mintic relatively against A. duodenale or .V. administered about 3 hours after supper in americanus. Liberia. The single dose or the first dose

of thiabendazole was given about 3 hours Results after supper and the second dose before breakfast. No purgative was given before Results of the latest evaluation made in or after therapy. No iron medication was Liberia in July 1969 are first showh in Table intended. The side efiects due to these 1, and the summary was further compared anthelmintics complained of by patients were with those in Taiwan in Tables 2-6. recorded. The therapeutic efficacy of phenylene-

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Table 1 Comparison of the therapeutic efficacy of 4 anthelmintics against N. americanus (Na) and A. duodenale (Ad) among Liberians

Results No. Regimen of cases Na Ad All species treated CR ERR CR ERR CR ERR

Phenylene-diisothiocyanate approximately 6 mg/kg 14* 29 79 26 21 77 weight divided in 3 doses at 12 hour interval Phenylene-diisothiocyanate approximately 6 mg/kg 16 44 90 36 95 19 92 weight divided in 2 doses at 12 hour interval Bephenium 1.25 or 2.5 gm 21 0 6d 81 99 0 81 once Bephenium 2.5 gm and Tetrachlorethylene (0.07- 18 22 93 78 98 96 0.11 ml/kg) once Piperazine citrate (63-100 8 0 84 25 81 0 82 mg/kg) once

CR : "cure" rate (%) ERR: Egg reduction rate (%) * Four of 14 cases are concurrently infected with A. duodenale diisothiocyanate with 3 doses of 100 mg (ap received the approximately 2 mg/kg (single proximately 2 mg/kg weight) given for Libe- dose). rian adults at 12 hour intervals was observed A single dose of bephenium hydroxyna- in 14 cases of N. americanus infections and phthoate (1.25-2.50 gm base) was given to 21 4 cases of A. duodenale in association with Liberians with both N. americanus and A. N. a men'can us infections. As shown in Table duodenale. As shown in Table 1, the egg 1, the 300 mg of phenylene-diisothiocyanate reduction rate was 81 % for the group ; 99 % (approximately 2 mg/kg weight) reduced the for A. duodenale and 65 % for N. america egg-count by 77%. Despite their light infe nus. Eighty-one % of A. duodenale infections ction, none of the 4 cases of A. duodenale but none of N. americanus infections were infections was "cured". However, the "cured". Therefore, on the whole, none "cure'* rate was 29% for N. americanus of the 21 Liberians infected with the two and 21% for all hookworm infections. When species was "cured" with a single dose of 200 mg of this drug were given in 2 doses bephenium hydroxynaphthoate. (approximately 3 mg/kg weight) for 16 Libe- When a combined dose of tetrachlore rion children at 12 hour interval, as shown thylene and bephenium hydroxynaphthoate in Table 1, the egg reduction rate was was given to 18 Liberians infected with both improved to 92%. The "cure" rate was N. americanus and A. duodenale, as shown improved to 44 % for Ar. americanus, 36 % in Table 1, the egg reduction rate was raised for A. duodenale and 19 % for all hookworm to 96 % for the group ; 93 % for N. america?ius infections. The above two groups equally and 98 % for A. duodenale. And the " cure " received approximately 6 mg/kg of phenylene- rate was also raised to 17 % for the group ; diisothiocyanate as the total dose. However, 22%) for N. americanus and 78% for A. the egg reduction and "cure" rates in the duodenale. second group which received the approxima A single dose of piperazine citrate (ap tely 3 mg/kg (single dose) were apparently proximately 63-100 mg/kg weight) was given higher than those in the first group which to 7 cases with N. americanus and A. duo-

( 90) 527 deiude, and to 1 case with A. duodenale. In Taiwan a single dose of bephenium As shown in Table 1, even the single dose hydroxynaphthoate (2.5 gm base for adults of piperazine citrate caused an egg reduction and children), usually caused a 90% or more as high as 82%, although none of the 8 egg reduction and a 50 % or more "cure" cases became negative. The egg reduction rate. The "cure" rate among the lightly- rate for the two hookworm species showed infected groups (below 2,000 EPG) was ap no signifference, but 25% of A. duodenale parently greater than that of the heavily- was "cured'. Further investigations should infected group. For treatment of schoolchl- be made to confirm the efficacy of piperazine dren infected with both A. duodenale and derivatives against hookworm. N. anierica?ius, one or two reduced doses of bephenium hydroxynaphthoate (1.25 gm base) Discussion proved to be as effective as those with the

The therapeutic efficacy and the side ef 2.5 gm dosage. The reduced dose could fects of 8 anthelmintics evaluated by the produce 86 to 99 % reduction of the egg-count author and his co-workers during the last but the "cure " rate varied from 27 to 96 decade may be compared and discussed as %. The variation might be chiefly due to below : difference in the ratio of N. americanus to As shown in Tables 2-6, when given writh A. duodenale in the worm burden. one or two doses a day without purgation, Bephenium hydroxynaphthoate has a bitter l-bromo-2-naphthol (Wormin), tetrachlore- taste, yet it is acceptable to both children thylene, bephenium hydroxynaphthoate (Al- and adults. Daily doses sf 2.5 gm (base) for copar), and phenylene-diisothiocyanate (Jonit) 5 to 7 days caused dizziness, nausea, vomiting, were found to be more effective than the abdominal discomfort, diarrhea and headache rest. The patients in Taiwan best tolerated in children. These side effects were of suf l-bromo-2-naphthol and complained of con ficient severity and frequency to limit the siderable side effects due to other drugs. use of the therapeutic regime in mass therapy. As shown in Tables 2-3, bephenium hydro When the dosage was reduced to 1.0 to 1.5 xynaphthoate was effective against both A. gm of the compound twice daily for 2 days duodenale and N. americanus but it showed or 2.5 gm twice daily for 1 day, the side a special efficacy against the former species. effects were greatly reduced and consisted of

Table 2 The therapeutic efficacy of Bephenium hydroxynaphthoate (BH), for schoolchildren and adults, published by Hsieh et al. from 1960 to 1970 in Taiwan and Liberia

Egg Authors Dosage Cases Method of "Cure" rate reduction (year) (base) studied evaluation rate (%)

# Hsieh et al. BH, 2.5 gm once 6 Ad>Na: 83 100 MTFC & Stoll (1960) daily for 7 days

Hsieh et al. BH, 2.5 gm once 48 Ad 58 93 rr (1961)

// (59 Ad>Na 28 91 it

// // 69 Ad 78 — MTFC

// tr 69 Na 19 — ft

Hsieh et al. BH, 1.25 ro 2.5 21 Ad>Na 0 81 MTFC & Sto-i

(1970)* gm once Ad 81 Na 0

* Table 1 in this paper * Ad>Na : more Ad than Na

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Table 3 The therapeutic efficacy of Bephenium hydroxynaphthoate (BH), for schoolchildren, published by Hsieh et al. from 1960 to 1970, in Taiwan

Egg Authors Dosage Cases Method of " Cure " rate (%) reduction (year) (base) studied evaluation rate (%)

% Hsieh et al. BH, 2.5 gm once 9 Ad>Na : 100 100 MTFC & Stoll (1960) daily for 5 days

it BH, 1-1.5 gm twice 17 Ad>Na: 64 100 a daily for 2 days

n BH, 2.5 gm twice 23 Ad>Na: 74 99 ii daily

Hsieh et al. BH, 1.25 gm once 54 Ad: 89 97 n (1961)

// BH, 1.25 gm twice 47 Ad>Na: 96 99 ii

n BH, 1.25 gm once 33 Ad>Na : 70 86 ii

n BH, 1.25 gm twice 33 Ad>Na: 79 96 !?

ii BH, 1.25 gm once 33 Ad>Na: 27 89 /; Ad: 85 Na: 27

ii BH, 1.25 gm twice 33 Ad>Na : 58 95 II Ad': 97 Na: 58

Hsieh et al. BH, 1.25 gm once 296 Ad>Na : 80 93 fl (1965)

% Ad>Na : more Ad than Na only occasional vomiting and headache, diar "cure" rate-of 81% with 72% of side ef rhea and abdominal discomfort. All side ef fects and tetrachlorethylene 91 % with 71 % fects quickly subsided when the drug was of side effects. The anthelmintic efficacy discontinued. Yokogawa et al. (1962) reported was evaluated by concentration method. The that side effects due to bephenium hydro incidence of side effects due to tetrachlore xynaphthoate occurred in 34.9 % of 149 scho thylene observed by Hsieh in this paper was olchildren treated in Japan but they are also higher than that reported by Fan et al. (1956). transient. Approximately 80% of the people receiving As shown in Table 4, tetrachlorethylene tetrachlorethylene showed one or more of was also effective against the two hookworm the following side effects : dizziness, nausea, species among Chinese and Liberians, but it vomiting, headache, drunkenness, and abdo was more active against N. americanus. A minal pain. About one per 100 persons trea single dose of this drug (0.1 mg/kg weight) ted showed apprehensive emotional reactions. caused a 67 % reduction ih the egg-count When bephenium hydroxynaphthoate were and a 33% "cure" rate among schoolchil combined for the treatment of A. duodenale dren in Taiwan. The Taiwan result gave a in association with N. americanus, the rem lower removal rate of N. a?nericanus with oval rate was greater than that with a single tetrachlorethylene viewed in the light of the dose of each drug. The side effects due report of Carr et al. (1954), who removed to the combined dose was also greater than 92 % of N. americanus from a large group those with the separate dose. However, the of adults with a single dose of the same side effects were tolerated. drug. Fan et al. (1956) reported their result As showh in Table 5, l-bromo-2-naphthol of hookworm treatment that astin (active which was developed and mostly used in principle of oleum chenopodium) gave a Japan was observed to be another useful anti-

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Table 4 The therapeutic efficacy of Tetrachlorethylene (TCE) and its combination with Bephenium hydroxynaphthoate (BH), published by Hsieh et al. from 1960 to 1970, in Taiwan and Liberia

Egg Authors Dosage Cases Method of " Cure " rate (%) reduction (year) (base) studied evaluation rate (%)

Hsieh et al. TCE 2 ml & BH, Ad>Na 22 MTFC & Stoll (1961) 2.5 gm once for Ad 89 adults Na 22

TCE 5 ml & BH, Ad>Ma 67 100 2.5 gm once for Ad 67 adults Na 100

TCE 0.1 ml/kg & 18 Ad>Na 94 99 /' BH, 1.25gm once Ad 94 for children Na 100

Hsieh et al. TCE 0.2 ml/year 190 Ad &Na 16 — MTFC (1960) of age up to 3 mi as the maximum dose

51 Ad&Na 16 55 MTFC & Stoll

Hsieh et al. TCE 0.1 ml/kg 33 Ad &Na 33 67 /' (1961) for children Ad 39 Na 70

Hsieh TCE 0.07-0.11 18 Ad

gm once Na 99

* Table 1 in this paper (study in Liberia) % Ad>Na : more Ad then Na hookworm drug. The comparative anthelm- clinical trial (4gm base of " Wormin " gra intic effects of l-bromo-2-naphthol against nules as the adult dose twice at 10 hour A. duodenale and N. americanus were made interval) made by Hsieh et al. (1960 a, 1965) by Matsuzaki (1957), Yamazaki (1955), Yo- in Taiwan indicated that this drug reduced shida etal. (1960), Hsieh et al. (1960 a, 1965). from 75 to 86% of the egg-count, and Matsuzaki (1957) and Hsieh et al. (1960 a, "cured" from 39 to 58% of the patients 1965) reported that this drug is more effective infected with A. duodenale and N. americanus. against N. americanus than A. duodenale Hsieh et al. (1965) later treated 143 children although Yoshida et al. (1960) reported that with 2 or 3 gm base of l-bromo-2-naphthol this drug is almost equally effective against once a day for 2 consecutive days. The initial both species of hookworm in man. The treatment reduced 92 % of the eggcount evidence obtained by Hsieh et al. (1960 a, and "cured" 58% of hookmorm infections, 1965) as to the efficacy of l-bromo-2-naphthol who were predominantly infected with A. against A. duodenale and N. americanus is duodenale. This regimen was repeated every in full agreement with earlier data reported other month for about one year and the egg by Yamazaki (1955). It might be safely reduction rate was maintained at a low level, mentioned that l-bromo-2-naphthol is effective although the "cure" rate varied from 75 to against both species of hookworm but more 90%. Children tolerated well repeated doses effective against N. amei'icanus. Komyia & of l-bromo-2-naphthol. Approximately 25 % Kobayashi (1963) recommended that a single of the people who received l-bromo-2-naph- dose of 6 gm of this cmpound (9 gm of thol showed one or some of the following '* Wormin" granules) is the best in mass tolerable side effects : abdominal pain, nausea, treatment of N. americanus. The results of a dizziness and headache.

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531

Table 6 The therapeutic efficacy of Phenylene-diisothiocyanate (PD) and Thiabendazole observed among Chinese and Liberians by Hsieh or Hsieh et al. from 1960 to 1970.

Authors Dosage Cases Egg Method of " Cure " rate (%) reduction (year) (base) studied evaluation rate (%)

Hsieh el al. PD 100 mg thrice 30 Ad>Na: 47 98 MTFC & Stoll (1970) at 12 hour inte Ad: 47 rval for adults Na: 100

Hsieh // 14 Ad>Na: 21 77 rt (1970)* Ad: 0 Na: 29

Hsieh PD 100 mg twice 16 Ad>Na: 19 92 ft (1970)* at 12 hour inte Ad: 36 rval for school Na: 44 children

Hsieh PD 50 mg twice 6 Ad>Na: 0 63 tt (1970)* at 12 hour inte Ad: 0 rval for school Na: 0 children

Hsieh PD 50 mg once 5 Ad>Na: 0 68 tt (1970)# for schoolchil Ad: 0 dren Na: 20

Hsieh Thiabendazole 50 23 Ad: 39 62 tt (1963)n mg once for adults

tt // 41 Ad>Na: > 33 ft

tt Thiabendazole 25 7 Ad>Na: 71 97 tt mg twice a day for 2 days for adults

ft Thiabendazole 25 10 Ad>Na: 100 100 tt mg twice a day for 3 days for adults

Table 1 in this paper (study in Liberia) Unpublished data from Liberia Unpublished data from Taiwan countries like Liberia, where people used to against N. americanus than against A. duo- believe manifestation of side effects due to denale. A single dose of 50 or 70 mg/kg drugs as an indication of effective medicines, weight yielded 81 or 96 % reduction of the this anthelmintic might be useful. The egg-count respectively. HowTever, the severe •commonest side effects due to 3 doses of 100 side effects due to the drug made it very mg for 30 adults in Taiwan were anorexia, unpopular. The commonest side effects were diarrhea, abdominal fullness, nausea, malaise dizziness, abominal pain and vomiting. and vomiting etc. They were however well Stilbazium iodide was found by Swartzwe- tolerated. The commonest side effects com lder et al. (1962) that a significant anthelm plained of by Liberians were diarrhea and intic against E. vermicularis, A. lunbrlcoides, vertigo, and their severity and frequency T. trichiura and S. stercoralis. Hsieh et al. were apparently milder than those complained (1963 a) confirmed the anthelmintic activity of by the Chinese. of this drug against K.vermicularis, A. lum- As shown in Table 5 trichlorophenol pipera- bricoides and T. trichiura, and also reported (Hsieh et al., 1963 c) was more effective excellent results against F. buski and moderate

( 95 ) 532 efficacy against .4. duodenale (62 % of the diisothiocyanate (approximately 3 mg/kg wei egg reduction). Huang and Brown (1964) ght) caused a 92 % egg reduction and a 19 further confirmed the moderate efficacy of % "cure" rate, which was close to that this drug against A. duodenale and N. ame- due to the combination of tetrachlorethylene ricanus. They evaluated the efficacy by the with bephenium hydroxynaphthoate. smearing, flotation and Stoll dilution egg When the therapeutic efficacy of bephenium count methods. Vomiting and abdominal hydroxynaphthoate, tetrachlorethylene, their discomfort wTere common among those who combination, and phenylene-diisothiocyanate received 300 mg base twice daily on 3 conse against hookworm were compared among the cutive days, but no other side effects were groups in Taiwan and Liberia with similar complained of by the patients. methods for evaluation, the Taiwan groups As shown in Table 5, a single dose of generally showed better results than the piperazine citrate (63-100 mg/kg), which is Liberian groups. On the other hand, the also useful for the mass treatment of A. lumb- Chinese complained of more side effects due ricoides, produced 82 % reduction of the egg- to anthelmintics than the Liberians. count for hookworm and the "cure' rate Two general approaches to the control of for N. americanus and A. duodenale was 0 hookworm infections are known. One method or 25 % respectively. consists in prevention of new or additional Thiabendazole, as shown in Table 6, was infection, the other in treatment of existing confirmed to be an effective drug for ho infections. The first approach resolves itself okworm. When 25 mg/kg of this drug was largely into the improvement of sanitary given twice a day for 2 or 3 days against conditions with conditions with consequent mixed infections of N. americanus and A. elimination of soil pollution until effective duodenale, the result showed 97 or 100% of vaccination can be developed, while the the egg reduction and 71 or 100% "cure ''. second approach necessitates the use of Franz (1963) reported the therapeutic efficacy anthelmintics. The first approach is unive of thiabendazole against S. stercoralis. This rsally recognized as the one of choice, and anthelmintic might be a choice of drug for the only method which can be depended the patients infected with both S. stercoralis upon to bring permanent relief. But simple and hookworm. A single dose regimen of as it seems in theory, it is no easy matter 50 mg/kg produced only moderate anti-ho to induce hundreds of millions of people to okworm activity in 2 groups of adults. change habits which are ingrained by coun Although transient side reactions of dizziness tless of use. Consequently sanitary reforms and nausea following administration of the are slow, requiring labor, patience and time. drug were not serious, the incidence of these The treatment method, on the othr hand, reactions was high. Huang & Brown (1963) can bring immediate relief to the individuals reported that thiabendazole in the dosags of involved, but to have any prolonged effect it 2 gm, approximately 40 mg/kg, as a single must be applied to the majority of a group dose for 1 day in adult patients has a mode all at once in the form of a mass treatment, rate anthelmintic activity against both A. and must be repeated at intervals. The duodenale and N. americanus as judged by benefits of mass treatments can be better egg-count reduction. demonstrated on estates, plantations, and For the treatment of the mixed infection isolated islands of regions. of N. americanus with A. duodenale, a single For the mass treatment of hookworm in dose of tetrachlorethylene in combination the endemic area, simple medication is always with bephenium hydroxynaphthoate could advisable. For this reason, the use of one improve the egg reduction and " cure " rates dose of tetachlorethylene, and bephenium especially against N. americanus. However, in hydroxynaphthoate, or 2 doses of l-bromo-2- the Liberian groups two doses of phenylene- naphthol, and phenylene-diisothiocyanate mi-

( 96 ) 533 ght be recommended until cheaper and less compared with those of bephenium hydro- toxic drugs could be developed. The egg xynaphthoate (Alcopar), tetrachlorethylene, reduction rate of these anthelmintics was combination of bephenium hydroxynaphthoate found to be considerably high against both and tetrachlorethlene, and piperazine citrate A. duodenale and N. americanus, although in Liberia, West Africa. The result was their "cure" rate against each species was further compared with results of 8 anthelm different and the frequency of side effects intics evaluated by the author and his co- complained of by the patients were not workers in Taiwan during the last decade. uncommon. 2. Among the 8 anthelmintics against Emphasis is made that administration of endemic hookworm, one dose of tetrachlo one or two doses of these selected anthelm rethylene (0.1 ml/kg weight) or bephenium intics at a reasonable interval has demon hydroxynaphthoate (1.25 gm base for children strated to be useful for bringing the worm and 2.5 gm base for adults) or 2 doses of 1- burden from moderate or high level to a low bromo-2-naphthol (4gm base for adults and level with lessened clinical significance. This reduced dose for children at 10 hour interval) approach seems to be sufficient as the ma or 2 doses of phenylene-diisothiocyanate (3 jority of hookworm cases in most of the mg/kg weight at 12 hour interval) produced endemic villages in Taiwan and Liberia ap a considerably higher reduction of the egg- peared to be lightly infected and without count in spite of their different " cure " rate clinical significance. The frequency of med against A. duode?iale and N. americanus. ication and the worm burden without clinical Bephenium hydroxynaphthoate was more ef significance in each country, however, should fective against A. duodenale, but the other be determined by the nutritional condition, drugs were more effective against N. ameri

and the socioeconomical status, and the canus. endemic species as A. duodenale is generally 3. The "cure" rate of phenylene-diiso accepted to be more pathogenic than N. thiocyanate, bephenium hydroxynaphthoate americanus. and tetrachlorethylene among Chinese were Pefia Chavarria et at. (1969) reported that found to be higher than that among Liberians. cure rates of infections, with a single oral On the other hand, more side effects due to dose (12 mg/kg weight) of dichlorvos, were these anthelmintics were complained of by 85.7 % for hooeworm, 87.8 % of T. trichiura, Chinese than Liberians. and 77.8% for A. lumbricoides; egg-count reductions in the cases not completely cured Acknowledgements were 97.3, 98.5, and 83.7%, respectively. Cervoni et at. (1969) also reported that the The author is grateful to Dr. N. R. Stoll, trichuricidal action, broad-spectrum anthelm- Professor Emeritus (Parasitology) of The Rocke intic activity, and good tolerance upon single feller University ; and Dr. E. W. Reber, Deputy dosage (6 or 12 mg/kg weight) of dichlorvos. Director of the Liberion Institute of the American The relative efficacy of this drug against A. Foundation for Tropical Medicine and his staff for their advice and cooperation given to the duodenale and Ar. americanus has not been evaluation made in Liberia; and to Dr. D. G. evaluated but if the broad-spectrum anthelm- Economy of Farbwerke Hoechst AG. for his intic activity of this new drug could be constructive oriticism in respect to this paper, confirmed, it might have a place for the and his company for the supply of phenylene- mass treatments of hookwxrm and associated diisothiocyanate. Part of this investigation in helminths. Liberia was supported by USPHS Research Grant No. A 1-05775-04 through the National Institutes Summary of Health. Part of the investigations made in Taiwan was supported from the Sino-American 1. The anti-hookworm activity of phen- Joint Commission on Rural Reconstruction (JCRR) ylene-diisothiocyanate (Jonit), was recently in Taipei, Republic of China.

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13) Hsieh, H. C. (1959) : Hookworm disease in References Taiwan (in Chinese). Pao Chien Yue Kan, 1) Bibliography of hookworm disease, Publica 2, 15-17. tion No. 11. The Rockefeller Foundation 14) Hsieh, H. C, Chow, L. P. and Shih, C. C, International Health Board, New York City, (1960 a) : Mass treatment of hookworm in 1922. fections with tetrachlorethylene and 1-bromo- 2) Bozzolo, C. and Pagliani, L. (1880) : L'ane- naphthol-(2) at two rural villages in Southern mia al trafolo del Gottardo da punto di Taiwan. J. Formosan M. Assoc, 59, 53- vista igienico e clinio. Gior. d. r. Soc. ital. 59. d'ig. Milano ii, 276-346. 15) Hsieh, H. C, Brown, H. W., Fite, M., 3) Brown, H. W., Cheng, C. S., Chen, C. Y., Chow, L. P., Cheng, C. S. and Hsu, C. C. Lin, K. EL, Chang, C. R., Lee, L. T., (1960 b): The treatment of hookworm, Hsu, C. C, Chow, L. P. and Hsieh, H. C. Ascaris and Trichuris infections with (1959) : The treatment of Fasciolopsis buski bephenium hydroxynaphthoate. Amer. J. infections with dithiazanine iodide, 1-bromo- Trop. Med. Hyg., 9, 496-499. naphthol-(2), ascaridol, piperazine and tet 16) Hsieh, H. C, Yuan, J. C, Kuo, M. and rachlorethylene. J. Formosan M. Assoc, Shih, C. C. (1961 a) : Experiment on the 58, 792-798. mass treatment of ascariasis with piperazine 4) Caius, J. F. and Mhaskar, K. S. (1921) : The derivatives and combination of santonin and correlation between the chemical composi kainic acid. J. Formosan M. Assoc, 60, tion of anthelmintics and their therapeutic 341-348. values in connection with hookworm in 17) Hsieh, H. C, Brown, H. W., Chow, L. P., quiry in the Madras Presidency. 10. Bata- Cheng, C. S., Chen, C. Y., Chang, C. R., naphthol. Indian J. Med. Res. 9, 33-55. Pan, M. M., Kuo, M. and Shin, C. C. 5) Carr, P., Pichardo-Sarda, M. E. and Aude (1961 b) : Further experiments in the treat Nunez, N. (1954) : Anthelmintic treatment ment of hookworm, Ascaris, and Trichuris of uncinariasis. Amer. J. Trop. Med. & with bephenium hydroxynaphthoate. J. Hyg., 3, 495-503. Formosan M. Assoc, 60, 508-519. 6) Cervoni, W. A., Oliver-Gonzalez, J., Kaye, 18) Hsieh, H. C, Kuo, M., Chow, L. P., Cheng, S. and Slomka, M. B. (1969) : Dichlorvos C S., Chen, C. Y. and Chang, C. R. as a single-dose intestinal anthelmintic (1961 c) : A combined dose of bephenium therapy for man. Amer. J. Trop. Med. hydroxynaphthoate and tetrachlorethylene a- Hyg. 18, 912-919. gainst mixed infection of A. duodenale and 1) Fan, P. C, Hsu, J. and Liu, J. C. (1959) : N. americanus. J. Formosan M. Assoc, Survey and treatment of intestinal helminths 60, 926-937. in rural primary school children in northern 19) Hsieh, H. C, Brown, H. W., Chen, E. R., Taiwan, Free China. Chinese Med. J. 3, Chen, C. Y. and Shih, C. C. (1963 a) : 60-69. Treatment of Fasciolopsis buski, Ancylos- 8) Franz, K. H. (1963) : Clinical trials with toma duodenale, Ascaris lumbricoid.es, thiabendazole against human Strongyloidiasis. Trichuris trichiura, and Enterobius uer- Amer. J. Trop. Med. Hyg., 12, 211-214. micularis infections with Stilbazium Iodide. 9) Hall, M. C. (1921 a) : Carbon tetrachlorid J. Parasit., 49, 425-427. for the removal of parasitic worm, especially 20) Hsieh, H. C, Kuo, M., Shih, C. C, Chen, hookworm. J. Agric. Res. 21, 157-175. C. Y. and Yii, C. Y. (1963 b) : A com 10) Hall, M. C. (1921 b) : The use of carbon parative study with pyrvinium pamoate tetrachlorid for the removal of hookworm. (Vanquin) and piperazine in the mass treat J. Amer. Med. Ass. 77, 1641-1643. ment of Enterobius infection among children 11) Hall, M. C. and Shillinger, J. E. (1925) : in Southern Taiwan (Formosa). J. Formo Tetrachlorethylene, a new anthelmintic. san Med. Assoc, 62, 373-378. Amer. J. Trop. Med. 5, 229-237. 21) Hsieh, H. C, Chen, E. R., Shih, C. C, 12) Hoechst (1968) : Abstracts of Symposium on Chen, C. Y. and Yii, C. Y. (1963 c) : The Jonit (Compound 16842). Schloss Reinhart- efficacy of trichlorophenol piperazine against shausen Erbach on the Rhine, Germany. mixed infections of Ancylostoma duodenale April 1 and 2, 1968. and Necator americanus, and Ascaris lumb-

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ricoides. J. Formosan M. Assoc, 62, 457- an anthelmintic for hookworm. Shinyaku 463. to Rinsho, 6, 112-114. 22) Hsieh, H. C. (1963 a) : Clinical trials on 35) Miura, K., Ikeda, M., Ohashi, T. and thiabendazole against hookworm in man. Yasuda, S. (1953) : Studies on anthelmintic Unpublished. Part 4. Anthelmintic efficacy of halogenat- 23) Hsieh, H. C. (1963 b) : A test-tube filter- ed naphthalene compounds for the worm in paper method for the diagnosis of Ancylos- the toad. Juzen Igakukai-Zassi, 55, 577- toma diwdenale, Necator americanus and 583. Strongyloides stercoralis. WHO Techn.Rep. 36) Pena Chavarria, A., Swartzwelder, J. C. Ser. No. 255, 27-30. Villarejos, V. M., Kotcher, E. and Arguedas, 24) Hsieh, H. C. and Chen, E. R. (1965): J. (1969) : Dichlorvos, an effective broads- Recent studies on hookworm control in pectrum anthelmintic. Amer. J. Trop. Med. Taiwan : The use of anthelmintics. J. Hyg. 18, 907-911. Fromosan M. Assoc, 64, 367-374. 37) Perroncito, E. (1879-1880) : Observazioni 25) Hsieh, H. C, Chen, E. R. and Wu, Y. T. elmintologiche relative alia mallattia svilup- (1965) : Some investigation on the control patasi endemica fra gli operai del Gottardo- of ascariasis with piperazine among Atti d. r. Accad. dei. Lincei. Roma, ser, 3, schoolchildren. J. Formosan M. Assoc, Trans, iv : 179-184. 64, 587-590. 38) Stoll, N. R. (1962) : For hookworm diag 26) Hsieh, H. C, Chen, C. Y., Yii, C. Y., Chen, nosis is finding an egg enough? Ann. N. M. H. and Hong, J. M. (1970) : The the Y. Acad. Sci., 98: 712-724. rapeutic efficacy of phenylene-diisothiocyanate 39) Swartzwelder, J. C, Frye, W. W., Muhlei- (1,4) against duodenale and N. americanus sen, J. P., Miller, J. H., Lampert, R., in Taiwan. J. Formosan M. Assoc, 69, Chavarria A. P., Abadie, S. H. Anthony, 405-410. S. O. and Sappenfield, R. W. (1957): 21) Hsieh, H. C. (1970) : Endemic hookworm Dithiazanine, an effective broad-spectrum in Liberia : 2. Combining MTFC and Stoll anthelmintic J. Amer. Med. Assoc 165, dilution egg counting for species analysis, 2063-2067. (in press) 40) Swartzwelder, J. C, Miller, J. H., Lampert, 28) Huang, W. H. and Brown, H. W. (1963) : R., Pena-Chavarria, A., Abadie, S. H., Frye, The efficacy of thiabendazole against hook W. W., Muhleisen, P. and Lizano, C. (1962) : worm and Ascaris of man. J. Parasitol., Anthelmintic activity of stilbazium iodide 49, 1014-1018. (Monopar) against intestinal nematodiasis of | 29) Huang, W. H. and Brown, H. W. (1664) : man. J. Parasitol., 48, 29-30. Clinical trial of Stilbazium iodide (Monopar) 41) The Bibliography of Hookworm Disease in the treatment of Trichuris and Ascaris (Ancylostomiasis). World Health Organiza infections. Amer. J. Trop. Med. Hyg., 13, tion, Geneve, 1965. 54-56. 42) Vervoort, H. (1913) : Oleum chenopidii [ 30) Komiya, Y. (1958) : Hookworm and hook anthelmintici, een wormmiddel tegen anky- worm disease, Page 56-74 Sekibundo Publica lostomum en ascaris. Geneesk. Tijdschr. tion Company LTD. Tokyo. Nederl.-Indie, Batavia. liii, 435-446. ' .31) Komyia, Y. and Kobayashi, A. (1963) : 1- 43) Yamasaki, H., Mannami, C. and Takaoka, bromo-2-naphthol (" Wormin "), an anthel T. (1954) : Patentiation of anthelmintic mintic developed and used preferably in efficacy by the combination of Alkylresorci- Japan for the mass treatment of hookworm nols. Jap. J. Pharmacol. 4, 52-61. infections. WHO/Helminth/51. 44) Yamazaki, T. (1955) : Treatment of hook 32) Lee, Y. S., Chen, C. Y. and Hsieh, H. C. worm disease with l-bromo-naphthol-(2). (1969) : A clinical trial of Hetol in the Shinyaku to Rinsho, 5, 482-487. treatment of Clonorchiasis sinensis. J. 45) Yokogawa, M., Yoshimura, H., Sano, M. and Formosan M. Assoc, 68, 158-162. Inasaka, Y. (1962) : Studies on the anthel 33) Maplestone, P. A. and Mukerji, A. K. mintic effect of bephenium hydroxy- (1932) : Hexylresorcinol as an anthelmintic naphthoate (Alcopar) on mass treatment of Indian Med. Gaz. 67, 610-612. school-children. Jap. J. Parasit., 11, 126- 34) Matsuzaki, Y. (1957) : l-bromo-naphthol-(2), 132.

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46）Yoshida,Ｙ､，Nakanishi,Ｙ､，Shimatani,Ｔ・and naphthoate， tetrachlorethylene， l-bromo‐ Matsuo，Ｋ・（1960)：Comparativestudieson naphthol-(2) and4-iodothymolagainsthuman theanthelminticeffectofbepheniumhydroxy‐ hookworm． Jap．Ｊ・Parasit.，9,620-628.

地方病性鉤虫に関する研究： 2．台湾およびリベリヤにおける駆虫剤の比較研究＊〔特別掲載〕

謝献臣 (高雄医学院寄生虫学科中華民国台湾省高雄市）

‘`治癒率,，が高くて副作用少く且つ経済的な駆虫剤７．trichlorophenolpiperazine を求める研究は地方病性鉤虫の防逼に関する諸研究の中８．thiabendazole でも依然として重要な－項である．著者は約１０年間台これらのうちの１から４までの４種駆虫剤は両種の鉤湾と熱帯アフリカのリベリヤ共和国において鉤虫に対し虫に対する“治癒率，’は同一ではないがリベリヤと台て種々の駆虫剤を比較研究する機会に恵れた，“治癒', 湾両地において１回乃至２回の投与法で８０％又はそれの判定には始めは原田･森濾紙培養法後には著者の考案以上のＥＰＧ減少率が得られたので大幅のＥＰＧ減少をした試験管濾紙培養変法ＭＴＥＣとストール氏虫卵計算ねらう集団治療作業には有用である．ゾピニ鉤虫優先分法を併用した．ＥＰＧの減少率はストール氏法を採用し布の台湾では駆虫効果の点からはbepheniumhydrox‐ た． ynaphthoateが好ましいが，l-bromo-2-naphtho］をの本文では最初にリベリヤにおける実験成績を報告したぞけば他の駆虫剤も|可様であるが，bepheniun1hydro‐ 後台湾成績と比較考察した．実験に供した鉤虫駆虫剤は xynaphthoateに対して副作用を訴へるものが多かっ次の８種である．た．リベリヤの如きアメリカ鉤虫優先地ではtetrachlo‐ Lphenylene-diisothiocyanate（１，４） rethyleneが高い駆虫効果と薬価の低い点から好まし２．bepheniumhydroxynaphthoate い．phenylene-diisothiocyanate或いは１－bromo-El‐ atetrachlorethylene naphtholもよいが，鉤虫と糞線虫の混合感染がしばし４．１－bromo-2-naphthol ばみられるリベリヤの場合はthiabendazoleが良い．リ５．piperazinecitrate ベリヤでの少数例についての実験では意外にもpipera‐ ６．stilbaziumiodide zinecitrateが高い鉤虫のＥＰＧ減少率を上げた，一般

＊本研究の一部はＮＩＨ(ＵＳＡ）と中国農村復興奥委的にいってリベリヤ黒人は中国人より諸種の駆虫剤に対員会の補助によって行なはれた．記して謝す．して副作用を訴へるものが少いことが注目された．

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