Integrative EcoHealth/One Health Approach for Sustainable Liver Fluke Control: The Lawa Model.

The Lawa model is a successful integrative and sustainable means of controlling opisthorchiasis in Thailand. The model integrates the EcoHealth and One Health holistic approaches with systems thinking to target the interruption of Opisthorchis viverrini transmission. Using the six principles of EcoHealth and emphasizing the three domains of One Health (human-animal-ecosystem), the program targets each step of the parasite life cycle, thus maximizing the chances of interrupting the life cycle of the parasite. The main drivers of success are the village health volunteers and health-promoting hospitals, together with the support of the government and academia. The success of the model has led to continuous expansion, adoption nationally and internationally and application to the control of other neglected tropical diseases as well as noncommunicable diseases.

Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro.

The liver fluke Opisthorchis felineus (Rivolta, 1884) is the causative agent of opisthorchiasis felinea in Eurasia. Opisthorchiasis is a serious human and fish-eating animal's disease affecting bile ducts and the gall bladder. Currently, the main drug for specific therapy of opisthorchiasis is praziquantel. We have previously shown that azole inhibitors of O. felineus cytochrome P450 significantly reduced survival of the worms in vitro. Here, we studied in vitro anthelmintic effects of drug combinations involving azole substances approved by the US Food and Drug Administration together with praziquantel against adult or juvenile O. felineus liver flukes. A synergistic interaction was shown for praziquantel-clotrimazole (CI = 0.68) combination and for praziquantel-miconazole (CI = 0.68) combination against adult helminths in vitro. Praziquantel-miconazole (CI = 0.30) had a strongly synergistic effect against newly excysted metacercariae. We also tested anthelmintic effects of azole substances and their combinations with praziquantel in vivo in an animal model of chemotherapy. The treatment of juvenile worms (1 day postinfection) with 100 mg/kg miconazole resulted in a worm burden reduction (WBR) of 37.5% (P = 0.049), with 100 mg/kg clotrimazole causing a WBR of 31.25% (P = 0.025). The treatment of adult worms (5-6 weeks postinfection) with 100 mg/kg or 200 mg/kg miconazole yielded a WBR of 23.8% (P = 0.01) and 21.4% (P = 0.006), respectively. When praziquantel was administered together with clotrimazole or with miconazole, a WBR slightly greater than the effect of ED50 praziquantel was observed (WBR of 59.5 and 54.7%, respectively).In conclusion, the synergistic effect of the praziquantel-clotrimazole and praziquantel-miconazole combinations observed in vitro was not confirmed in vivo. Thus, this combination chemotherapy revealed no benefits over praziquantel monotherapy in the treatment of opisthorchiasis felinea.

Identification of novel natural inhibitors of Opisthorchis felineus cytochrome P450 using structure-based screening and molecular dynamic simulation.

Opisthorchis felineus is the etiological agent of opisthorchiasis in humans. O. felineus cytochrome P450 (OfCYP450) is an important enzyme in the parasite xenobiotic metabolism. To identify the potential anti-opisthorchid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,65,869) against the OfCYP450. The ligands were screened against OfCYP450 in four sequential docking modes that resulted in 361 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 10 compounds were found to fit well with re-docking studies. After refinement by docking and drug-likeness analyses, four potential inhibitors (ZINC2358298, ZINC8790946, ZINC70707116, and ZINC85878789) were identified. These ligands with reference compounds (itraconazole and fluconazole) were further subjected to molecular dynamics simulation (MDS) and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the OfCYP450 and bound complexes. The binding energy analyses were also calculated. The results suggested that the compounds had a negative binding energy with -259.41, -110.09, -188.25, -163.30, -202.10, and -158.79 kJ mol-1 for itraconazole, fluconazole, and compounds with IDs ZINC2358298, ZINC8790946, ZINC70707116, and ZINC85878789, respectively. These lead compounds displayed significant pharmacological and structural properties to be drug candidates. On the basis of MDS results and binding energy analyses, we concluded that ZINC8790946, ZINC70707116, and ZINC85878789 have excellent potential to inhibit OfCYP450.

[Chronorehabilitation of the patients suffering from chronic cholecystitis with concomitant gallbladder dysfunction and opisthorchiasis]. / Khronoreabilitatsiia bol'nykh khronicheskim kholetsistitom s disfunktsiei zhelchnogo puzyria i opistorkhozom.

The importance of the development of the effective rehabilitative measures for the patients suffering from chronic cholecystitis with concomitant gallbladder dysfunction and opisthorchiasis is beyond question. The adequate methods for the rehabilitation of the patients after an intensive de-worming remain to be developed. It is known that de-worming is not infrequently followed by the immediate amplification of the manifestations of the stagnation of bile in the gallbladder that become even more pronounced than before the de-worming procedure. With the purpose of improving the effectiveness of the spa and health resort-based rehabilitation and prevention of the complications, it is recommended to make use of the modern therapeutic physical factors to be prescribed taking into consideration the characteristics of the biological rhythms in the functional activity of the biliary system in the individual patients. The most effective rehabilitation methods for the treatment of the pathology in question include the application of the therapeutic physical factors known to produce the beneficial effect on the functional state of the biliary system and exert the normalizing influence on the structure of the biological rhythms of the functional activity of various organs and systems. We used a range of approaches for the treatment of 123 patients with chronic cholecystitis and concomitant gallbladder dysfunction plus opisthorchiasis including extremely high-frequency electromagnetic irradiation (EHF therapy) in the combination with the oral intake of the choleretic herbal remedies followed by the transverse galvanization of the epigastric region with due regard for the phase of the rhythm of the functional activity of the gallbladder. The results of such treatment gave evidence of the positive dynamics of all the studied indicators of the functional activity of the biliary system and the organism as a whole which suggests the highest therapeutic effect (87.9%) of the proposed treatment that was maintained during 6 to 12 months.

Balancing biomedical and ecological perspectives in research framing of liver fluke and cholangiocarcinoma in NE Thailand.

This review examines the association of Asian liver flukes and cholangiocarcinoma (CCA) from the standpoint of two contrasting research perspectives: that aligned with the biomedical model predominantly employed to date; and, that aligned with ecological (and evolutionary) thinking increasingly being used to frame research questions that address this association in Northeast Thailand. An examination of the assumptions that underlie most of this research, requisite of evidence-based health research, shows how a broadened research frame that incorporates 'ecologic' perspectives provides alternatives to the prevailing scientific interpretations and public narrative. A more balanced and integrative research approach that combines elements of the biomedical model and ecologic models of health is suggested to overcome the limited progress toward the reduction of liver fluke infection prevalence and CCA incidence in this region. Similarly, this approach presents an opportunity to further enhance collaborative research programs involving Parasitology and the complementary fields in the health sciences.

Uncovering the Pathogenic Landscape of Helminth (Opisthorchis viverrini) Infections: A Cross-Sectional Study on Contributions of Physical and Social Environment and Healthcare Interventions.

BACKGROUND: Helminth infections have proven recalcitrant to control by chemotherapy in many parts of Southeast Asia and indeed farther afield. This study isolates and examines the influence of different aspects of the physical and social environment, and uneven intervention effort contributing to the pathogenic landscape of human Opisthorchis viverrini infections. METHODOLOGY: A cross-sectional survey, involving 632 participants, was conducted in four villages in northeast Thailand to examine the impact on prevalence and parasite burden of the reservoir dam environment, socio-economic, demographic, and behavioral factors, and health center intervention efforts. Formalin-ether concentration technique was used for diagnoses, and multivariate models were used for analyses. PRINCIPAL FINDINGS: The importance attributed to O. viverrini infections varied among health centers in the four study villages. Villages where O. viverrini infections were not prioritized by the health centers as the healthcare focus were at a higher risk of infection (prevalence) with odds ratio (risk factor) of 5.73 (3.32-10.27) and p-value < 0.01. Priority of healthcare focus, however, did not appear to influence behavior, as the consumption of raw fish, the main source of O. viverrini infections in the study area, was 11.4% higher in villages that prioritized O. viverrini infections than those that did not (p-value = 0.01). Landscape variation, notably proximity to reservoir, affects vulnerability of local population to infection. Infection intensity was higher in population located closer to the reservoir with risk ratio of 2.09 (1.12-4.02) and p-value < 0.01. Patterns of infection intensities among humans were found to match fish infection intensity, where higher infection intensities were associated with fish obtained from the reservoir waterbody type (p-value = 0.023). CONCLUSIONS/SIGNIFICANCE: This study demonstrated the importance of environmental influence and healthcare focus as risk factors of infections in addition to the socio-economic, demographic, and behavioral factors commonly explored in existing studies. The reservoir was identified as a crucial source to target for opisthorchiasis intervention efforts and the need to consider infection intensity in disease control efforts was highlighted. The holistic approach in this study, which underscores the close relationship between the environment, animals, and humans in development of human infections or diseases, is an important contribution to the framework of One Health approach, where consideration of helminth diseases has largely been overlooked.

Anti-inflammatory, antioxidant and hepatoprotective effects of Thunbergia laurifolia Linn. on experimental opisthorchiasis.

Thunbergia laurifolia Linn (Rang Chuet) possesses antioxidant and anti-inflammatory properties as well as anticancer activities. The aim of the present study was to evaluate the efficacy of T. laurifolia in reducing inflammation from pathological changes in Syrian hamsters infected with the human liver fluke Opisthorchis viverrini. Hamster groups were also administered N-nitrosodimethylamine (NDMA) and treated with T. laurifolia. Light microscopic observation of histopathological changes, liver function tests for alanine transaminase (ALT) and alkaline phosphatase (ALP) and kidney function tests for blood urea nitrogen (BUN) and creatinine were performed. Antioxidant effects of both fresh and dried Rang Chuet solutions were observed. Analysis of the histopathological changes showed anti-inflammatory properties, both in the case of O. viverrini infection or with NDMA administration, by reducing the aggregation of inflammatory cells surrounding the hepatic bile ducts as indicated by normal serum ALT, ALP, BUN and creatinine levels in treated Syrian hamsters. The present study found that fresh and dried Rang Chuet solutions clearly reduced the inflammatory cells in both O. viverrini-infected and NDMA-administered groups and was correlated with the total antioxidant capacity. These findings suggest that T. laurifolia possesses antioxidant and anti-inflammatory properties and that its application may be useful for prevention of the inflammatory process, one of the risk factors of O. viverrini-associated cholangiocarcinoma (CCA).

[Systemic responsiveness and the efficiency of antihomotoxic therapy for chronic opisthorchiasis. 3. Responsiveness].

The authors consider systematic responsiveness in chronic opisthorchiasis and a relationship between acute inflammation and responsiveness. A number of regularities that take place in the patho- and sanogenesis of chronic disease in general and that are important in the evaluation of the severity and prognosis of the disease and the efficiency of therapy are demonstrated on a model of severe opisthorchiasis. The reversion syndrome indicative of recovered responsiveness during therapy is described in detail. Differences in the interpretation of the helminthoovoscopic findings are shown in the context of the priority of clinical data.

[The technology for manufacturing antiparasitic preparations. 6. The development of a technology for producing the anthelmintic Azinox (praziquantel) and the evaluation of its toxic and anthelmintic properties]. / Tekhnologiia proizvodstva protivoparazitarnykh preparatov. 6. Razrabotka tekhnologii polucheniia antigel'mintika Azinoksa (prazikvantelia) i otsenka ego toksicheskikh i protivogel'mintnykh svoistv.

The paper outlines a procedure for manufacturing the anthelminthic Azinox (biltricide) using the new interfacial transfer catalyst benzyl-di-propyl (beta-hydroxyethyl)ammonium chloride. Azinox has been shown to be identical to biltricide (praziquantel) in its properties. Azinox tests on models of Opisthorchis felineus in golden hamsters and of Hymenolepis nana in albino outbred mice have indicated that the agent is not inferior to biltricide in its antitrematodal and anticestodal activities. Azinox displayed a high activity at the preimaginal stages of O. felineus and H. nana and at the larval stage of H.nana.

[The results of an experimental study of an anti-Opisthorchis preparation made from plant raw material]. / Rezul'taty éksperimental'nogo izucheniia protivoopistorkhoznogo preparata iz rastitel'nogo syr'ia.

Agents and biologically active fractions derived from medical plants grown in Siberia were tested in vitro and in vivo. The extract from the aspen bark displayed the highest antiopisthorchiatic activity. This agent given at a concentration of 10(-3) caused 100% death of Opisthorchis 72 hours later. In golden hamster experiments, the efficiency of the aspen bark extract was 73.48-83.0%. Butanolic and ethylacetatic extracts were found to have the greatest antiopisthorchiatic activity. The results of chemical and chromatographic studies indicated that active fractions contained salicine and its derivatives. The aspen bark extract produces no substantial toxic effect on laboratory animals and belongs to the class "Low-toxic substances".