Development and application of anthelminthic drugs in China.

China was once a country plagued by parasitic diseases. At the beginning of the founding of the People's Republic of China, nearly 80% of the population suffered from parasitic diseases because of poverty and poor sanitary conditions. After nearly 70 years of development, China has made remarkable achievements in the prevention and control of parasitic diseases, and the prevalence of parasitic diseases has been greatly reduced. In addition to organizational leadership from the government and various preventive measures, drug treatment and drug research & development are important and irreplaceable links in prevention and control work. Since the 1950s, China has begun to introduce, produce and imitate antiparasitic drugs from abroad, such as santonin, benzimidazole, and praziquantel. Chinese scientists have also contributed to the optimization of production techniques, improvements in drug formulation, the application in the clinic and the mechanisms of actions of generic drugs. At the same time, China has independently developed tribendimidine (TrBD, a broad spectrum anthelminthic), and its anthelminthic spectrum has been comprehensively studied. It is active against almost 20 parasites, is especially superior to benzimidazoles against Necator americanus, and surpasses the effectiveness of praziquantel against Clonorchis sinensis. In the treatment of tapeworm disease, the traditional Chinese medicines pumpkin seeds and betel nuts have good curative effects for taeniasis. Chinese scientists have explored the action modes and clinical administration methods of pumpkin seeds and betel nuts, which is still the main clinical regimen for the disease. This paper reviews the history and progress of the study of anthelmintics in intestinal helminth infections since the founding of the People's Republic of China and aiming to support clinicians and drug researchers in China and other countries.

Controlling Taenia solium and soil transmitted helminths in a northern Lao PDR village: Impact of a triple dose albendazole regime.

Taenia solium taeniasis-cysticercosis and soil-transmitted helminths (STHs) are parasitic Neglected Tropical Diseases endemic throughout Southeast Asia. Within Lao PDR, a remote northern hill tribe village had previously been identified as a hyper endemic focus for T. solium. To reduce this observed prevalence, a One Health intervention covering both pigs and humans was implemented, which included two Mass drug administrations (MDA1 and MDA2) for village residents using a triple dose albendazole 400mg treatment regime. In addition to the effect on T. solium levels, the dual impact of this anthelmintic regime on STHs within the community was also monitored. Faecal samples were collected pre and post MDA1 and MDA2 and analysed for the presence of Taenia species and the STHs Ascaris lumbricoides, Trichuris trichiura and hookworm species. The McMaster technique was used to measure the changes in both prevalence and intensity of infection. Molecular characterisation of Taenia and hookworm species was conducted to detect zoonotic species. The level of taeniasis within the sampled population decreased by 79.4% after MDA1, remained steady during the five month inter-treatment interval and decreased again by 100% after MDA2. The prevalence of STHs decreased by 65.5% and 62.8% after MDA1 and MDA2 respectively; however an increase to 62.1% of pre MDA1 levels was detected during the inter-treatment interval. Individually, hookworm prevalence decreased by 83.4% (MDA1) and 84.5% (MDA2), A. lumbricoides by 95.6% and 93.5% and T. trichiura by 69.2% and 61%. The intensity of infection within the sampled population also decreased, with egg reduction rates of 94.4% and 97.8% for hookworm, 99.4% and 99.3% for A. lumbricoides and 77.2% and 88.5% for T. trichiura. Molecular characterisation identified a T. solium tapeworm carrier from 21.6% (13/60) of households in the village. T. saginata was identified in 5% (3/60) of households. The zoonotic hookworm A. ceylanicum was detected in the resident dog population. These results suggest that the triple dose albendazole 400mg treatment regime achieved a significant reduction in the level of taeniasis whilst simultaneously reducing the STH burden within the village. The increased STH prevalence detected between MDAs reflects the need for behavioural changes and a sustained chemotherapy programme, which may also need to include the resident dog population.

SCHISTOSOMICIDAL ACTIVITY OF THE CRUDE EXTRACT OF ARTOCARPUS LAKOOCHA.

Puag-Haad is a traditional anthelmintic drug used to treat taeniasis in Thailand and Lao PDR. It is derived from the aqueous extract of the plant Artocarpus lakoocha. We investigated the in vitro anthelmintic properties of Puag-Haad against Schistosoma mansoni. Adult worms were incubated in M-199 medium containing 250, 500 and 750 µg/ml of Puag-Haad or praziquantel (PZQ) at a concentration of 175 µg/ml for 3, 6, 12 and 24 hours. The relative motility (RM value), survival index (SI) and tegument alterations seen under scanning electron microscope were assessed at each incubation time. The results showed the crude extract of A. lakoocha at a concentration of 250 µg/ml was more effective in causing damage than PZQ at a concentration of 175 µg/ml using RM and SI values. The major target organ affected by Puag-Haad was the tegument. The damage was greater at higher concentrations of the crude extract. It is likely tetrahydroxystilbene (THS), the main compound in Puag-Haad, caused the damage. THS could be a future candidate as a schistosomal drug. Further studies are needed to explore its mechanism, efficiency and safety in vivo.

Mini review on chemotherapy of taeniasis and cysticercosis due to Taenia solium in Asia, and a case report with 20 tapeworms in China.

A 43-year-old Tibetan woman living in northwest Sichuan, China, confirmed to be a taeniasis carrier of Taenia solium was treated with pumpkin seeds combined with Areca nut extract in October 2009. All 20 tapeworms except one without scolex were expelled under good conditions. She was free of secondary cysticercosis within one year follow up. Although the first choice for treatment of taeniasis is still praziquantel, it may often cause serious side effect on asymptomatic cysticercosis cases to suddenly become symptomatic within a half day of the treatment. Therefore, the problems in treatment of taeniasis and/or cysticercosis in Asia are briefly overviewed, since other platyhelminthic diseases including schistosomiasis, opisthorchiasis etc. are more common and praziquantel is strongly recommended for mass treatment of these trematodiases with no idea on the co-infection with eggs of T. solium which cause asymptomatic cysticercosis.

Genotoxicity induced by Taenia solium and its reduction by immunization with calreticulin in a hamster model of taeniosis.

Genotoxicity induced by neurocysticercosis has been demonstrated in vitro and in vivo in humans. The adult stage of Taenia solium lodges in the small intestine and is the main risk factor to acquire neurocysticercosis, nevertheless its carcinogenic potential has not been evaluated. In this study, we determined the genotoxic effect of T. solium infection in the hamster model of taeniosis. In addition, we assessed the effect of oral immunization with recombinant T. solium calreticulin (rTsCRT) plus cholera toxin as adjuvant on micronuclei induction, as this protein has been shown to induce 33-44% protection in the hamster model of taeniosis. Blood samples were collected from the orbital venous plexus of noninfected and infected hamsters at different days postinfection, as well as from orally immunized animals, to evaluate the frequency of micronucleated reticulocytes as a measure of genotoxicity induced by parasite exposure and rTsCRT vaccination. Our results indicate that infection with T. solium caused time-dependent DNA damage in vivo and that rTsCRT immunization reduced the genotoxic damage induced by the presence of the tapeworms.

Usefulness of pumpkin seeds combined with areca nut extract in community-based treatment of human taeniasis in northwest Sichuan Province, China.

Taeniasis refers to the infection with adult tapeworms of Taenia spp. in the upper small intestine of humans, which is also a cause of cysticercosis infection in either both humans and/or animals. Currently the most commonly applied anthelminthics for treatment of taeniasis are praziquantel and niclosamide. Praziquantel is very effective, but has the risk of induction of epileptic seizures or convulsions in carriers with asymptomatic concurrent neurocysticercosis. In contrast, niclosamide is safe and effective, but is not readily available in many endemic countries including China. In the current community-based study, we assessed the curative effect of either pumpkin seeds or areca nut extract alone in taeniasis, and also looked at synergistic effects of these two herb drugs on tapeworms. In the study group with the pumpkin seed/areca nut extract treatment, 91 (79.1%) of 115 suspected taeniasis cases (with a history of expulsion of proglottids within the previous one year) released whole tapeworms, four (3.5%) expelled incomplete strobila, and no tapeworms or proglottids were recovered in the remaining 20 cases. In these 115 persons, 45 were confirmed as taeniasis before treatment by microscopy and/or coproPCR. Forty (88.9%) of 45 confirmed cases eliminated intact worms following treatment. The mean time period for complete elimination of tapeworms in 91 taeniasis cases was 2 h (range 20 min to 8 h 30 min), and 89.0% (81) of 91 patients discharged intact worms within 3h after drug administration. In Control Group A with treatment of pumpkin seeds alone, 75.0% (9/12) of confirmed taeniasis cases expelled whole tapeworms, but the mean time period for complete elimination was about 14 h 10 min (range 3 h 20 min to 21 h 20 min), which was much longer than that (2 h) for the study group, whereas in Control Group B treated with areca nut extract alone, only 63.6% (7/11) of taeniasis cases discharged whole tapeworms, and the mean time period was 6 h 27 min (range 1-22 h). Mild side effects included nausea and dizziness in about 46.3% of patients with the pumpkin seeds/areca nut extract treatment, but all discomforts were transient and well tolerated. In conclusion, a synergistic effect of pumpkin seed and areca nut extract on Taenia spp. tapeworms was confirmed in the current study, primarily in producing an increased rate of effect on tapeworm expulsion (average time 2 h for combination vs 6-21 h for individual extracts). The pumpkin seed/areca combined treatment was indicated to be safe and highly effective (89%) for human taeniasis.

Tribendimidine and albendazole for treating soil-transmitted helminths, Strongyloides stercoralis and Taenia spp.: open-label randomized trial.

BACKGROUND: Tribendimidine is an anthelminthic drug with a broad spectrum of activity. In 2004 the drug was approved by Chinese authorities for human use. The efficacy of tribendimidine against soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) has been established, and new laboratory investigations point to activity against cestodes and Strongyloides ratti. METHODOLOGY/PRINCIPAL FINDINGS: In an open-label randomized trial, the safety and efficacy of a single oral dose of albendazole or tribendimidine (both drugs administered at 200 mg for 5- to 14-year-old children, and 400 mg for individuals > or = 15 years) against soil-transmitted helminths, Strongyloides stercoralis, and Taenia spp. were assessed in a village in Yunnan province, People's Republic of China. The analysis was on a per-protocol basis and the trial is registered with controlled-trials.com (number ISRCTN01779485). Both albendazole and tribendimidine were highly efficacious against A. lumbricoides and, moderately, against hookworm. The efficacy against T. trichiura was low. Among 57 individuals who received tribendimidine, the prevalence of S. stercoralis was reduced from 19.3% to 8.8% (observed cure rate 54.5%, p = 0.107), and that of Taenia spp. from 26.3% to 8.8% (observed cure rate 66.7%, p = 0.014). Similar prevalence reductions were noted among the 66 albendazole recipients. Taking into account "new" infections discovered at treatment evaluation, which were most likely missed pre-treatment due to the lack of sensitivity of available diagnostic approaches, the difference between the drug-specific net Taenia spp. cure rates was highly significant in favor of tribendimidine (p = 0.001). No significant adverse events of either drug were observed. CONCLUSIONS/SIGNIFICANCE: Our results suggest that single-dose oral tribendimidine can be employed in settings with extensive intestinal polyparasitism, and its efficacy against A. lumbricoides and hookworm was confirmed. The promising results obtained with tribendimidine against S. stercoralis and Taenia spp. warrant further investigations. In a next step, multiple-dose schedules should be evaluated.

[Preclinical studies of cucurbita maxima (pumpkin seeds) a traditional intestinal antiparasitic in rural urban areas]. / Estudios preclínicos de cucurbita máxima (semilla de zapallo) un antiparasitario intestinal tradicional en zonas urbano rurales.

Experimental research was carried out at the Parasitology and Chemistry laboratories of the Jorge Basadre Grohmann National University, in Tacna. The process involved two phases: (1) determination of the minimum inhibitory concentration (MIC) of Cucurbita Maxima as an antiparasitic agent using canine tapeworms with an intestinal isolation of 5 to 6 hours, and (2) determination of the side-effects of Curbita Maxima on exposed albino rats. It was found that the MIC of 23 gr. of pumpkin seed in 100 ml. of distilled water can produce an antihelminthic effect. This concentration is equivalent to +/- 73 pumpkin seeds (x2 = 5.6, p<0.01). Macroscopically, alterations in helminthic motility are present at a dose of > 23 gr. There is a protheolithic effect with an average survival time of 38.4 minutes. Microscopically the mature proglottids present a destruction of the tegument involving the basal membrane. In the gravid proglottids there is egg destruction. These findings are accentuated when experimenting with Cucurbita Maxima in a concentration of 30 and 32 gr. Superficial non-erosive gastritis was found in weys rats after 4 hours of administering 9 gr/kg.

Case of megaloblastic anemia caused by intestinal taeniasis.

A 61-year-old eutrophic male was diagnosed with vitamin B12 deficiency and megaloblastic anemia. A modified Schilling test suggested intestinal malabsorption unrelated to intrinsic factor deficiency. Subsequent colonoscopy revealed the presence of a Taenia tapeworm. The anemia resolved within days under therapy with niclosamide and temporary vitamin B12 supplements. The present case suggests that, in addition to other well-known parasitic agents, e.g., Diphyllobothrium latum and Giardia lamblia, Taenia infestation can also be a cause of intestinal vitamin B12 malabsorption.

[Clinical study and electron microscope observation of tapeworm scolices on 548 cases of taeniasis treated with Binlang Chengqi Decoction].

OBJECTIVE: To observe the effect and mechanism of Chinese herbs in the treatment of taeniasis. METHODS: Five hundred and forty-eight cases of taeniasis were treated with Binlang Chengqi Decoction (BLCQD). The tapeworm scolices of ten cases were observed by electron microscope (EM). RESULTS: Among the 548 cases, 521 cases were cured and 27 cases were improved. The total effective rate was 100%. Foam-like secretion in the sucker of the tapeworm scolices and erosion of the epithelium in the cervical part were observed by scanning electron microscope. Observed by transmission electron microscope, the cortex was seriously damaged. The microvilli were exfoliated. The cells in the muscle layer and parenchyma layer were injured in various degrees. The mitochondria were tumefied or caved. And the nerve cord was damaged. CONCLUSION: BLCQD can not only paralyze the tapeworm scolex, but also injury the cells of the tapeworm scolex.

Ethiopian traditional herbal drugs. Part I: Studies on the toxicity and therapeutic activity of local taenicidal medications.

The quantitative toxicities of 33 taenicidal herbal drugs are presented, expressed as their intraperitoneal LD50 values in mice and their respective median effective oral dose and worm expulsion time in humans. Rank orders of toxicity, taenicidal potency and worm expulsion time of the herbal medications are indicated along with a discussion of their respective therapeutic merits and untoward effects. On the basis of considerations of lower toxicity, higher potency and shorter worm expulsion time, the taenicidal herbal medications are arranged in decreasing rank order of preference. Other therapeutic uses of the herbs are also presented and discussed.

Field trial of Saussurea lappa roots against nematodes and Nigella sativa seeds against cestodes in children.

Antinematodal efficacy of Saussurea lappa roots (Qust-e-Shereen) and anticestodal effect of Nigella sativa seeds (Kalonji) was studied in children infected naturally with the respective worms. The activities were judged on the basis of percentage reductions in the faecal eggs per gram (EPG) counts. The 50 mg/kg single dose of S. lappa and equivalent amount of its methanolic extract produced on days 7 and 15 percentage EPG reduction similar to 10 mg/kg of pyrantel pamoate. Similarly, single oral administration of 40 mg/kg of N. sativa, equivalent amount of its ethanolic extract and 50 mg/kg of niclosamide reduced the percentage of EPG counts not significantly different from each other on the days 7 and 15. Therefore, it is conceivable that these indigenous medicinal plants contain active principles effective against nematodes and cestodes. The crude drugs did not produce any adverse side effects in the doses tested.

The optimum dose of Puag-Haad in the treatment of taeniasis.

Forty-two per cent of 24 patients with Taeniasis saginata were cured by two-gram dose of a crude aqueous extract of the wood Artocarpus lakoocha, Puag-Haad, while eighty per cent of 25 patients were cured by three-gram dose which is comparable to the results of five-gram dose but had less side-effect. Thus, the three-gram dose of Puag-Haad is recommended in the treatment of taeniasis.

Antiparasitic agents. 6. Synthesis and anthelmintic activities of novel isothiocyanatophenyl-1,2,4-oxadiazoles.

The syntheses and anthelmintic activities of 31 3- and 5-(isothiocyanatophenyl)-1,2,4-oxadiazoles are reported. In the primary anthelmintic screen, 3-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (39) showed 100% nematocidal activity and 3-(2-furanyl)-5-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (63), 3-(2-furanyl)-5-(2-chloro-4-isothiocyanatophenyl)-1,2,4-oxadiazole (64), and 3-(2-furanyl)-5-(4-chloro-3-isothiocyanatophenyl)-1,2,4-oxadiazole (66) showed 100% taeniacidal activity when administered orally to mice. The two most active members of this series, 39 and 63, were active against the gastrointestinal nematodes of sheep at 100 mg/kg. In addition, 39 was also found to be active against hookworms in dogs at a single, oral dose of 200 mg/kg.

Purgative and anthelmintic effects of Mallotus philippinensis in rats against tape worm.

A resin isolated from Mallotus philippinensis (Kamala) caused a significant purgative effect after an oral dose (120 mg/kg) in rats as assessed from the weight of faeces as well as from the surface area of blotting paper soaked by liquid faeces. The anthelmintic effect of the resin was evaluated in albino rats found to be infested with tape worms. The resin in 60 and 120 mg/kg dose had a lethal effect on 35.69% and 78.21% population of tape worms respectively, in small intestine.

Treatment of taeniasis with Puag-Haad: a crude extract of Artocarpus lakoocha wood.

Thirty-nine patients with tapeworm infection were treated with five grams of crude aqueous extract of Artocarpus lakoocha wood, "Puag-Haad". Seven of them vomited the drug immediately. Of the 32 patients, segments with scolices of Taenia saginata and of Taenia solium were recovered from 24 and 2 patients respectively. The side effects were vomiting and nausea.

Oral treatment of human taeniasis by ethereal extract of male-fern (aspidium) preceded by the administration of hypertonic solution of magnesium sulphate.

29 Patients of ages varying from 12 to 60 years were treated orally with doses of 0.07 g/kg body weight of ethereal extract of male-fern, preceded by the administration of hypertonic solution of magnesium sulphate (15 g in 200 ml of water). All of them were previously treated with other anthelminthics without success. 25 of the patients obtained total cure. One woman expelled 14 scoleces of T. solium. The species determination for the 29 cases of Taeniasis revealed 3 cases of T. solium (10.3%) and 26 cases of T. saginata (89.7%).