tribendimidine and Disease-Models--Animal

Opisthorchiasis, caused by the liver fluke Opisthorchis viverrini, a food-borne trematode, is an important public health problem; however, only a single drug, praziquantel is available. We investigated tribendimidine-praziquantel combinations against O. viverrini in vitro and in vivo. The IC50 values of 0.16 μg/ml and 0.05 μg/ml were determined for praziquantel and tribendimidine, respectively, against adult O. viverrini in vitro. When O. viverrini was exposed to both drugs simultaneously (using a drug ratio based on the IC50 (1:3.2)) a synergistic effect was calculated (combination index (CI) at the IC50= 0.7). A similar result was observed when drug addition in vitro was spaced by the respective half-lives of the drugs (a CI of 0.78 at the IC50 for tribendimidine followed by praziquantel and a CI of 0.47 at the IC50 for praziquantel followed by tribendimidine). In vivo median-effect dose (ED50) values of 191 mg/kg and 147 mg/kg were calculated for praziquantel and tribendimidine, respectively. Low to moderate worm burden reductions (38-62%) were observed in O. viverrini infected hamsters when both drugs were administered simultaneously or on subsequent days, pointing to antagonistic effects in vivo. Further studies are necessary to understand the striking differences between the in vitro and in vivo observations using combinations of praziquantel and tribendimidine on O. viverrini.

Topics: Animals; Cricetinae; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Inhibitory Concentration 50; Male; Mesocricetus; Opisthorchiasis; Opisthorchis; Parasite Load; Phenylenediamines; Praziquantel; Survival Analysis

Angiostrongyliasis, also known as eosinophils meningitis, is caused by Angiostrongylus cantonensis parasites in the human central nervous system. Currently, the drug of choice for treatment of angiostrongyliasis is albendazole, but dead worm lysis causes severe inflammatory response, which leads to central nervous system damage. Tribendimidine, a broad-spectrum anti-helmintic drug developed in China, is a derivative of amidantel. This study was designed to test the efficacy of tribendimidine against A. cantonensis in mice. We treated 65 infected female BALB/c mice with tribendimidine or albendazole by oral route. We observed that tribendimidine at doses of 50, 100 and 200 mg/kg/day was effective, and the worm reduction rates were 54.8 %,77.4 %, and 100 % compared with the control group. In addition, the therapeutic effect of early tribendimidine treatment (7 days post-infection [PI]) was better than the late treatment (14 days PI), in comparison with the albendazole group (20 mg/kg/day). The index of therapeutic efficacy included body weight, neurological function, survival time, worm reduction, mRNA levels of proinflammatory cytokines in brain tissue, histopathological examination and electron microscopy scanning. The results showed that tribendimidine could kill the larvae of A. cantonensis in the mice model, and the worm's body wall was observed to be damaged. After treatment with tribendimidine, the survival conditions such as body weight and neurological function were improved, and brain inflammation was reduced in infected mice. This study showed a strong efficacy of tribendimidine against A. cantonensis and provided suitable alternative treatments to further explore its potential use in treatment of human angiostrongyliasis.

Topics: Administration, Oral; Albendazole; Angiostrongylus cantonensis; Animals; Anthelmintics; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Parasite Load; Phenylenediamines; Strongylida Infections; Survival Analysis; Time Factors; Treatment Outcome

Worldwide, 3 billion people are at risk of hookworm infection, particularly in resource-poor countries. While control of soil-transmitted helminthiases relies mostly on chemotherapy, only few drugs are available and concern about potential emergence of drug resistance is rising. In the present study, tribendimidine, a derivative of amidantel, and its metabolites deacylated amidantel (dADT) and acetylated deacylated amidantel (AdADT) were tested in vitro and in vivo against Heligmosomoides bakeri and Ancylostoma ceylanicum, two hookworm rodent models, alone or in combination with standard drugs. Tribendimidine achieved IC(50)s ≤ 5 μg/ml against both H. bakeri third-stage larvae and adults in vitro and a single 2 mg/kg oral dose resulted in complete worm elimination in vivo. Comparable results were obtained with dADT, whereas AdADT displayed no effect in vitro and gave a moderate worm burden reduction of 42.9% in H. bakeri-infected mice. Tribendimidine combined with albendazole, levamisole or ivermectin revealed antagonistic interactions against H. bakeri in vitro and no significant killing effect in vivo. Tribendimidine and dADT exerted high efficacies against A. ceylanicum third-stage larvae (IC(50)s < 0.5 μg/ml) whereas adults were moderately affected in vitro (IC(50)s > 88 μg/ml). In vivo at single oral doses of 10 mg/kg, dADT showed a slightly higher efficacy than tribendimidine, achieving worm burden reductions of 87.4% and 74.8%, respectively. At the same dose, AdADT reduced the worm burden by 57.9%. Synergistic interactions were observed with tribendimidine-levamisole combinations against A. ceylanicum in vitro (combination index at IC(50)=0.5), and in vivo (combination index at ED(90)=0.19). In conclusion, tribendimidine and dADT show potent anti-hookworm properties. The potential of the promising tribendimidine-levamisole combination should be investigated in greater detail.

Topics: Administration, Oral; Ancylostoma; Ancylostomiasis; Animals; Anthelmintics; Cricetinae; Disease Models, Animal; Drug Synergism; Female; Inhibitory Concentration 50; Male; Mesocricetus; Mice; Phenylenediamines; Treatment Outcome; Trichostrongyloidea; Trichostrongyloidiasis

Tribendimidine has been registered for the treatment of human soil transmitted helminthiases in China. In the model nematode Caenorhabditis elegans it is an agonist of L-subtype nicotinic acetylcholine receptors and therefore shares its mode of action with levamisole and pyrantel. Besides its broad spectrum of nematicidal efficacy, tribendimidine is efficacious against several trematodes and has been attributed to have anti-cestodal effects. However, there are few published data available for the latter. The efficacy of tribendimidine and its nematicidal metabolite deacylated amidantel against Hymenolepis microstoma were examined for their anti-cestodal potential. Doses of 50 and 100mg/kg body weight deacylated amidantel and 10, 25, 50, and 100mg/kg tribendimidine were administered orally on three consecutive days to mice experimentally infected with eight cysticercoids. Necropsy was performed and the worm burdens were determined one day after the last treatment. Furthermore, levamisole was used in combination with tribendimidine (100mg/kg levamisole plus 10 and 25mg/kg tribendimidine, respectively) and alone (50 and 100mg/kg) to investigate any possible interactions of the partner compounds against cestodes. Tribendimidine showed a very high efficacy at dosages of 50mg/kg or higher. Surprisingly, deacylated amidantel led to no reduction of the worm burden in any of the treatments. Combinations of levamisole with tribendimidine did not augment the effects of tribendimidine alone and as expected levamisole alone also showed no anti-cestodal activity. To our knowledge, this study shows for the first time activity of tribendimidine against a cestode in a controlled laboratory study. Due to the excellent cure rates observed here, multiple tribendimidine treatments might be considered as useful scheme for treatments of cestode, nematode and trematode infections although this would significantly increase both costs and management efforts. Moreover, the differences between tribendimidine and deacylated amidantel indicate at least a strong difference in sensitivity of H. microstoma or a strong difference in drug availability.

Topics: Administration, Oral; Animals; Anthelmintics; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hymenolepiasis; Hymenolepis; Mice; Phenylenediamines; Treatment Outcome

To evaluate the efficacy of tribendimidine (TBD) against 3 geographical isolates of Trichinella spiralis in mice.. Isolates of T. spiralis from Henan (hereinafter referred to as HnT.s), Yunnan (referred to as YnT.s) and Heilongjiang (referred to as HIjT.s) were used in the study. 144 Kunming strain mice were divided into 2 groups: 72 mice in group A (adult stage, treatment at 5 d after infection), and 72 mice in group B (encapsulated larva stage, treatment at 53 d after infection). Group A was further divided equally into 12 sub-groups. Mice in every 3 sub-groups were each infected orally with 200 T. spiralis larvae of the 3 isolates respectively, and the remained 3 subgroups served as untreated control. Mice in the 3 sub-groups infected with one isolate were orally treated with TBD at a single dose of 10, 20, and 30 mg/kg, respectively. Group B was treated as group A but with a course of TBD once daily at a dose of 100, 200, and 300 mg/(kg x d) for 7 d, respectively. Mice in group A were sacrificed 2 d post-treatment and adult worms were recovered from the small intestine and counted. Those in group B were sacrificed 10 d after completion of 7 d treatment. The intact diaphragm was removed and digested for collecting larvae. Worm burden and worm reduction of each treated sub-group were calculated and statistically compared with the respective control.. In group A, the mean worm burden in the treated sub-groups infected with HnT.s and YnT.s were all significantly lower than that of the controls (P < 0.01), with a mean worm reduction rate of 39.0%, 57.9%, and 86.0% in HnT.s sub-groups, and of 34.9%, 69.3%, and 92.2% in YnT.s sub-groups, respectively, showing an increase with the dosage, 2 mice in each of the 30mg/kg sub-groups were cured. The worm burden in the 10 mg/kg of HljT.s subgroup was similar to that of the control (P > 0.05), but was significantly lower in the other 2 sub-groups than that of the controls (P < 0.01). The worm reduction rate in the 3 sub-groups was 27.9%, 57.4%, and 60.7%, respectively. In all treated sub-groups of group B, the mean worm burden was significantly lower than that of the controls (P < 0.05), with a mean worm reduction rate of 57.8%, 75.4%, and 87.5% in HnT.s sub-groups, of 74.5%, 92.4%, and 99.1% in YnT.s sub-groups, and of 50.5%, 53.3%, and 61.6% in HljT.s sub-groups, respectively, with the 3 dosages.. Tribendimidine shows adequate efficacy on Trichinella spiralis adults and on encapsulated larvae of the 3 geographical isolates in mice, with better effect on Yunnan isolate.

Topics: Animals; Disease Models, Animal; Mice; Mice, Inbred Strains; Phenylenediamines; Trichinella spiralis; Trichinellosis

The aim of the study is to understand the anti-Clonorchis sinensis properties of mebendazole and albendazole, and compare to praziquantel and tribendimidine. Two hundred and thirty rats were divided into five batches for experimental treatment. In four batches, each rat was infected orally with 50 or 100 C. sinensis metacercariae. Twenty-eight to 46 days post-infection, groups of rats were treated orally with single doses of mebendazole, albendazole, praziquantel, tribendimidine, or multiple daily doses of albendazole. While in the remaining batch, mebendazole or praziquantel was administered to groups of rats infected each with 50 metacercariae for 7 or 14 days. In each batch of test, untreated but infected rats served as control. All rats were euthanized 2-4 weeks post-drug administration for assessment of efficacy. In the first batch of test, rats treated with mebendazole or tribendimidine at single doses of 150, 75, and 37.5 mg/kg resulted in worm burden reductions of 99.0%, 94.0%, and 73.1%, or 98.0%, 80.6%, and 60.4%, respectively. When rats were treated with albendazole at the same dose levels, no or poor effect was seen. In the second batch of test, promising effect against adult C. sinensis in rats treated with mebendazole or tribendimidine at single doses of 100 and 50 mg/kg were also observed, but under the single dose of 25 mg/kg, only tribendimidine still remained the effect. In the third batch of test, the aforementioned three single dose levels of mebendazole, albendazole and praziquantel were applied. Again, mebendazole exhibited higher effect and albendazole exhibited no or poor effect. While praziquantel, administered at a higher dose of 300 mg/kg, also showed promising effect. In the fourth batch of test, oral administration of albendazole at a daily dose of 150 or 100 mg/kg for 2 or 3 days resulted in moderate or higher efficacy with worm burden reductions of 79.2% and 91.9%, respectively. In the fifth batch of test, single mebendazole doses of 150 or 75 mg/kg exhibited promising effect against 14-day-old C. sinensis in rats with worm burden reductions of 95.3% and 86.4%, respectively, but mebendazole was short of the effect against 7-day-old worms. Under the same dose level, praziquantel possessed an effect against both 7- and 14-day-old juvenile C. sinensis. The results confirm that in infected rats, mebendazole administered orally at a single dose of 150 mg/kg exhibits potential effect against juvenile (14-day-old) and adult C. sine

Topics: Albendazole; Animals; Antiprotozoal Agents; Clonorchiasis; Clonorchis sinensis; Disease Models, Animal; Male; Mebendazole; Metacercariae; Phenylenediamines; Praziquantel; Rats; Rats, Sprague-Dawley

The antinematode effect of tribendimidine (TBD) and its metabolites has been studied. A total of 107 hamsters were each infected with 250 Necator americanus third stage infective larvae (NaL3) for 25 days. In the first test, 75 hamsters were divided equally into 15 groups for determination of ED(50) and ED(90.) Among them, five groups were treated orally with TBD or its metabolite, p-(1-dimethylamino ethylimino)aniline (aminoamidine, deacylated amidantel, BAY d 9216, dADT), at single doses of 1, 2, 4, 8, and 16 mg/kg. The remaining five groups were administered with acetylated dADT (AdADT) at single oral doses of 8, 12, 18, 24, and 30 mg/kg. In the second test, 20 hamsters were equally divided into four groups. Two groups were treated intramuscularly with TBD and dADT at a single dose of 16 mg/kg, while in the remaining two groups, single intramuscular dose of AdADT 15 or 30 mg/kg was administered. In the third test, two groups of six hamsters were treated orally with terephthalaldehyde (TPAL) and terephthalic acid (TPAC) at a single dose of 1,000 mg/kg. Other 85 rats, each infected with 300 Nippostrongylus braziliensis third stage infective larvae (NbL3), were used in three tests. For determination of ED(50) and ED(90) in the first test, five groups of five rats were treated orally with TBD or dADT at single doses of 3.0, 4.2, 5.9, 8.2, and 11.5 mg/kg or 2.0, 2.9, 4.2, 6.1, and 8.8 mg/kg, respectively. In the second test, three groups of eight to nine rats were treated orally with TBD at a single 8.4-mg/kg dose (ED(90)) and AdADT 100 or 200 mg/kg, respectively. In the third test, two groups of four rats were treated orally with TPAL and TPAC at a single dose of 1,000 mg/kg. Twenty-four to 48 h post-treatment, all the feces of each hamster and rat were collected for recovery of worms expelled from the feces. Following this period, all of the animals were sacrificed, and the adult hookworm or N. braziliensis from small intestine and large intestine were recovered and counted for calculation of worm burden reduction. The results showed that the ED(50) and ED(90) for TBD, dADT, and AdADT determined in treatment of N. americanus-infected hamsters were 1.849 and 13.598, 3.922 and 54.354, as well as 20.966 and 51.633 mg/kg, respectively. In intramuscular administration of TBD and dADT at single dose of 16 mg/kg or AdADT 30 mg/kg, similar worm burden reductions of 71.4-76.3% were observed. Two other metabolites, i.e., TPAL and TPAC, exhibited no effect against N

Topics: Administration, Oral; Animals; Anthelmintics; Cricetinae; Disease Models, Animal; Feces; Injections, Intramuscular; Intestine, Large; Intestine, Small; Mesocricetus; Necator americanus; Necatoriasis; Nippostrongylus; Phenylenediamines; Rats; Treatment Outcome

To observe the efficacy of tribendimidine and albendazole against Trichinella spiralis in mice.. A total of 85 Kunming strain mice, infected orally with 100 T. spiralis larvae, was divided into 3 groups: group A (adult stage, 7 d after infection), group B (migrating larva stage, 15 d after infection), and group C (encapsulated larva stage, 35 d after infection). Group A (35 mice) was equally divided into 7 sub-groups, tribendimidine and albendazole were each orally administered to 3 sub-groups both with doses of 6.25, 12.5, and 25 mg/kg respectively, the untreated sub-group served as control. Groups B and C (25 mice each) were both divided equally into 5 sub-groups. Mice in 2 sub-groups were treated respectively with the 2 drugs in a dose of 100 or 200 mg/kg, the untreated sub-group served as control. Mice in group A were sacrificed 2 d post-treatment and adult worms recovered from the small intestine were counted. Those in groups B and C were sacrificed 15 d post-treatment and intact diaphragm was then removed from each mouse. The muscle of diaphragm was digested by digestive solution and the larvae were counted by stereomicroscope. Mean worm burden and mean worm reduction of each treated group were calculated and statistically compared with the control.. The mean worm burden in sub-groups of group A treated with tribendimidine was significantly lower than that of the control (P<0.01) with a mean worm reduction of 63.3%, 86.2%, and 98.5%, respectively. In the same batch of mice treated with albendazole at a single dose of 6.25 and 12.5 mg/kg resulted in similar mean worm burden compared to the control (P<0.05). While in the sub-group received albendazole at a higher dose of 25 mg/kg, the mean worm burden was significantly lower than that of the control (P<0.05), with a mean worm reduction of 41.2%. The mean worm burden in group B was significantly lower than that of the control (P<.01). The mean worm reduction in the 2 sub-groups treated with tribendimidine or albendazole was 64.4% and 89.6%, or 56.7% and 78.4%, respectively. In group C, significantly lower mean worm burden was only found in the subgroup treated with albendazole at a higher dose of 200 mg/kg than the control (P<0.01) with a mean worm reduction of 71.8%. No effect was seen in the other 3 groups.. Tribendimidine exhibits potential effect against adult and migrating larva stage of T. spiralis in mice, but lacks effect against encapsulated larva stage of the parasite. Albendazole administered at a larger or multiple doses to mice endorses effect against its adult, migrating larva and encapsulated larva stages.

Topics: Albendazole; Animals; Disease Models, Animal; Female; Larva; Mice; Mice, Inbred Strains; Phenylenediamines; Treatment Outcome; Trichinella spiralis; Trichinellosis

Food-borne trematodiasis is an emerging public health problem with more than 10% of the world's population at risk of infection, yet there are only 2 drugs available for treatment and morbidity control. We assessed the effect of a promising broad-spectrum anthelmintic drug, i.e., tribendimidine, with an experimental focus on adult Echinostoma caproni. Female NMRI mice were infected with 30 E. caproni for 2 wk and then administered single oral doses of tribendimidine ranging between 25 and 500 mg/kg. Three days post-treatment, mice were necropsied, and adult worms were recovered from their intestines. Worm burden reductions were assessed against untreated control mice. In addition, scanning electron microscopic observations were done on adult E. caproni recovered from mice given a single dose of 150 mg/kg tribendimidine intragastrically 2, 4, and 8 hr post-treatment. Worm burden reductions of 100% were achieved at doses of 125 mg/kg and above. Severe damage of the tegument, including extensive peeling, formation of blebs, and structural loss of the definition of collar and tegumentary spines already occurred within 2 hr after drug administration. Our findings call for further investigations using tribendimidine in other trematode-animal models, because this compound shows promising trematocidal activity.

Topics: Animals; Antiplatyhelmintic Agents; Biomphalaria; Disease Models, Animal; Echinostoma; Echinostomiasis; Female; Mice; Microscopy, Electron, Scanning; Phenylenediamines

Laboratory golden hamsters (Mesocricetus auratus) were infected with Necator americanus under several different parasite and host conditions to optimize the model for testing anthelminthic drugs. The results confirmed that male hamsters were more susceptible to infection than females. Host age in the range of 5-15 weeks was not a factor that impacted on adult worm burden, and similar worm burdens were achieved using doses of 150, 250 or 500 N. americanus L3 (NaL3). The largest numbers of adult hookworms were recovered on days 21-28 post-infection, with a significant decrease at days 40-50 post-infection. Therefore adult worm recovery is maximal approximately 11-18 days prior to patency and host blood loss. From these studies a drug evaluation protocol was developed using 150 NaL3 as the infectious dose and then evaluating the anthelminthic effects of the drugs albendazole, tribendimidine, and pyrantel pamoate on days 21-28 post-infection. The model confirms the anthelminthic activity of albendazole, tribendimidine, and pyrantel pamoate and has the potential as a laboratory animal model to detect emerging drug resistance.

Topics: Age Factors; Albendazole; Animals; Anthelmintics; Cricetinae; Disease Models, Animal; Erythrocyte Count; Female; Male; Mesocricetus; Necator americanus; Necatoriasis; Phenylenediamines; Pyrantel Pamoate; Sex Factors