A Prospective Observational Study of Hepatic Dysfunction in Children on Antitubercular Drugs.

The frequency, risk factors, and prognosis of antitubercular drug-induced liver injury (TB-DILI) was assessed in this prospective observational study. All consecutive children < 18 y put on antitubercular therapy (ATT) for pulmonary or extrapulmonary tuberculosis between July 2019 and December 2020 were included. Liver function tests (LFTs) were done at baseline and at 2, 4, 6 wk, and then 2 monthly after initiation of therapy till completion of ATT regimen. A total of 81 children [14.27 ± 3.38 y, 34 (42%) males] were included. Out of the patients enrolled, 10 (12.3%) developed TB-DILI at a median of 8.5 (3-18) d of starting ATT. All patients were symptomatic with the most common symptoms being anorexia and nausea (80%). A higher baseline ALT was independently associated with DILI with adjusted OR 2.1 (95% CI 1.3-3.4), p = 0.01. Eight patients tolerated reintroduction of ATT in a sequential manner, 9-24 d after discontinuation.

Acute fasciolosis in an alpaca: a case report.

BACKGROUND: The popularity of new world camelids, particularly alpacas, is growing rapidly in Ireland, presenting a clinical challenge to veterinary practitioners who may not have worked with these species previously. To the authors' knowledge, the clinical course of a case of acute fasciolosis in an alpaca has not previously been reported, and fasciolosis has not been reported at all in alpacas in Ireland, making this case report a valuable addition to the current literature. CASE PRESENTATION: A three-year-old male castrated huacaya alpaca was admitted to UCD Veterinary Hospital with a two-day history of colic and tenesmus. He had been treated with albendazole, dexamethasone and potentiated amoxycillin by the referring veterinary practitioner with no response. On initial clinical exam, sensitivity to abdominal palpation was the only abnormality. However, the alpaca proceeded to show abnormal lying positions, tenesmus and reduced faecal output over the next 24 h. A general blood panel demonstrated moderate anaemia, marked hyperglobulinaemia and moderately increased hepatocellular and hepatobiliary enzyme activity. Abdominal radiography revealed enlargement of the first forestomach compartment without evidence of gastrointestinal obstruction or peritonitis. An abdominal ultrasound exam revealed an elongated, heterogenous mass in the caudoventral abdomen that appeared to be contiguous with the liver. FNA of this mass revealed that it was in fact a liver lobe with biliary stasis and inflammation. Faecal sedimentation demonstrated Fasciola hepatica eggs. In spite of treatment with triclabendazole and supportive treatment including blood transfusion, the alpaca's condition continued to deteriorate and he was euthanised. On post-mortem exam, acute fasciolosis was diagnosed. CONCLUSIONS: The clinical presentation and course of a case of acute fasciolosis in an individual alpaca is described, including the results of a range of diagnostic tests that were carried out. The final diagnosis is supported by a description of post-mortem findings. This information will serve as a resource for veterinary practitioners involved in the diagnosis and treatment of similar cases.

Fasciola Hepatica Induced Hepatic Abscess Treated with Triclabendazole.

Fascioliasis is a zoonotic disease caused by Fasciola hepatica that infects mainly cattle, sheep, and goats. Humans can be infected by water or aquatic plants contaminated with metacercariae. The authors encountered two cases of F. hepatica infection. One patient reported abdominal discomfort with marked eosinophilia. The other patient had chest discomfort with marked eosinophilia. The abdominal CT images revealed hypodense lesions in the liver. The ultrasonography-guided liver biopsy findings in both patients were indicative of parasitic infections. Serological tests confirmed the definite diagnoses. Both patients were treated with a single dose of triclabendazole, which is the treatment of choice for fascioliasis. These findings suggest that a diagnosis of fascioliasis, particularly in the acute phase, should be considered in patients with abdominal pain, marked eosinophilia, and hypodense hepatic lesions on CT.

Selective flukicide treatment of non-lactating cows and the corresponding production impact of Fasciola hepatica in dairy herds in Sweden.

A control strategy against Fasciola hepatica infection based on selective treatment of non-lactating animals was evaluated in four Swedish dairy herds. The study was conducted over the course of two consecutive seasons in moderately to highly F. hepatica infected herds with robotic milking, where heifers and dry cows received an oral drench with albendazole (10 mg/kg) during three visits in January, February and March in both 2017 and 2018. This resulted in an anthelmintic coverage between 38 % and 58 % of the animals. Furthermore, on each visit, the infection status of all dewormed animals along with 15 randomly selected milking cows were monitored by detection of F. hepatica coproantigens. Individual milk samples were also collected quarterly from the whole herds for measurements of individual antibody levels against the parasite using milk ELISA. In addition, individual data on milk yield and quality were collected on a monthly basis between 2016 and 2018. To further study the impact of the infection on milk production, truly F. hepatica positive and negative cows in the first lactation were identified based on the results from coproantigen and milk ELISA assays. Total F. hepatica coproantigen prevalence in the herds varied between 28 % and 85 % in the first year, and between 27 % and 68 % in the second year of the study. We found that two years of treatments resulted in a significant decrease of coproantigen-positivity especially on the two most heavily infected farms. These results were confirmed by a similar drop in within-herd prevalences obtained by milk ELISA results. The infection had a significant negative impact on milk yields in untreated F. hepatica positive cows. No consistent long-term effect was observed at the herd level probably due to the influx of animals infected before puberty and/or adult animals that were re-infected at dry-off. This is the first study of the effects of F. hepatica infection on milk yield and quality in dairy herds in Sweden.

Opisthorchis felineus genes differentially expressed under praziquantel shed light on the nature of tegument disruption and indicate the adaptive role of cGMP-dependent protein kinase.

Opisthorchis felineus is a trematode flatworm that parasitises mammals, including humans, and is mainly spread throughout Eastern Europe and Western Siberia. The main drug used in treatment of opisthorchiasis and other trematode and cestode infestations is praziquantel (PZQ). We provide a possible explanation of PZQ-mediated tegument disruption. The idea is that the nature of tegument disruption is related to failure of surface renovation due to insufficiency of microtubule transport of vesicles. This insufficiency arises from microtubule destabilisation, which in the medium term leads to the decrease in tubulins alpha, beta and dynein mRNA amounts and deficiency of the corresponding proteins. We also found the upregulation of cGMP-dependent protein kinase gene, and we concluded that its protein product helped to overcome the effect of praziquantel and might be a promising target for combined anthelmintic therapy with PZQ. We concluded that function of saposin-like protein 2 (SAP2) is unlikely associated with membrane fusion, and SAP2 is probably able to bind some type of hydrophobic compounds including praziquantel.

Revisited - Failure of tetrodotoxin to protect red-spotted newts, Notophthalmus viridescens, from endoparasites.

Red-spotted newts, Notophthalmus viridescens, contain tetrodotoxin (TTX) and its analogue 6-epiTTX in variable concentrations. In a follow-up study, newts were sampled from a pond in Pennsylvania, USA, in 2010, 2014, and 2018. Their toxin levels were assayed by liquid-chromatography-fluorescence detection (LC-FLD), and assessment of their infection with endoparasites such as nematodes and helminths was performed by histological examination of internal organs. In the 2010 and 2014 samples, average prevalence of parasite infection was 53 and 60%, respectively, but reached 100% in the 2018 sample, where metacercaria stages of the digenean trematode genus Australapatemon/Apatemon (family: Strigeidae) were predominant causing severe tissue damage in liver and kidney. Mean values of TTX and 6-epiTTX were not significantly different in parasitized or parasite-free newts over the study period, confirming previous findings that host toxicity and parasite load are not negatively correlated. Whereas the role of TTX in defence against predators is undisputed, its efficacy to prevent parasitic infections is less obvious. Toxin-resistance of various metazoan parasites may promote their widespread occurrence in poisonous newts.

Treatment failure after multiple courses of triclabendazole in a Portuguese patient with fascioliasis.

Fascioliasis is a trematode flatworm infection caused by Fasciola hepatica Humans are incidental hosts, and the infection is most often acquired by eating watercress grown in contaminated water in livestock-rearing areas. Triclabendazole is the only highly effective treatment, with a reported cure rate of >90%. Treatment failure may be due to several factors, though resistance is rare in humans and scarcely reported, most probably a reflection of the widespread use of anthelmintics in livestock. There are three papers describing cases of treatment failure, possibly due to resistance, in the Netherlands, Chile and Peru. We document for the first time one case of failure after multiple treatment courses with triclabendazole in Portugal, probably due to resistance to the anthelmintic. Our aim is to alert for the emergence of resistance across continents, with consequent predictable difficulties in the management of the disease and encourage more investigation in the field.

Screening of in vitro antitrematodal activities of compounds and secondary metabolites isolated from selected Pteridophytes.

Four ferns Blechnum orientale Linn. (BO), Dicranopteris linearis (Burm.f ) Underw. (DL), Marattia fraxinea Sm. (MF), and Microlepia speluncae (L.) Moore (MS) were extracted in varied combination of organic solvents followed by the preparation of eluates and isolation of secondary metabolites using chromatography on a glass column with silica gel as the fixed phase. The chemical components were identified using HPTLC and GC-MS analysis. The in vitro anti-trematodal activities of these eluates and compounds were evaluated against the sheep trematode worm Gastrothylax crumenifer (Plagiorrchiida: Gastrothylacidae) at increasing concentrations (1 to 5 mg/mL), to find the relative motility (RM) values for 0 to 60 min of incubation as reflection of paralysis and death of the worms. Hedon-Fleig salt solution was used as negative control and Oxyclozanide® 1% as standard control. In vitro incubation study showed DL and MS extracts had strong trematodicidal activity. BO extract (5 mg/mL) produced moderate trematodicidal activity and MF (5 mg/mL) showed the least trematodicidal activity. Phytochemicals analysis revealed that the ferns are a potential source of trematodicidal compounds such as phytol isomers fern-8-ene and fern-9(11)-ene (terpenoid derivative), quercetin 7,3 ́,4 ́-trimethoxy (flavonoid derivative), etc., which offer scope for a more elaborate study for exploitation of ferns for human welfare.

Rafoxanide promotes apoptosis and autophagy of gastric cancer cells by suppressing PI3K /Akt/mTOR pathway.

Rafoxanide is commonly used as anti-helminthic medicine in veterinary medicine, a main compound of salicylanilide. Previous studies have reported that rafoxanide, as an inhibitor of BRAF V600E mutant protein, inhibits the growth of colorectal cancer, multiple myeloma, and skin cancer. However, its therapeutic effect on gastric cancer (GC) and the potential mechanism has not been investigated. Here, we have found that rafoxanide inhibited the proliferation of GC cells in vitro, arrested the cell cycle in the G0/G1 phase, and promoted apoptosis and autophagy in GC cells. Treatment with specific autophagy inhibitor 3-methyladenine drastically inhibited the apoptotic cell death effect by suppressing the switch from autophagy to apoptosis. Mechanistically, we found that rafoxanide inhibited the growth of GC cells in vitro by inhibiting the activity of the PI3K/Akt/mTOR signaling pathway. This process induced autophagy, which essentially resulted in the apoptosis of GC cells. Results from subcutaneous implanted tumor models in nude mice also indicated that rafoxanide inhibited the growth of GC cells in vivo. Taken together, our findings revealed that rafoxanide inhibited the growth of GC cells both in vitro and vivo, indicating a potential drug candidate for the treatment of GC.

Neurocysticercosis: A new concept and insight into basic and future pharmacotherapy.

Neurocysticercosis is a neurological infection caused by the larva of taenia solium. The larva infection may affect different parts of the human brain and spinal cord, leading to focal neurological deficit with/without inflammatory reactions. Neurocysticercosis is one of the major causes of epilepsy in the developing countries. It is of two types. One is extra-parenchymal neurocysticercosis in which cysticerci cysts at subarachinoid space and ventricles lead to obstructive hydrocephalus and increase in the intracranial pressure. The other type is intra-parenchymal neurocysticercosis in which the cysticerci cyst grows inside the brain parenchyma, causing the feature of space-occupying lesion. The common presentation of intra-parenchymal neurocysticercosis is secondary epilepsy which is due to focal lesion and/or local inflammatory reactions. Cysticidal therapy increases the risk of seizure due to the induction of host inflammatory reactions. Therefore, coadministration of corticosteroids reduces the risk of seizure through attenuation of inflammatory reactions and brain oedema. Praziquantel alone or in combination with albendazole is regarded as the basic cysticidal therapy against neurocysticercosis. Newer drugs and agents are recommended to overcome the partial failure of standard cysticidal therapy.

Triclabendazole in the treatment of human fascioliasis: a review.

Fascioliasis occurs on all inhabited continents. It is caused by Fasciola hepatica and Fasciola gigantica, trematode parasites with complex life cycles, and primarily affects domestic livestock. Humans become infected after ingestion of contaminated food (typically wild aquatic vegetables) or water. Fascioliasis may be difficult to diagnose as many symptoms are non-specific (e.g. fever, abdominal pain and anorexia). Treatment options are limited, with older effective therapies such as emetine and bithionol no longer used due to safety issues and unavailability, and most common anthelminthics having poor efficacy. Clinical trials conducted over a 25-year period, together with numerous case reports, demonstrated that triclabendazole has high efficacy in the treatment of human fascioliasis in adults and children and in all stages and forms of infection. Triclabendazole was approved for human use in Egypt in 1997 and in France in 2002 and a donation program for the treatment of fascioliasis in endemic countries was subsequently established by the manufacturer and administered by the World Health Organization. Here the published data on triclabendazole in the treatment of human fascioliasis are reviewed, with a focus on more recent data, in light of the 2019 US Food and Drug Administration approval of the drug for use in human infections.

Mass Drug Administration of Triclabendazole for Fasciola Hepatica in Bolivia.

Human infection with Fasciola hepatica leads to obstruction of the common bile duct by adult worms and disease characterized by biliary colic, epigastric pain, and nausea. Recommended treatment is a single dose of triclabendazole (TCBZ) (10 mg/kg). Because in the 1990s the Bolivian Altiplano bordering Lake Titicaca was thought to have the highest prevalence of human fascioliasis worldwide, the Bolivian Ministry of Health instituted TCBZ mass drug administration (MDA). From 2008 to 2016 (excepting 2015), one dose of 250 mg was administered, usually in September/October, to each resident of highly endemic regions willing to participate. This is apparently the first reported use of MDA for Fasciola. The proportion of persons in key regions receiving TCBZ MDA was 87% in 2016. In 2017, we resurveyed key regions, and found that the MDA program had been dramatically successful. Whereas Fasciola prevalence was reported as 26.9% in Huacullani/Tiahuanaco and 12.6% in Batallas in 1999, there was 0.7% prevalence in Huacullani/Tiahuanaco and 1% in Batallas in 2017. However, lessons from schistosomiasis control efforts suggest that for sustained control of Fasciola infection, Fasciola MDA needs to be maintained and coupled with measures to control infection in the intermediary snail and in the animal hosts of F. hepatica.

Lack of efficacy of triclabendazole against Fasciola hepatica is present on sheep farms in three regions of England, and Wales.

The liver fluke Fasciola hepatica is a parasitic trematode that has a major impact on livestock production and human health. Control of F hepatica is difficult and relies on anthelmintics, particularly triclabendazole, due to its efficacy against both adult and juvenile stages of the parasite. Emergence of triclabendazole-resistant F hepatica populations has been reported in a number of countries, including the UK, but the overall prevalence and distribution of triclabendazole resistance is unknown. In this study, the authors established the presence of reduced efficacy of triclabendazole in sheep flocks in England and Wales, using a validated composite faecal egg count reduction test. Seventy-four sheep farms were sampled from Wales, southwest, northwest and northeast England between Autumn 2013 and Spring 2015. F hepatica eggs were detected in samples from 42/74 farms. Evidence of a lack of efficacy of triclabendazole was detected on 21/26 farms on which the faecal egg count reduction test was completed, with faecal egg count reductions ranging from 89 per cent to 0per cent. Regression analysis suggested that both prevalence of F hepatica and lack of efficacy of triclabendazole were spatially correlated, with higher faecal egg counts and lower percentage reductions on farms located in the northwest of England, and Wales. Overall, the results show that reduced efficacy of triclabendazole is present across England and Wales, with a complete lack of therapeutic efficacy observed on 9/26 farms.

Flukicide efficacy against Fasciola hepatica of Triclabendazole and Nitroxynil in cattle of the central valley of Chile.

On a farm with permanent history of fasciolasis a study was performed aimed to know the efficacy of triclabendazole (TCBZ) and then to contrast with that of nitroxynil. Thirty-nine cattle naturally infected with Fasciola hepatica were randomly allocated into 4 experimental groups: Group 1 (control) was left untreated. Group 2 was treated with of 12 mg/kg body weight (bw) of TCBZ by oral route. Group 3 treated with 24 mg/kg bw TCBZ orally. Group 4 was treated with 10 mg/kg bw of nitroxynil subcutaneously. The anthelmintic efficacy was calculated as the percentage of reduction in faecal egg count (FEC) at 14 and 28 d post-treatment. Results indicated that there were no significant differences in the percentage of FEC reduction between control group and the groups treated with 12 or 24 mg/kg of TCBZ. On the contrary, the treatment with nitroxinyl significantly reduced the FEC and decreased the percentage of positive animals. In conclusion, Fasciola hepatica is reported for first time as resistant to TCBZ in Chile, which highlights the need of rotating drugs and assessing the efficacy of the administered drug in order to avoid the selection of resistant worms.

Flukicide efficacy against Fasciola hepatica of Triclabendazole and Nitroxynil in cattle of the central valley of Chile / Avaliação da eficácia de triclabendazol e nitroxinil para o tratamento da infeção por Fasciola hepatica em bovinos do Vale Central do Chile

Abstract On a farm with permanent history of fasciolasis a study was performed aimed to know the efficacy of triclabendazole (TCBZ) and then to contrast with that of nitroxynil. Thirty-nine cattle naturally infected with Fasciola hepatica were randomly allocated into 4 experimental groups: Group 1 (control) was left untreated. Group 2 was treated with of 12 mg/kg body weight (bw) of TCBZ by oral route. Group 3 treated with 24 mg/kg bw TCBZ orally. Group 4 was treated with 10 mg/kg bw of nitroxynil subcutaneously. The anthelmintic efficacy was calculated as the percentage of reduction in faecal egg count (FEC) at 14 and 28 d post-treatment. Results indicated that there were no significant differences in the percentage of FEC reduction between control group and the groups treated with 12 or 24 mg/kg of TCBZ. On the contrary, the treatment with nitroxinyl significantly reduced the FEC and decreased the percentage of positive animals. In conclusion, Fasciola hepatica is reported for first time as resistant to TCBZ in Chile, which highlights the need of rotating drugs and assessing the efficacy of the administered drug in order to avoid the selection of resistant worms.

Resumo Em uma fazenda com histórico de fasciolose permanente, foi realizado um estudo com o objetivo de conhecer a eficácia do triclabendazol (TCBZ) e depois contrastar com o do nitroxinil. Trinta e nove bovinos naturalmente infectados com Fasciola hepatica foram distribuídos aleatoriamente em 4 grupos experimentais: Grupo 1 (controle), sem tratamento. O grupo 2 foi tratado com 12 mg/kg de peso vivo (PV) do TCBZ por via oral (VO). Grupo 3 tratado com 24 mg/kg de PV TCBZ por VO. O grupo 4 foi tratado com 10 mg /kg de PV Nitroxinil via subcutânea. A eficácia anti-helmíntica foi calculada comparando a percentagem de redução na contagem de ovos fecais (FEC) 14 e 28 dias pós tratamento. Não houve diferença significativa na porcentagem de redução FEC entre o grupo controle e os grupos tratados com 12 ou 24 mg/kg de TCBZ. Entretanto, o tratamento com nitroxinil reduziu significativamente o FEC e diminuiu a porcentagem de animais positivos. Em conclusão, a Fasciola hepatica é relatada pela primeira vez como resistente ao TCBZ no Chile, o que destaca a necessidade de realizar uma rotação em relação aos medicamentos anti-helmínticos e avaliar a eficácia do mesmo, a fim de evitar a seleção de vermes resistentes.

Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections.

Opisthorchiasis, caused by the foodborne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People's Democratic Republic, pharmacokinetic samples were obtained from 125 adult and adolescent O. viverrini-infected patients treated with 400 mg tribendimidine following the design of a sparse sampling scheme at 20 min and 2, 7.75, 8, and 30 h after treatment using dried blood spot sampling. Pharmacokinetic data for the metabolites deacetylated amidantel (dADT) and acetylated dADT (adADT) were pooled with data from two previous ascending-dose trials and evaluated using nonlinear mixed-effects modeling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT, followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between O. viverrini cure and both the dADT maximum concentration and the area under the concentration-time curve (P < 0.001), with younger age being associated with a higher probability of cure. Modeling and simulation of exposures in patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment, praziquantel, for the treatment of O. viverrini infections.

Using serum s100-ß protein as a biomarker for comparing silent brain injury in carotid endarterectomy and carotid artery stenting.

BACKGROUND: S100-ß protein has been introduced as a sensitive biomarker of silent cerebral injury. This study compares its serum levels before, during, and 24 hours after carotid artery stenting (CAS) and carotid endarterectomy (CEA). METHODS: We measured serum level of S100-ß in arterial blood before (S100Ba), during (S100Bb), and 24 hours after (S100Bc) CAS and CEA. We assessed differences in S100-ß levels using non-parametric tests. We analyzed the relationship between carotid plaque type (echolucency) and S100-ß protein level. We also examined its relation to the oximetry results in the CEA group (ipsilateral and contralateral). RESULTS: Thirty patients were enrolled, including 15 CAS and 15 CEA patients, with no significant differences in baseline atherosclerotic characteristics. There was no significant difference in S100Ba or S100Bb levels between CAS and CEA patients. However, a significant difference was found in S100Bc: 331.3 pg/mL (IQ range 56.4-583.5) for CAS vs. 76.3 pg/mL (IQ range 29.7-117.4) for CEA (P=0.01). Type I and II plaques were associated with the higher S100Bc levels in CAS (P=0.048). S100Bc was higher in CEA patients when the contralateral cerebral hemisphere had oximetry values less than 60% (P=0.043). CONCLUSIONS: Our study suggests that CAS might produce silent brain injury. Moreover, vulnerable plaques might be associated with higher levels of S100-ß protein, especially in CAS. This pilot study demonstrates that S100-ß is a useful biomarker for silent brain injury in carotid revascularization. Large scale studies are still needed to confirm these findings.