Albendazole chemotherapy for human cystic and alveolar echinococcosis in north-western China

340 TRANSACTIONS

OF THE ROYAL

Albendazole north-western

SOCIETY OF TROPICAL

chemotherapy China

MEDICINE

AND

HYGIENE(1994) 88, 34&343

for human cystic and alveolar

echinococcosis

in

Wen Hao1a2, Zou Pei-Fan’, Yang Wen-Guang’, Lu Jian’, Wang Yun-Hai ‘, Zhang Jing-Hui’, Roger R. C. New3 and Philip S. Craig2 ‘Department of Surgery, Xinjiang Medical College, Urumqi 830000, Xinjiang, China; 2Department of Biological Sciences, University of Salford, Salford, MS 4WT, UK; 3Cortecs Research Laboratory, The School of Pharmacy, University of London, 29130 Brunswick Square, London, WCIN IAX, UK Abstract

Human echinococcosisis highly endemic in north-western China; the main treatment is by surgery. In this naner. we renort the results of chemotheranv with albendazole (ABZ). 15-20 rng/kg/d orallv. for 30 d with $t&&ls of i0 d between treatments for 3-&courses. For multi-brgan cystic ecl&oFoccosis ICE) and alveolar echinococcosis (AE), patients were given 12-18 coursesof ABZ. Patients were divided into 4 groups: (i) ABZ surgery group, albendazole with surgery for 21 CE cases:(ii) non-ABZ surgery group, 80 CE cases treated by surgery alone; (iii) ABZ CE group, albendazole treatment alone in 58 CE cases,and (iv) ABZ AE group, 14 AE patients treated by albendazole and surgical intervention and 5 AE patients treated by albendazole alone. Twenty-seven of 34 (79.4%) cysts in group (i) patients showed increased necrotic changesand decreasedviability of the cysts compared to group (ii). However, 10 of 84 (11.9%) cysts in group (ii) patients showed spontaneous evidence of necrosis at surgery. In group (iii), ABZ treatment alone was successful in 14 (24.1%)1,resulted in improvement in 29 (50%) and had no effect in 15 (25.9%) patients. Seven casesin group (iv) improved, with diminished size of lesions which were non-viable. The remaining 7 casesin group (iv) showed evidence of cyst viability at surgery; 2 could not be saved after a further 15 courses of albendazole. Of the five AE patients in group (iv) who received only ABZ, one improved, 2 stabilized, one deteriorated and one died. Albendazole chemotherapy, while not completely effective, has an important role in treatment of both cystic and alveolar echinococcosis. Introduction

Cystic echinococcosis (CE), causedby a larval stageof Echinococcus granulosus, is cosmopolitan in distribution, with greatest endemicity in north-western China, parts of South America, East Africa, the Middle East, Australasia, central Europe, central Asia and the Mediterranean littoral (MATOSSIANet al.. 1977). Alveolar echinococcosis (A@, caused by a larval stag&of E. multilocularis, is restricted to the northern hemisphere, with higher prevalence in Alaska, central western Europe, Siberia, Japan and China iGEMMELL etal., 1987; CRAIG et al., 1991).E. granulosus grid E. multilo&laris &cur sympatricalfy in north-west China, where CE is most widespread and is a major public health problem in several central and northwestern nrovinces. The first CE case was renorted in China in-1905 (CHI et al., 1990), while the first AE patient was described much later, m 1965 (YAo, 1965). At present, surgery is still the main form of treatment for human echinococcosis in most endemic areas, including China, commonly involving removal of the endocyst or partial hepatectomy for CE patients. The surgical treatment of AE cases is usually more difficult (VUITTON, 1990; ZOU et al., 1992). Effective anti-hydatid drugs would be of great benefit, becausesurgery for recurrent or complicated hydatid cases,such as those with multiple foci and multi-organ foci, is only a tentative treatment and often results in further recurrence, and even death. Benzimidazoles, especially mebendazole, have been used in the treatment of human echinococcosis since the mid 1970s(BEKHTI et al., 1977; BRYCESON et al., 1982; SAIMOT et al., 1983; AMMANN et al., 1988). Albendazole appears to be more soluble than other benzimidazoles and has an active primary metabolite, albendazole sulphoxide (BOGAN& MARRINER,1980; WEN et a&, 1993). Chemotherapy with albendazole for human cystic and alveolar echinococcosis has become more frequently used, with significant success(DAVIS et al., 1986, 1989; WILSON et al., 1987,1992; HORTON, 1989; WEN et al., 1990; TODOROV et al., 1992a; LIU et al., 1993). In this paper, we report the results of chemotherapy with albendazole for CE in patients who also received surgery, compared with 80 CE casestreated by surgery alone. Fifty-eight CE patients, who were either inoperable or unwilling to be operated on, were also treated with albendazole. In addiAddressfor correspondence: Dr H. Wen, Departmentof BiologicalSciences,University of Salford,Salford,M5 4WT, UK.

tion, the results of albendazole treatment of 19 AE patients are reported. Methods Patients and albendazole treatment

One hundred and fifty-nine CE patients and 19 AE caseswere identified on the basis of clinical manifestation, imaging techniques (ultrasound and computerized tomography [CT]), immunodiagnostic tests (indirect haemagglutination test and counter immunoelectronhoresis) a$, in some cases, by surgery and histopathblogy. A basic chemotherapeutic course consisted of oral albendazole twice dailv for 30 d with an interval of 10 d between courses. Childien (under 12 years old) and older patients (aged over 60 years) were given 400-800 mg albendazole daily, and adults 15-20 mgikgid with a maximum of 1200 mg daily for 3-6 courses. Regular follow-up of patients was undertaken by physical examinatio?, blood and urine profile, liver and kidney function, imaging techniques (mainly ultrasonography with someCT scans) and chest X-ray once per course. Hydatid patients were divided into 4 groups, as follows. (i) ABZ surgery group. Twenty-one hepatic CE patients, with a total of 34 cysts (including multiple cysts), volunteered for albendazole treatment combined with surgery; 10 were male and 11 female, with agesbetween 3.5 and 64 years (average 23 years). The patients received 3 courses of albendazole, followed by an operation. Concentrations of albendazole sulphoxide in the plasma, bile and cystic fluid were measured by high performance liquid chromatography in 12 CE patients as described previously (ZHANG & WEN, 1989). (ii) Non-ABZ surgery group. Eighty CE cases with a total of 111 cvsts (including multinle cvsts) were treated by surgery alone;’ 38 weremales-and “42 iemales, with ages between 2.5 and 66 vears iaveraee 25 vears‘i. The bisic criteria for assessing’anti-dydati& effeits w&e the endocyst collapse rate, histopathological changes in the cysts,. protoscblex viability, and pathological changes. Pathological changes were subdivided into 3 categories: appearance of normal structure of germinal an& laminated layers, degeneration of germinal and laminated layers, and necrosis of germinal and laminated layers. (iii) ABZ CE group. This inoperable group consisted of 58 hepatic CE cases,an equal number of male and female patients with an age range between 6 and 63 years (average 33 years); they included 7 complicated cases

341 with multiple cysts in the organs and abdominal cavity, who were given 12-18 courses of albendazole. In the absenceof surgery chemotherapeutic effects were evaluated as (i) successful, if clinical symptoms and signs disappeared, or were markedly alleviated, if hydatid cysts became fibrotic, solid and calcified, or were shown to disappear by ultrasonograhy or CT scan; (ii) improved, if clinical symptoms and signs were alleviated gradually, if cyst size diminished by at least 2 cm on ultrasound or CT scan, and/or the cysts were partially calcified, and (iii) no effect, if clinical manifestations were aggravated and the size and shape of the cysts did not change, or even increased. (iv) ABZ AE group. Nineteen AE cases,including a rare case of mixed CE and AE in the liver (WEN er al., 1992): ,, 13 were male and 6 female, with aaesbetween 15 and 56 years. Fourteen AE cases’wereg&en pre-operative treatment with ABZ for 3-12 weeks, followed by surgery to evaluate its efficacy, and 3-15 coursesas postsurgical treatment. Evaluation of albendazole therapv was based on the gross morphology and pathological characteristics of surgically excised lesions and on inoculation of excised material into mice for viability assessment. The basic surgical techniques used were radical hepatectomy, partial hemihepatectomy with surgical drainage, and tentative surgical drainage depending upon the focus size and location. Five of the patients had albendazole alone for 12-18 courses. In those patients who were unsuitable or unwilling to be treated by surgery, chemotherapy was the only option. All of the CE and AE patients have been followed up for 3-7 years. Statistical analysis

Rates and means of differences between treated and control groups were compared by Student’s t test and the x2 test. Pathological changes of the cyst wall in 4 groups were assessedby an identified distribution unit (RIDIT) analysis (P
TICS,

THE

FIRST

SHANGHAI

MEDICAL

UNIVERSITY,

1979). Results Clinical findings Groups (i) and (ii). The results are summarized in

Table 1. Rates of endocyst collapse and necrotic pathological changes in the ABZ surgery group were significantly higher than those in the non-ABZ surgery group (P
22

12

17 (77%)

Surgery only Multiple Simple daughter cyst cysts 84

27

13 (15%)

-

Protoscolex Infectivity”xh Mean viability”,‘ Cyst wall pathology Normal” Degenerating Necrotic

l/13 (8%) 5%


717(100%) 82%

34%

0 5 (32%) 17 (77%)

0 2 (17%) 10 (83%)

37 (44%) 37 (44%) 10 (12%)

3 (11%) 11 (41%) 13 (48%)

“Differences between albendazole and non-albendazole groups significant (P
Table 2. Results of albendazole able cystic hydatid patients

chemotherapy

in 58 inoperNo

Successful Improvement

effect Total

Cyst type

Single 5 (20%) Multiple 6 (33%) Multiple daughters Total 1i i:iz${0

29 (50%)

15 (26%)

58

Chemotherapy was successful in 14 cases (24.1%), resulted in improvement in 29 cases(50%) and had no effect in 15 cases(25.9%). Group (iv). Seven of the AE patients treated by ABZ and surgery showed improvement, with hydatid masses diminished or disappeared, jaundice subsided, and appetite and enerev regained. The AE massesof these Datients were m’;‘st pkbably inactive or non-viable, judged by pathology and viability assaysin viva, as previously reported in Alaskan AE patients (WILSON et al., 1987). The remaining seven AE cases,whose excised parasitic massesat surgery were still viable, continued to receive albendazole for 615 more courses. Of these 7 cases, 4 were stabilized while 3 deteriorated with both lesion develoument and accomnanving iaundice. Two of these AE casesdied. The 5 Ae p&e& treated with ABZ alone had varied responses including one patient who improved, 2 who stabilized, one who deteriorated, and one who died. In total, therefore, 3 AE patients died: one patient died within 12 months from post-operative complications, which included hepatic failure and secondary infection of the biliary system; the other 2 cases deteriorated and died within 3 years from poor appetite, diarrhoea, malnutrition, fever, jaundice and hepatic failure. Clinical side-effects of albendazole

Follow-up of the 79 CE and 19 AE patients with adequate doctimentation demonstrated that 18 patients 118.4%) comnlained after oral administration of ABZ. *he main side-effects were gastrointestinal symptoms (diarrhoea, nausea, abdominal pain, vomiting), in 13 cases.Serum transaminase levels were increased initially in 8 patients but returned to normal levels within 3 weeks. Central nervous system symptoms (dizziness, headache)and rash or pruritus developed in 3 cases,one of wh,m was withdrawn with intolerable itch after one week of ABZ therapy. No significant abnormality was detected by haematology or urinalysis during the followup period of 3-7 years. Discussion

In the last few years, an increasing number of CE patients has been treated by albendazole chemotherapy with encouraging results (DAVIS et al., 1986, 1989; HORTON, 1989; WEN et al., 1990; WILSON et al., 1992; LIU et al., 1993). The evidence for an effect of benzimidazoles in CE caseshas usually been basedon individual patients in relation to regression of hydatid cyst size and shape, change in cyst wall structure, or examination of protoscolex activity before and after chemotherapy. We have compared a group of CE patients treated by combined ABZ (3 courses) and surgery with another group of CE patients who underwent surgery alone without chemotherapy. There were significant differences in the endocyst collapse rate, protoscolex viability (mouse infectivify and e&in uptakk) and histopathological changesin the cvsts between the 2 ErouDs(Table 1). The rates of endocyst collapse assessedY by-ul&asound and the proportion of necrotic cysts assessedby histopathology were very similar, suggesting that the 2 techniques may be detecting the same phenomenon. The observation that 11 of 84tE cysts had necrosed spontaneously in the nonABZ surgery group indicated the danger of identifying a chemotherapeutic effect in a small number of caseswith-

342 out comparison with a control group not receiving drug

(GIL-GRANDEet al., 1993). Drug concentration in cystic fluid appeared to be a more reliable indicator of efficacy than that in plasma or bile. Better clinical responses were obtained from patients with ABZ sulphoxide levels in

cvstic fluid >SOO &L;

responses were noor if levels

were <300 &L. ’Oral ABZ was successful in treating

14 of the 58

inoperable CE cases.The hydatid cysts were affected to varying degrees in different

individuals.

Some smaller

cysts in the abdominal cavity or liver disappearedrapidly and completely, while the larger ones either diminished in size or increased in density. Our observations supported those of TODOROVet ~2. (1992b), that cyst size, wall thickness, and location affected the successof chemotherapy. In our experience, better results were obtained with smaller. thin walled E. mmulosus cvsts located near the centie of the liver rath& than with bigger, thick walled cysts at the liver’s edge. Chemotherapy was successful even in some recurrent casesand those with multiple cysts. AE is more serious than CE. Therefore, for ethical reasons, we included no non-albendazole group in the study of AE chemotherapy. Human AE usually responds less well to benzimidazole chemotherapy than human CE (HORTON, 1989). In the current study, there was evidence in 7 AE patients of significant histological damage and somedegeneration; biopsy material was&able to iifeet mice after 6-12 weeks of ABZ theranv. These findings suggested that ABZ was parasitic:d>l, at least in someAE patients, although long-term chemotherapy and follow-up are required to confirm this. Partial hepatectomy, in combination with chemotherapy, should be essential treatment for AE patients, becauseonly 2 of our 14 AE casescould be treated by radical hepatectomy; in such cases,at least 10 courses are recommended (Zoti et al.. 1992: LIU et al.. 1993). ABZ alone was relativelv ineff&i& in 5 AE p&ients’because their lesions we& too big and too badly sited to be removed by surgery. Side effects of ABZ occurred in about 20% of the patients; they were usually slight at initial doses and returned to normal without discontinuing the drug, except in one patient who had prurigo. Animal studies have provided no evidence that ABZ, at the recommended oral dosage, was teratogenic or embryotoxic (WEN et al., 1989). , Nevertheless. all females of renroductive aae should be warned about the risk of ABZ,*particularly zs long-term use (MORRIS et al., 1985). The usual recommended oral dosageof ABZ for CE is 10-15 mgikg, or 800 mg, daily for l-12 months; 600 mg twice dailv has been used for someAE natients (DAVIS et al., 1986,J1989; HORTON, 1989; WILSON et ai., 1992). The reported duration of ABZ therapy for AE varies from one month upwards, the longesf being 10 mgikg everv 12 h for 60 months ~LIU et al.. 1993). Our CE and AE patients were given ABZ orally at 15-20 mgikg, with a maximum of 1200mg daily, for 3-18 months, and most of them tolerated a high dosage and long duration of treatment well. The duration of ABZ administration should be related to the size and/or number of hydatid lesions, their location, and their condition. Generally, most uncomplicated cystic hydatid patients should respond after 3-6 courses. However, most AE casesand some complicated CE patients, e.g., those with multiple cysts or multi-organ infections or recurrent cases,require prolonged medication provided their drug responses are monitored. There are still many questions about ABZ therapy for human echinococcosis. Although we obtained encouraging results with about 70% oFCE and 40% of AE patients. there were about 25% of CE caseswho did not responi and 6 AE cases who deteriorated (including 3 deaths) even after 2 years of therapy. ABZ chemotherapy, while not completely effect&, has an important role in the treatment of both cvstic and alveolar echinococcosis.

Acknowledgements We are grateful to Professors Ding Zhao-Xun, Xu De-Zhen, Ma Xing-Ming and Yang Han-Wei and Drs Luan Mei-Xiang, Tian Wen-Lin and Oiou lie of Xiniiang. Medical College for their contributions, a;d all” the surge&s if the surgical duepartment of Xinjiang Medical College for their co-operation. This study was supported in part by an STD-2 grant from the European Commission’s Science and Technology for Development Programme (TS2 0056. UK), by the British Council’s Academic Links with China Scheme, and by Smith Kline & French Laboratories, Tianjin, People’s Republic of China. References Ammann, R., Tschudi, K., von Ziegler, M., Meister, F., Cotting, J., Witassek, F. & Freiburghaus, A. (1988). The longterm course of 60 patients with alveolar echinococcosis in continuous therapy with mebendazole (197685). Klinische Wochenschrifi, 66,1060-1073.

Bekhti, A., Schaps, J. I’. & Capron, M. (1977). Treatment of hepatic hydatid diseasewith mebendazole: preliminary results on four cases.British MedicalJournal, ii, 1047- 1051. Bogan, J. A. & Marriner, S. E. (1980). Analysis of benzimidazoles in body fluids by high performance liquid chromatography.Journal ofPharmacological Sciences, 69, 122-123. Bryceson, A. D. M., Woestenborghs, P,., Michiels, M. & van den Bossche, H. (1982). Bioavailablhty and tolerability of mebendazole in patients with inoperable hydatid disease. Transactions of the Royal Society of Tropical Medicine and Hy-

giene,76,563-564. Craig, I’. S., Deshan, L. & Zhaoxun, D. (1991). Hydatid diseasein China. Parasitoloat Todav. 7.46-50. Chi, P., Zhang, W., ZhanE Z., &&y&t, M., Liu, F., Ding, Z., Andersen, F. L., Tolley, H. D. & Schantz, I’. M. (1990). Cystic echinococcosisin the Xinjiang Uygur Autonomous Region, People’s Republic of China. I. Demographic and epidemiologic data. Tropical Medicine and Parasitology, 41, 157-lh2. __. __-.

Davis, A., Pawlowski, Z. S. & Dixon, H. (1986). Multicentre clinical trials of benzimidazole carbamates in human echinococcosis.Bulletin of the World Health Organization, 64, 383386. ___. Davis, A., Dixon, H. & Pawlowski, Z. S. (1989). Multicentre clinical trials of benzimidazole carbamates in human echinococcosis(phase II). Bulletin of the World Health Organization, 67,503-508. Department of Hygiene Statistics, The First ShangHai Medical University (1979). Medical Statistics. Shanghai: Shanghai Scienceand Technology Publisher, pp. 121, 123& 176. Gemmell, M. A., Lawson, J. R. & Roberts, M. G. (1987). Towards global control of cystic and alveolar hydatid disease. Parasitology Today, 3, 144-151. Gil-Grande, L. A., Rodriguez-Caabeiro, F., Prieto, J. G., Sanchez-Ruano, J. J., Brasa, C., Aguilar, L., Garcia-Hoz, F., Casado, N., Barcena, R. & Alvarez, A. I. (1993). Randomised controlled trial of efficacy of albendazole in intra-abdominal hydatid disease.Lancet, 342,1269-1272. Horton, R. J. (1989). Chemotherapy of Echinococcus infection in man with albendazole. Transactions of the Royal Society of Tropical Medicine and Hygiene, 83,97-102. Liu Yue-Han, Wang Xiao-Gen, Chen Ya-Tang & Yao YunQing. (1993). Computer tomography of liver in alveolar echinococcosistreated with albendazole. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87,3 19-321. Matossian, R. M., Rickard, M. D. & Smyth, J. D. (1977). Hydatidosis: a global problem of rising importance. Bulletin of the World Health Organization, 55,499-507.

Morris, D. L., Dykes, I’. W., Marriner, S., Bogan, J., Burrows, D., Skeene-Smith, H. & Clarkson, M. J. (1985). Albendazole-objective evidence of response in human hydatid disease. Journal of the American Medical Association, 253, 3n~xm57 -“_- -“-.

Saimot, A. G., Cremieux, A. C., Hay, J. M., Meulmans, A., Giovanangeli, M. D., Delaitre, B. & Coulaud, J. P. (1983). Albendazole as a potential treatment for human hydatidosis. Lancet, ii, 652-656. Todorov, T., Mechkov, G., Vutova, K., Georgiev, I’., Lazarova, I., Tonchev, Z. & Nedelkov, G. (1992a). Factors influencing the response to chemotherapy in human cystic echinococcosis.Bulletin of rhe World Health Organization, 70, 347-358.

Todorov, T., Vutova, K., Mechkov, G., Tonchev, Z., Georgiev, I’. & Lazarova, I. (1992b). Experience in the chemotherapy of severe, inoperable echinococcosis in man. Infection, 20, 19-24. Vuitton, D. A. (1990). Alveolar echinococcosis of the liver: a

343 parasitic diseasein searchof a treatment. Hepatology, 12,617618. Wen, H., New, R. R. C. & Craig, P. S. (1993). Diagnosis and treatment of human hydatidosrs. British Journal of Clinical Pharmacology, 35,565-574.

Wen, H., Yao, P. L., Zou, P. F. & Zhong, C. M. (1989). Observation on mutagenesis of albendazole. Acta Academiae Medicinaexinjiang, 12, 159-161. Wen, H., Zou, P. F., Yao, P. L. & Lu, J. (1990). Researchon chemotherapy of hydatidosis with albendazole. Chinese MedicalJourna$70,47-49. Wen, H., Tran, W. L., Zou, P. F. & Xiang, M. X. (1992). A rare caseof mixed cystic and alveolar hydatrdosis. Trunsactions

nal of Tropical Medicine and Hygiene, 31,162-168. Wilson, J. F., Rausch, R. L., McMahon, B. J. & Schantz, P. M. (1992). Parasiticidal effect of chemotherapy in alveolar hydatid disease: review of experience with mebendazole and al‘o~o;;;f m Alaskan Eskrmos. Clmzcal Infectious Dzseases, 15, Yao, P. L. (1965). Hepatic alveolar hydatid disease in China. Chinese SurgicalJournal,13,400-402.

Zhang, H. W. & Wen, H. (1989). The determination of albendazole and its main metabolites in human bv HPLC. Chinese

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ZOLI,P. F., Li, J., Wen, H., Wang, Y. H., Lu, J. &Yang, H. W. (1992). Treatment and follow-up of hepatic alveolar echinococcosis(a report of 28 cases). General SurgeryJournal, 1, 13-15.

Wilson, J. F., Rausch, R. L., McMahon, B. J., Schantz, P. M., Trujillo, D. E. & O’Gorman, M. A. (1987). Albendazole therapy in alveolar hydatid disease: a report of favourable results in two patients after short-term therapy. AmericanJour-

Received 18 August 1993; revised 15 December 1993; acceptedfor publication 25 Janua y 1993

SOCIETY OFTROPICAL MEDICINE ANDH~mm(1994) 88, 343

TP.ANSACTIONS OF THE ROYAL

I

I

1I Short Report 1I The first use of ivermectin for the treatment of onchocerciasis in Yemen Yasin Al-Qubati National Leprosy Control Programme, Ministry of Public Health, P.O. Box 55722, Taiz, Yemen Republic Onchocerciasis was first reported from Yemen by FAWDRY (1957) who gave a clear description of the skin diseasewell known to local people as sowda. This is a lo-

calized hyper-reactive form of onchocerciasis initially thought to be peculiar to south-west Arabia but now known to occur sporadically throughout Africa. A single limb, usually a leg, is affected. There is severe pruritis, usually moderate oedema, pachydermia and papular or uustular eruntion. Enlargement of the femoral lymph node is characteristic and there is usually a noticeable darkening of the skin colour which gives rise to its local name (sowda=dark). BUTTNER et al. (1982) gave a detailed account of onchocerciasisin Yemen. Until 1991 diethvlcarbamazine had been used to treat individuals with onchocerciasis symptoms but on the advice of a World Health Oraanization consultant it was decided to assessthe effects gf ivermectin. In December 1991, 200 tablets of ivermectin were obtained from Dr Philippe Gaxotte of the Merck Sharpe & Dohme ivermectin donation programme. These were distributed in Wadi Al-Ghail, Yemen, where BUTTNER et al. (1982) had shown onchocerciasis to be endemic. Each patient was examined and diagnosed as having onchocerciasis after confirmation of some or all of the following diagnostic clinical criteria: (i) severe, intolerable itching occurring day and night; (ii) blackish colouration of one limb or nart of the trunk; (iii) skin showing papules, pustules, cr*ustsand scratching marks; (iv) enlarged regional lymph nodes, mostly femoral; and (v) rarely present onchocercomataon bony areas. We did not try to find microfilariae in the skin as it is time-consuming and they are rare in our patients (BUTTNERet al., 1982). Treatment with a single dose of 6 mg ivermectin tablets was given as follows: 15-25 kg, l/2 tablet; 26-35 kg, 1 tablet;%--50 kg, 15’2 tablets; above’50kg, Ztablets. -. The first visit was made on 12 Ianuarv 1992. when 24 patients received treatment. Four follow-up visits were made at monthly intervals to examine the treated patients and to search for additional patients who needed treatment. The last visit for this purpose was on 13 May 1992, during which time 42 patients (2 female, 40 male) with an average age of 38 years (range 7-80 years) had

been treated. Monthly visits are being continued for other purposes. Most of the patients complained of severe oedema of the affected part, exaggeration of the pre-existing itching, fever, headache and body ache for one or 2 d after taking ivermectin (positive Mazotti reaction). After this, all the patients reported complete relief from their subjective symptom, i.e. itching. On examination one month after taking the drug we noticed improvement in the appearanceof the skin, i.e. clearanceof the papules, pustules, crusts and scratching marks. Also, the blackish hyperpigmentation faded away and the affected skin became clearer; the colour of both limbs became similar instead of one being darker than the other. The affected regional lymph nodes became smaller in size and softer in consistency. In one case,the size of the left inguinal lymph node decreased from 7 x 3.5 cm to 3x 1.5 cm, within one month. No patient mentioned expulsion of any intestinal worms. On the third visit, i.e. after 3 months, most of the patients complained of recurrence of their symptoms. On clinical examination, most of the signs of reactivation of the diseasehad reappeared, both on the skin and on the lymph nodes. As a result of this, we repeated the dose for these patients on the third visit and every 3 months after that, and some patients still needed treatment every third month one year after our first visit. Although the signs and symptoms of the diseasewere greatly alleviated within one month of ivermectin treatment, to maintain these effects it has proved necessaryto repeat the treatment every 3 months. This may be connected with immunological factors that might play a role in resistance to reinfection, currently being studied in collaboration with Professor R. Lenoble, Faculty of Medicine, University of Tours, France. During this study there was no untoward side-effect, though most patients exhibited mild Mazotti reactions. It is therefore clear that ivermectin is an excellent drug for the control of onchocerciasis in Yemen. However, to achieve lasting improvement the drug has to be taken at intervals of 3 months until transmission is controlled. A national control campaign is desirable, as this might lead to a reduction in transmission levels. References Buttner, D. WI, van Laer, G., Mannweiler, E. & Buttner, M. (1982). Clinical, parasitological and serological studies on onchocerciasisin the Yemen Arab Republic. Tropenmedizinund Parasitologic, 33,202-212.

Fawdry, A. L. (1957). Onchocerciasisin South Arabia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 51,253-256. Received 15 June 1993; revised 27 June 1993; accepted for publication 4 August I993 (inadvertently delayed in proof