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Paragonimiasis, one of the important food-borne parasitic zoonosis, is widely prevalent in Southeast Asia, Africa and America. According to a WHO estimation, there have been as many as 20 million cases of the disease, making it a serious public health issue.［1］ In China, paragonimiasis patients are mainly affected by two clinical forms: Paragonimiasis westermani (P.westermani) and Paragonimiasis skrjabini (P.skrjabini). ( Table 1 ) The latter is a new species discovered in China and is caused by its actively motile juvenile larva as helminthic larva migrans.［2］
Triclabendazole ［Fasinex, 2-methylthio-5 (6)-chloro-6 (5)-(2', 3'-dichloro) phenoxy-benzimidazle］ is a new anthelmintic benzimidazole compound jointly developed by Ciba-Geigy Pharma and World Health Organization. It had been used in the treatment of fascioliasis in sheep with remarkable therapeutic effect.［3］ It has also been found highly active against Paragonimus uterrobilateralis in cotton rats［4］ and Paragonimus westermani in dogs.［5］ In this study, the effect of triclabendazole on Paragonimus skrjabini in rats and treatment of patients is investigated.
METHODS
Experimental therapy
Metacercariae of P. skrjabini were isolated from crabs (Sinopotamon) collected from two endemic areas, Weiyuan County of Sichuan Province and the Nandong district of Chongqing Municipality, China. Wistar rats were supplied by Animal Center of Sun Yet-cen University. In the first experiment, each of the rats was infected intraperitoneally with 40 metacercariae (from Weiyuan county). In the second experiment, each of the rats was infected with 25 metacercariae (from Nandong district). In each experiment, a group of infected rats was left untreated to serve as a control.
Triclabendazole was provided by Ciba-Geigy Pharm. and praziquantel was obtained from the Sixth Pharmaceutical Factory, Shanghai, China. Both drugs were finely ground with 0.4% carboxylmentyl cellulose for oral inoculation by gastric syringe. In the first experiment, the infected rats were treated with triclabendazole and praziquantel. The dosage of triclabendazole was 150 mg·kg(-1)·d(-1), for two consecutive days. The dosage of praziquantel was 75 mg·kg(-1)·d(-1), for two consecutive days. They were treated 30 days after infection. In the second experiment triclabendazole alone was used with 2 dose regimes. 150 mg·kg(-1)·d(-1) and 200 mg·kg(-1)·d(-1), for 3 consecutive days.
Assessment of efficacy
All groups of treated and untreated control rats were sacrificed one month after cessation of treatment. Necropsy was done to remove all worms from muscles, liver, abdominal and chest cavities, and lungs according to methods described by Habe.［6］ The total number of worms were recorded and compared between the treated and untreated control groups.
Clinical trial
Five patients were enrolled, two adults and three children, aged 7-38 years. All had a history of eating raw crab in rural endemic areas of Chongqing municipality. Paragonimus antigen intradermal test and serum emzyme-linked immuno sorbent assay (ELISA) were positive. Various clinical symptoms and signs were tabulated in Table 1 .Chest X-rays were taken of each patient.
Treatment and dosage of regimen
Triclabendazole as a chemically pure powder was given orally in the dosage of 10 mg/kg bid for 3 days. One patient had cerebral involvement and received two courses of treatment at an interval of 3 days. All patients agreed to treatment with written consent. Drug side effects were closely monitored during the course of treatment. Hemogram, hepatic and renal function tests were done before and after treatment.
RESULTS
Experimental therapy
The rats in the control group were all found to be infected. Juvenile worms were widely distributed at various sites in the muscles, liver, abdominal and chest cavities and lungs in different sizes and development stages.［5］ On day 30, the juvenile worms were found in the liver, muscles and abdominal cavity. Those in the muscles were very small in size with their excretory vesicles still visible. About 50% of worms were found in the chest cavity and lung, with formation of worm cysts. In the first experiment, triclabendazole was given at a dosage of 150 mg·kg(-1)·d(-1), for 2 days with a total dosage of 300 mg/kg.The worm reduction rate was 50.3%. In the second experiment, the dose of triclabendazole was increased to 150 mg·kg(-1)·d(-1) and 200 mg·kg(-1)·d(-1), for 3 days with a total dosage of 450 mg/kg and 600 mg/kg, respectively, and worm reduction rates of 80.8% and 86.7%, respectively. The living juvenile worms almost all disappeared in the muscles, liver and abdominal cavity. Only one juvenile worm was found in the muscle in one rat in group A. The number of living worms in the chest cavity and lung was also markedly reduced ( Table 2 ).
Dead worms were also found in various viscera and serous cavities in both treated groups by careful examination. They were whitish and opaque in color and much smaller (about the size of sesame seeds) than that of the worms in the control group ( Table 3 ). There was no marked difference in number of worm cysts found in the lung between the treated groups and control group. However in the control group the worm cysts were much larger in size, black in color and distended bulging on the pleural surfaces with a mean transverse diameter of 9.7 mm (5-17 mm), while those in the treated groups, only hemorrhagic-necrotic patches were seen.
Clinical results
All the five patients were followed up 3-10 months after treatment. Migratory subcutaneous nodules completely disappeared in four patients. Chest X-rays of two patients with pulmonary inflammation and two patients with small amounts of pleural effusion showed that all inflammation and effusion was completely absorbed. Cerebral lesions and severe headache disappeared entirely in one patient and MRI showed a bean-sized calcified spot in the right frontal region. Two patients with hepatomegaly were not palpable on follow-up. Blood eosinophilia completely disappeared. There was no marked drug reaction observed. Hepatic and renal function tests were within normal limits. All the five patients were cured.
DISCUSSION
Paragonimiasis, one of the important parasitic zoonosis in China, is widely distributed in 22 provinces and autonomous regions.［1］ These are of two clinical types: one is caused by P. westermani［7］ with classical symptoms including cough and rust colored sputum in which worm eggs are found. The other is caused by P. skrjabini which cannot develop into sexually mature adult worms in humans. The disease is caused by its actively motile juveniles as helminthic larva migrants and clinically is characterized by migrating subcutaneous nodules and pleurisy with effusion.［8］
From our experimental results, it is evident that triclabendazole had a high activity［9］ against P.skrjabini infection in rats. At the dosage of 450 mg·kg(-1)·3d(-1) and 600 mg·kg(-1)·3d(-1), it was 80.8% and 86.7% efficient against the flukes aged 2 months. A few living adult worms recovered in the chest cavities and lungs one month after cessation of treatment might be developed from migrating juveniles not killed by triclabendazole. Dead worms found in muscles, liver, abdominal and chest cavities and lungs were greatly diminished in size. On microscopic examination of the dead worms, all internal structures were destroyed. The mechanism of action of triclabendazole may be due to inhibition of protein synthesis of flukes［10］ leading to protein depletion, generalized atrophy of internal organs and death.Clinically triclabendazole is highly effective in treatment of various forms of P. skrjabini including pulmonary, pleural, cerebral and subcutaneous tissue lesions. It is one of benzimidazole compound with very low toxicity .It had been used in the treatment of children with African paragoniamiasis (P.africanus) in Cameroon［11］ and human pulmonary paragonimiasis (P.Mexicanus) with good therapeutic effect.［12］ Triclabendazole in the treatment of paragonimiasis has the advantage of requiring a much smaller dosage and and with less frequency of delivery than praziquantel. The drug is very well tolerated, so it is a new alternative drug recommended for paragonimiasis.
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