Triclabendazole for the treatment of human fascioliasis and the threat of treatment failures.

INTRODUCTION: The only drug effective against the infection caused by Fasciola hepatica or F. gigantica is triclabendazole (TCBZ), recommended by the WHO and recently approved by the FDA. Here, we describe the evolution of TCBZ regimens and the emergence of TCBZ failure to Fasciola infection. AREAS COVERED: The present review focuses on the evidence of TCBZ for the treatment of fascioliasis. For acute fascioliasis, there is a lack of studies to measure the presence of eggs of Fasciola in stool samples on the follow-up after initial TCBZ treatment. For chronic fascioliasis, WHO recommends a single oral dose of TCBZ 10 mg/kg whereas CDC recommends two doses of TCBZ 10 mg/kg 12 h apart. Incremental number of treatment failures have been documented worldwide. There are currently no therapeutic alternatives for the treatment of fascioliasis in humans. EXPERT OPINION: Most cases of human fascioliasis are successfully treated with TCBZ, but some continue excreting eggs in the stools despite 1-2 standard of care regimens of TCBZ. A precise regimen is unclear for those patients who fail the initial treatment with TCBZ. Further clinical trials are needed to address the possible TCBZ emerging resistance.

Improving the Dissolution of Triclabendazole from Stable Crystalline Solid Dispersions Formulated for Oral Delivery.

Triclabendazole belongs to the class II/IV of the Biopharmaceuticals Classification System, and its low aqueous solubility represents a major drawback during the development of effective dosage forms. Therefore, the goal of this study was to elucidate whether polymeric solid dispersions would represent a suitable approach to overcome such disadvantage. Due to the lack of information on triclabendazole release, four different dissolution media were evaluated to analyze drug dissolution rate. The polymeric solid dispersions were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The selected final formulations were further stored for 24 months, and their physical stability was evaluated by means of X-ray diffraction and drug dissolution assays. Drug solubility studies indicated that poloxamer 407 (P407) solubilized a higher amount of drug than polyethylene glycol 6000. Drug-to-carrier ratio, nature of the selected carriers, and the type of dissolution media were important factors for increasing dissolution. By infrared spectroscopy, there were no specific interactions between the drug and polymers. The physicochemical characterization of the systems showed a detectable evidence of drug amorphization by increasing the carrier ratio. Micromeritic studies indicated that raw triclabendazole, physical mixtures, and reference formulation showed poor flow properties, in contrast to the triclabendazole:P407 solid dispersion sample. Both the crystalline properties and dissolution rate of selected samples were very similar after 24 months at room temperature. Thus, considering physical stability and dissolution studies, the development of the solid dispersion is a very suitable methodology to improve triclabendazole dissolution and, potentially, its biopharmaceutical performance.

[Pulmonary paragonimiasis. Pediatric case report]. / Paragonimiasis pulmonar. Reporte de caso pediátrico.

Paragonimiasis is a parasite infection caused by several species of Paragonimus, a trematode that is transmitted through the consumption of raw or undercooked crabs and that has been found in the subtropical areas of America, Asia and Africa. This infection mainly affects the lungs, causing clinical and radiological manifestations very similar to pulmonary tuberculosis, so it should always be included in the differential diagnosis. We present the case of a 7-year-old school patient, hospitalized with the diagnosis of pulmonary paragonimiasis, who had a favorable evolution after receiving treatment with triclabendazole.

La paragonimiasis es una parasitosis provocada por varias especies de Paragonimus, un trematodo que se transmite a través del consumo de cangrejos poco cocidos o crudos y que se ha encontrado en áreas tropicales y subtropicales de América, Asia y África. Esta infección afecta, principalmente, los pulmones y provoca manifestaciones clínicas y radiológicas muy similares a la tuberculosis pulmonar, por lo cual siempre debe incluirse dentro del diagnóstico diferencial. Se presenta el caso de una niña escolar de 7 años de edad, hospitalizada con el diagnóstico de paragonimiasis pulmonar, quien presentó evolución favorable luego de recibir tratamiento con triclabendazol.

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.

Effects of fenbendazole and triclabendazole on the expression of cytochrome P450 1A and flavin-monooxygenase isozymes in bovine precision-cut liver slices.

Combinations of the anthelmintics fenbendazole (FBZ) and triclabendazole (TCBZ) have shown enhanced efficacy against the liver fluke Fasciola hepatica. This study aimed to measuring the constitutive expression of CYP1A1, CYP1A2, FMO1 and FMO3, thought to be involved in the metabolism of those compounds, by using an absolute quantitative real time (RT)-PCR approach in bovine precision-cut liver slices (PCLS). It also aimed to characterize the effects of FBZ and TCBZ (alone and in combination) on the expression and activity of the aforementioned isozymes. Both FMO1 and FMO3 were equally represented in control PCLS, whereas CYP1A2 was expressed more than CYP1A1 (P<0.05). PCLS cultured in the presence of beta naphthoflavone (ß-NF; CYP1A inducer) had higher mRNA levels of CYP1A1, CYP1A2, FMO1 and FMO3 (P<0.05). No clear-cut evidence of transcriptional effects of the anthelmintics were recorded. After incubation of PCLS with FBZ, there was a significant increase (P<0.05) vs. controls and TBCZ was observed for CYP1A1. PCLS treated with FBZ showed a higher (P<0.05) expression of CYP1A2 compared to controls, TCBZ alone, and the combination FBZ+TCBZ. The gene expression profiles of FMO1 and FMO3 were not affected by the presence of the anthelmintics; the only exception was an upregulation of FMO3 by TCBZ alone. The observed transcriptional effects of the xenobiotics were not mirrored by increased enzyme activities using prototypical substrates of the isozymes under study. Although further confirmatory studies are needed, these results suggest that PCLS represent an alternative in vitro tool for studies on the expression, regulation and function of relevant xenobiotic-metabolizing enzymes in cattle.