The nematode serotonin-gated chloride channel MOD-1: A novel target for anthelmintic therapy.

Anthelmintics are used to treat human and veterinary parasitic diseases and to reduce crop and livestock production loss associated with parasitosis. The free-living nematode Caenorhabditis elegans, a model system for anthelmintic drug discovery, has a serotonin (5-HT)-gated chloride channel, MOD-1, which belongs to the Cys-loop receptor family and modulates locomotory and behavioral functions. Since MOD-1 is unique to nematodes, it is emerging as an attractive anthelmintic drug target, but details of MOD-1 function are unclear. Here, we revealed novel aspects of MOD-1 function from the molecular level to the organism level and identified compounds targeting this receptor, which may provide new directions for anthelmintic drug discovery. We used whole-cell current recordings from heterologously expressed MOD-1 to show that tryptamine (Tryp), a weak partial agonist of vertebrate serotonin type 3 (5-HT3) receptors, efficaciously activates MOD-1. A screen for modulators revealed that GABAergic ligands piperazine (PZE) and muscimol reduce 5-HT-elicited currents, thus identifying novel MOD-1 allosteric inhibitors. Next, we performed locomotor activity assays, and we found 5-HT and Tryp rapidly decrease worm motility, which is reversible only at low 5-HT concentrations. Mutants lacking MOD-1 are partially resistant to both drugs, demonstrating its role in locomotion. Acting as an antagonist of MOD-1, we showed PZE reduces the locomotor effects of exogenous 5-HT. Therefore, Tryp- and PZE-derived compounds, acting at MOD-1 through different molecular mechanisms, emerge as promising anthelmintic agents. This study enhances our knowledge of the function and drug selectivity of Cys-loop receptors and postulates MOD-1 as a potential target for anthelmintic therapy.

Simple method for the determination of anthelmintic drugs in milk intended for human consumption using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Helminth infections in animals to be consumed by humans are an important medical and public health problem. Pharmaceutical research has focused on developing new anthelmintic drugs for parasite control in these animals. However, the incorrect use of anthelmintics can leave residues in animal products intended for human consumption. Their determination is therefore crucial in terms of food safety. RESULTS: In this work, a simple and sensitive method has been developed for the analysis of anthelmintic drugs in milk. The method involves extraction of the analytes using a QuEChERS (quick, easy, cheap, effective, rugged, and safe) method, and separation and determination by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The use of a core-shell column significantly reduced the analysis time compared with conventional columns. The method was validated and applied to the analysis of different commercial milk samples: whole, semi-skimmed and skimmed cows' milk, and goats' milk. None of the benzimidazoles studied was found in the samples analyzed, so these were spiked with the analytes at three concentration levels (10, 50, and 100 µg kg-1 ). CONCLUSIONS: The proposed method provided high sensitivity compared with other methods for the determination of anthelmintics in milk samples, at concentration levels well below the established maximum residue limit (MRLs) values. The proposed method is simple, easy, precise, accurate, and leads to good recovery levels. It can be used successfully for the routine analysis. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses.

Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to humans for the treatment of multiple parasitic infectious diseases. The first-in-human study evaluating the disposition of oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg of body weight shows that oxfendazole pharmacokinetics is substantially nonlinear, which complicates correlating oxfendazole dose to exposure. To quantitatively capture the relation between oxfendazole dose and exposure, a population pharmacokinetic model for oxfendazole and its metabolites, oxfendazole sulfone and fenbendazole, in humans was developed using a nonlinear mixed-effect modeling approach. Our final model incorporated mechanistic characterization of dose-limited bioavailability as well as different oxfendazole metabolic processes and provided insight into the significance of presystemic metabolism in oxfendazole and metabolite disposition. Oxfendazole clinical pharmacokinetics was best described by a one-compartment model with nonlinear absorption and linear elimination. Oxfendazole apparent clearance and apparent volume of distribution were estimated to be 2.57 liters/h and 35.2 liters, respectively, at the lowest dose (0.5 mg/kg), indicating that oxfendazole is a low extraction drug with moderate distribution. The disposition of both metabolites was adequately characterized by a one-compartment model with formation rate-limited elimination. Fenbendazole formation from oxfendazole was primarily through systemic metabolism, while both presystemic and systemic metabolism were critical to the formation of oxfendazole sulfone. Our model adequately captured the concentration-time profiles of both oxfendazole and its two metabolites in healthy adults over a wide dose range. The model can be used to predict oxfendazole disposition under new dosing regimens to support dose optimization in humans.

Exploring the complex associations over time among albendazole treatment, cyst evolution, and seizure outcomes in neurocysticercosis.

OBJECTIVE: To develop a causal model for the occurrence of neurocysticercosis (NC)-related seizures and test hypotheses generated from the model. METHODS: We used data from a randomized controlled trial comparing albendazole with placebo among patients newly diagnosed with NC. Based on our causal model, we explored the associations among albendazole treatment, NC cyst evolution, and seizure outcomes over 24 months of follow-up using generalized linear mixed effect models. RESULTS: We included 153 participants, of whom 51% received albendazole. The association between seizure outcomes and treatment over time demonstrated lack of linearity and heterogeneity, requiring the inclusion of time-treatment interaction terms for valid modeling. Participants in the albendazole group had fewer seizures overall and of partial onset at all time points compared with the placebo group, but the difference increased over the first few months following treatment, then decreased over time. Generalized seizures exhibited a more complex association; those in the albendazole group had fewer seizures compared with those in the placebo group for the first few months after treatment, and then the association reversed and those in the placebo arm had fewer seizures. Adjusting for the number of NC cysts in each phase resulted in an attenuation of the strength of association between albendazole and seizure outcomes, consistent with mediation. Among participants in whom all cysts had disappeared (n = 21), none continued to have seizures. SIGNIFICANCE: Albendazole treatment is associated with a possible reduction in focal seizures in the short term (3-6 months), perhaps by hastening the resolution of the cysts. However, the effect is not discernible over the long term, because most cysts either calcify or resolve completely, regardless of whether treated with albendazole. The stage of evolution of the cysticercus is an important consideration in the evaluation of albendazole effect on seizure outcome.

Host pharmacokinetics and drug accumulation of anthelmintics within target helminth parasites of ruminants.

Anthelmintic drugs require effective concentrations to be attained at the site of parasite location for a certain period to assure their efficacy. The processes of absorption, distribution, metabolism and excretion (pharmacokinetic phase) directly influence drug concentrations attained at the site of action and the resultant pharmacological effect. The aim of the current review article was to provide an overview of the relationship between the pharmacokinetic features of different anthelmintic drugs, their availability in host tissues, accumulation within target helminths and resulting therapeutic efficacy. It focuses on the anthelmintics used in cattle and sheep for which published information on the overall topic is available; benzimidazoles, macrocyclic lactones and monepantel. Physicochemical properties, such as water solubility and dissolution rate, determine the ability of anthelmintic compounds to accumulate in the target parasites and consequently final clinical efficacy. The transcuticular absorption process is the main route of penetration for different drugs in nematodes and cestodes. However, oral ingestion is a main route of drug entry into adult liver flukes. Among other factors, the route of administration may substantially affect the pharmacokinetic behaviour of anthelmintic molecules and modify their efficacy. Oral administration improves drug efficacy against nematodes located in the gastroinestinal tract especially if parasites have a reduced susceptibility. Partitioning of the drug between gastrointestinal contents, mucosal tissue and the target parasite is important to enhance the drug exposure of the nematodes located in the lumen of the abomasum and/or small intestine. On the other hand, large inter-animal variability in drug exposure and subsequent high variability in efficacy is observed after topical administration of anthelmintic compounds. As it has been extensively demonstrated under experimental and field conditions, understanding pharmacokinetic behaviour and identification of different factors affecting drug activity is important for achieving optimal parasite control and avoiding selection for drug resistance. The search for novel alternatives to deliver enhanced drug concentrations within target helminth parasites may contribute to avoiding misuse, and prolong the lifespan of existing and novel anthelmintic compounds in the veterinary pharmaceutical market.

Entry of Migrant Workers to Malaysia: Consideration to Implement Mass Drug Administration Against Intestinal Parasitic Infections.

Over the last five decades, widespread industrialisation and urbanisation have resulted in the influx of low-skilled workers, particularly from Southeast and West Asia to Malaysia. The current practice for migrant workers entry for employment requires mandatory medical screening for infectious diseases. However, screening for parasitic infections in Malaysia is woefully inadequate. Many migrants come from low-income countries where parasitic infections are common, which may have public health implications for their overall well-being as parasitic infections, although not critical, may impact their overall productivity. The high prevalence of intestinal parasitic infections (IPIs) recorded among migrant workers in Malaysia necessitates improvement in the national health policy to include mandatory mass administration of a single dose of anthelmintic drugs to all low-skilled migrant labourers, particularly upon entry into the country, admission, and encourage continuous surveillance. A constant stream of migrant labourers is anticipated, potentially resulting in an ongoing occurrence of parasitic infections within the population. The implementation of economic measures like health awareness initiatives, routine deworming campaigns, and improved sanitation facilities holds the potential to reduce the spread of these infections notably. More often than not, taking preventive actions proves to be more financially efficient over time compared to addressing severe infections at a later stage.

Photodegradation of anthelmintic drugs under natural sunlight and simulated irradiation: kinetics, mechanisms, transformation products, and toxicity.

Albendazole (ALB) and bithionol (BIT) are two anthelmintic drugs (ADs) with high consumption from benzimidazole group and diphenylsulfide group, respectively. However, information on the transformation of the two anthelmintics under environmental condition is scare. Therefore, in the present study, we investigated the natural attenuation of the two ADs in the aquatic environment, including biodegradation, hydrolysis, and direct and indirect photodegradation. The direct photodegradation occupied a vast portion among other degradation pathways of the two ADs in natural water, with near-surface summer half-lives of 0.272-0.387 h and 0.110-0.520 h for ALB and BIT, respectively. Suspended particles in water were found to facilitate the photodegradation of the two ADs. Study on the indirect photodegradation demonstrated the positive roles of singlet oxygen (1O2) and excited triplet dissolved organic matter (3DOM*) in the photolysis of the two ADs, whereas the hydroxyl radical (•OH) affected little on the overall photodegradation procedures of ALB due to the scavenging effect of HCO3-. Dual effects of DO, DOM, HCO3-, NO3-, and NO2- on the photodegradation of ALB and BIT were perceived. Transformation intermediates (TIs) of the two ADs during photodegradation were analyzed by UHPLC-QTOF-MS. Six TIs of ALB were identified, including a broad-spectrum fungicide carbendazim and another common AD ricobendazole. Two TIs of BIT yielded from dechlorination were also detected. Probable transformation mechanism and predicted aquatic ecotoxicity based on the identified TIs were unveiled.

Soluble thiabendazolium salts with anthelminthic properties.

Thiabendazole is an anthelmintic drug used to treat strongyloidiasis (threadworm), cutaneous and visceral larva migrans, trichinosis, and other parasites. The active pharmaceutical ingredient is typically administered orally as tablets that should be chewed before swallowing. Current formulations combine the active ingredient with excipients, including sodium saccharinate as a sweetener. Thiabendazole's low aqueous solubility hinders fast dissolution and absorption through the mucous membranes. We sought to reformulate this medicine to improve both solubility and palatability. We utilized the possibility of protonation of the azole nitrogen atom and selected four different hydrogen donors: saccharin, fumaric, maleic, and oxalic acids. Solvothermal synthesis resulted in salts with each co-former, whereas neat and liquid-assisted grinding enabled the synthesis of additional formulations. Product formation was observed by powder X-ray diffraction. To better understand the structural basis of the proton transfer, we solved the crystal structures of the salts with saccharin, maleic acid, and oxalic acid using single-crystal X-ray diffraction. The structure of the salt with fumaric acid was solved by powder X-ray diffraction. We further characterized the salts with vibrational spectroscopic and thermoanalytical methods. We report a broad tunability of the aqueous solubility of thiabendazole by salt formation. Reformulation with maleic acid provided a 60-fold increase in solubility, while saccharin and oxalic acid gave a modest improvement. Fumaric acid resulted in a solid with only slightly higher solubility. Furthermore, saccharin is a sweetener, while the acids taste sour. Therefore, the salts formed also result in an intrinsic improvement of palatability. These results can inform new strategies for oral and chewable tablet formulations for treating helminthic infections.

Repurposing Selamectin as an Antimicrobial Drug against Hospital-Acquired Staphylococcus aureus Infections.

The emergence of multidrug-resistant strains requires the urgent discovery of new antibacterial drugs. In this context, an antibacterial screening of a subset of anthelmintic avermectins against gram-positive and gram-negative strains was performed. Selamectin completely inhibited bacterial growth at 6.3 µg/mL concentrations against reference gram-positive strains, while no antibacterial activity was found against gram-negative strains up to the highest concentration tested of 50 µg/mL. Given its relevance as a community and hospital pathogen, further studies have been performed on selamectin activity against Staphylococcus aureus (S. aureus), using clinical isolates with different antibiotic resistance profiles and a reference biofilm-producing strain. Antibacterial studies have been extensive on clinical S. aureus isolates with different antibiotic resistance profiles. Mean MIC90 values of 6.2 µg/mL were reported for all tested S. aureus strains, except for the macrolide-resistant isolate with constitutive macrolide-lincosamide-streptogramin B resistance phenotype (MIC90 9.9 µg/mL). Scanning Electron Microscopy (SEM) showed that selamectin exposure caused relevant cell surface alterations. A synergistic effect was observed between ampicillin and selamectin, dictated by an FIC value of 0.5 against methicillin-resistant strain. Drug administration at MIC concentration reduced the intracellular bacterial load by 81.3%. The effect on preformed biofilm was investigated via crystal violet and confocal laser scanning microscopy. Selamectin reduced the biofilm biomass in a dose-dependent manner with minimal biofilm eradication concentrations inducing a 50% eradication (MBEC50) at 5.89 µg/mL. The cytotoxic tests indicated that selamectin exhibited no relevant hemolytic and cytotoxic activity at active concentrations. These data suggest that selamectin may represent a timely and promising macrocyclic lactone for the treatment of S. aureus infections.

Ionic liquid-based dispersive liquid-liquid microextraction of anthelmintic drug residues in small-stock meat followed by LC-ESI-MS/MS detection.

An ionic liquid-based dispersive liquid-liquid microextraction (IL-DLLME) of 20 anthelmintic drugs followed and detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed, optimized, and validated. The parameters affecting the anthelmintic extraction efficiencies such as selection of extraction solvent (ionic liquids), selection of disperser solvent, volume of extraction solvent, volume of disperser solvent, pH of the aqueous phase, extraction time, salt addition, and centrifugation time were optimized. Validation was conducted according to ISO/IEC 17025:2017 and Commission Implementing Regulation (EU) 2021/808 of 22 March 2021. Validation parameters such as calibration function, matrix effect, limit of detection (LOD), limit of quantification (LOQ), decision limit (CCα), accuracy, and precision were established. Coefficient of determination (R 2) values ranging from .99938 to .99995 were obtained using the matrix calibration curve spiked at 0, 0.25, 1.0, 1.5, and 2.0 times MRL. The LODs and LOQs were calculated using the standard deviation of the response and the slopes of the calibration curves ranged from 0.35 to 26.1 µg/kg and from 1.2 to 87.0 µg/kg, respectively, and were dependent on calibration range. The CCα values ranged from 23 to 1022.0 µg/kg and are also dependent on the MRL concentration levels. The coefficient of variation (CV) values calculated are within the reproducibility range of 16%-30% adapted from the Horwitz Equation CV = 2(1-0.5 log C) and ranged from 1.7% to 16.9%. The developed and validated and the standard QuEChERS method were compared. The IL-DLLME LC-MS/MS method was applied to 32 small stock (18 caprine [goat] and 14 ovine [sheep]) liver samples received from municipal abattoirs at Botswana National Veterinary Laboratory for the analysis of anthelmintic drug residues. The results obtained indicated that the anthelmintic drug residues were all below the detection capability, and therefore, the samples were passed as fit for human consumption.

Simultaneous analysis of the of levamisole with triclabendazole in pharmaceuticals through developing TLC and HPLC-PDA chromatographic techniques and their greenness assessment using GAPI and AGREE methods.

Two simple and rapid chromatographic methods were developed and validated for the analysis of levamisole and triclabendazole simultaneously in pure and pharmaceutical products. The first method is thin-layer chromatography (TLC) with densitometry, and the second method is high-performance liquid chromatography with PDA detection (HPLC-PDA). A Hypersil BDS C18 column with dimensions of 4.6 × 150 mm and a particle size of 5 µm was used in the HPLC-PDA method. An isocratic condition was used to carry out the separation, and the mobile phase was made up of acetonitrile and a 0.03 M potassium dihydrogen phosphate buffer in double-distilled water. The ratio of the mobile phase preparation was 70:30 (v/v), and the flow rate was 1 mL/min. A wavelength of 215 nm was employed for analyte detection. Precoated silica gel 60 F254 aluminium plates were used for the TLC method's separation. Mobile phase was made of ethyl acetate, hexane, methanol, and ammonia (69:15:15:1) for the separation. The detection wavelength selected was 215 nm. According to the International Council for Harmonization (ICH) guidelines, the proposed methods were validated and it was found that the two chromatographic methods are accurate, precise, and linear for both compounds in the range of 3.75-37.5 and 6-60 mg/L for the HPLC method for levamisole and triclabendazole, respectively and in the range of 2-14 µg/spot for the TLC method. The developed methods greenness profile was assessed using AGREE and ComplexGAPI tools.

Repurposing of Benzimidazole Anthelmintic Drugs as Cancer Therapeutics.

Benzimidazoles have shown significant promise for repurposing as a cancer therapy. The aims of this review are to investigate the possibilities and limitations of the anti-cancer effects of benzimidazole anthelmintics and to suggest ways to overcome these limitations. This review included studies on the anti-cancer effects of 11 benzimidazoles. Largely divided into three parts, i.e., preclinical anti-cancer effects, clinical anti-cancer effects, and pharmacokinetic properties, we examine the characteristics of each benzimidazole and attempt to elucidate its key properties. Although many studies have demonstrated the anti-cancer effects of benzimidazoles, there is limited evidence regarding their effects in clinical settings. This might be because the clinical trials conducted using benzimidazoles failed to restrict their participants with specific criteria including cancer entities, cancer stages, and genetic characteristics of the participants. In addition, these drugs have limitations including low bioavailability, which results in insufficient plasma concentration levels. Additional studies on whole anti-cancer pathways and development strategies, including formulations, could result significant enhancements of the anti-cancer effects of benzimidazoles in clinical situations.

Antiviral Activity of Approved Antibacterial, Antifungal, Antiprotozoal and Anthelmintic Drugs: Chances for Drug Repurposing for Antiviral Drug Discovery.

Drug repurposing process aims to identify new uses for the existing drugs to overcome traditional de novo drug discovery and development challenges. At the same time, as viral infections became a serious threat to humans and the viral organism itself has a high ability to mutate genetically, and due to serious adverse effects that result from antiviral drugs, there are crucial needs for the discovery of new antiviral drugs, and to identify new antiviral effects for the exciting approved drugs towards different types of viral infections depending on the observed antiviral activity in preclinical studies or clinical findings is one of the approaches to counter the viral infections problems. This narrative review article summarized mainly the published preclinical studies that evaluated the antiviral activity of drugs that are approved and used mainly as antibacterial, antifungal, antiprotozoal, and anthelmintic drugs, and the preclinical studies included the in silico, in vitro, and in vivo findings, additionally some clinical observations were also included while trying to relate them to the preclinical findings. Finally, the structure used for writing about the antiviral activity of the drugs was according to the families of the viruses used in the studies to form a better image for the target of antiviral activity of different drugs in the different kinds of viruses and to relate between the antiviral activity of the drugs against different strains of viruses within the same viral family.

Individual and Combined Application of Nematophagous Fungi as Biological Control Agents against Gastrointestinal Nematodes in Domestic Animals.

Gastrointestinal nematodes (GINs) are a group of parasites that threaten livestock yields, and the consequent economic losses have led to major concern in the agricultural industry worldwide. The high frequency of anthelmintic resistance amongst GINs has prompted the search for sustainable alternatives. Recently, a substantial number of both in vitro and in vivo experiments have shown that biological controls based on predatory fungi and ovicidal fungi are the most promising alternatives to chemical controls. In this respect, the morphological characteristics of the most representative species of these two large groups of fungi, their nematicidal activity and mechanisms of action against GINs, have been increasingly studied. Given the limitation of the independent use of a single nematophagous fungus (NF), combined applications which combine multiple fungi, or fungi and chemical controls, have become increasingly popular, although these new strategies still have antagonistic effects on the candidates. In this review, we summarize both the advantages and disadvantages of the individual fungi and the combined applications identified to date to minimize recurring infections or to disrupt the life cycle of GINs. The need to discover novel and high-efficiency nematicidal isolates and the application of our understanding to the appropriate selection of associated applications are discussed.

Anthelmintic Drugs for Repurposing against Gram-Negative Bacilli Infections.

Bacterial infections are among the leading causes of death worldwide. The emergence of antimicrobial resistance factors threatens the efficacy of all current antimicrobial agents, with some already made ineffective, and, as a result, there is an urgent need for new treatment approaches. International organizations, such as the World Health Organization and the European Centre for Diseases Control, have recognized infections caused by multi-drug-resistant (MDR) bacteria as a priority for global health action. Classical antimicrobial drug discovery involves in vitro screening for antimicrobial candidates, Structure-Activity Relationship analysis, followed by in vivo testing for toxicity. Bringing drugs from the bench to the bedside involves huge expenditures in time and resources. This, along with the relatively short window of therapeutic application for antibiotics attributed to the rapid emergence of drug resistance, has, at least until recently, resulted in a waning interest in antibiotic discovery among pharmaceutical companies. In this environment, "repurposing" (defined as investigating new uses for existing approved drugs) has gained renewed interest, as reflected by several recent studies, and may help to speed up the drug development process and save years of expensive research invested in antimicrobial drug development. The goal of this review is to provide an overview of the scientific evidence on potential anthelmintic drugs targeting Gram-negative bacilli (GNB). In particular, we aim to: (i) highlight the potential of anthelmintic drugs for treatments of GNB infections, (ii) review their mechanisms of action against these bacteria, (iii) summarize the outcome of preclinical studies investigating approved anthelmintic drugs that target these bacteria, (iv) provide critical challenges for further anthelmintic repurposing drugs development, and (v) list the specific anthelmintic drugs that may be more likely to be repurposed.

The Effects of Nitric Oxide and Inhibitor, and Combination of Albendazole and Praziquantel On Liver in Mice Injected with Echinococcus granulosus Larvae.

In this study, the role of nitric oxide (NO) in the pathogenesis of hydatidosis and the interaction with effects of anthelmintic drugs, albendazole and praziquantel, were examined in larval infection caused by protoscolices obtained from hydatid cysts of sheep liver in Albino Balb/c mice. Animals were divided into ten groups including controls and infected groups. Larval infection was established with intraperitoneal injection of protoscolices. Eight months after infection with protoscolices, the infected animals were divided into 6 groups. The infected animals were given a selective inhibitor of inducible nitric oxide synthase (iNOS) L-N6-(1-Iminoethyl) lysine-hydrochloride (L-NIL), NO donor sodium nitroprusside (SNP), albendazole and praziquantel as anthelmintic drugs for 7 days. In addition, control groups were composed of intact group, control, anthelmintic drugs + L-NIL, and anthelmintic drugs + SNP. The liver and blood samples were taken for cytological, histological, immunohistochemical and biochemical analyses 7 days after treatments at the end of experiment. The animals injected with protoscolices showed histopathological changes including inflammation areas, infiltration and accumulation of leukocytes, dilation of sinusoids, and damage in endothelial cells and hepatocytes at light microscopy. Electron microscopy were revealed severe damage in sinusoidal endothelial cells, leukocytes especially eosinophils in sinusoid lumens and disorganization in endoplasmic reticulum and nuclear membrane. Endothelial nitric oxide synthase (eNOS) and iNOS reactions were increased in the tissue. Anthelmintic drugs decreased inflammation areas and damages; however, it did not change NOS reactions in the animals given protoscolices. L-NIL and SNP diminished both iNOS and eNOS reactions. Unlike the group administered the inhibitor, SNP treated group exhibited less inflammation areas. Combination of these substances and drugs resulted in decreased inflammation areas. eNOS and iNOS reactions decreased in the drugs and SNP administered group, while only iNOS reaction was decreased in L-NIL given infection group. In addition, the infected groups which received SNP displayed expanded sinusoids and hepatocytes with vacuoles, intriguingly. While levels of serum nitrite/nitrate elevated only in the infection group given drugs and SNP, it decreased in the L-NIL administered group. Tissue level of malondialdehyde increased in infection groups with drugs and SNP. In conclusion, the results indicated that NO plays an important role in the pathogenesis of hydatidosis.

Hydatid cyst of the ovary - a very rare type of cystic ovarian lesion: A case report.

BACKGROUND: Hydatid disease is a zoonotic condition caused by the adult or the larval stages of tapeworms belonging to the species Echinococcus granulosus or less commonly Echinococcus multilocularis. The presentation depends on the site of involvement. Many cases are not symptomatic and may be discovered accidentally. Hydatid cyst of the ovary is an extremely rare presentation and accounts for 0.2-1% of the diagnosed cases. It may be mistaken for ovarian cysts or cystic tumors of the ovary. CASE PRESENTATION: An 18-year-old woman complained of episodes of lower abdominal pain and frequent urination for the last 3 months. During abdominal examination, there was deep tenderness in the supra-pubic region with no palpable organs or masses. Ultrasound of the abdomen showed evidence of cystic left adnexal lesions. A computerized tomography scan of the abdomen revealed evidence of cystic left adnexal lesion with no enhancement after contrast injection. Laparoscopy was performed and there was evidence of a hydatid cyst of the left ovary. The cyst was extracted from the cavity using a retrieval bag. Anthelmintic medications were prescribed for 3 months, and follow-up ultrasound after 6 months was normal. CONCLUSION: A high index of suspicion is required for the diagnosis, particularly in the presence of any cystic lesion, in any part of the world. The enzyme-linked immunosorbent assay test may be informative in the active stages of the disease. Laparoscopic management involves cyst excision. Anthelmintic drugs are required after surgery to decrease the recurrence rate.

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs.

Infections caused by Schistosoma haematobium and Opisthorchisviverrini are classified as Group 1 biological carcinogen and it has been postulated that parasites produce oxysterol and estrogen-like metabolites that might be considered as initiators of infection-associated carcinogenesis. Chemotherapy for these helminthic infections relies on a single drug, praziquantel, (PZQ) that mainly targets the parasite. Additionally, PZQ has some major drawbacks as inefficacy against juvenile form and alone it is not capable to counteract pathologies associated to infections or prevent carcinogenesis. There is an urgent need to develop novel therapeutic approaches that not only target the parasite but also improve the pathologies associated to infection, and ultimately, counteract or/and prevent the carcinogenesis processes. Repurposing the drug in combination of compounds with different modes of action is a promising strategy to find novel therapeutics approaches against these helminthic infections and its pathologies. Here, we emphasized that using antioxidants either alone or combined with anthelmintic drugs could ameliorate tissue damage, infection-associated complications, moreover, could prevent the development of cancer associated to infections. Hence, antioxidants represent a potential adjuvant approach during treatment to reduce morbidity and mortality. Despite the success of some strategies, there is a long way to go to implement novel therapies for schistosomiasis.

Plant-Based Natural Products for the Discovery and Development of Novel Anthelmintics against Nematodes.

Intestinal parasitic nematodes infect approximately two billion people worldwide. In the absence of vaccines for human intestinal nematodes, control of infections currently relies mainly on chemotherapy, but resistance is an increasing problem. Thus, there is an urgent need for the discovery and development of new anthelmintic drugs, especially ones with novel mechanisms of action. Medicinal plants hold great promise as a source of effective treatments, including anthelmintic therapy. They have been used traditionally for centuries and are mostly safe (if not, their toxicity is well-known). However, in most medicinal plants the compounds active against nematodes have not been identified thus far. The free-living nematode C. elegans was demonstrated to be an excellent model system for the discovery of new anthelmintics and for characterizing their mechanism of action or resistance. The compounds discussed in this review are of botanical origin and were published since 2002. Most of them need further studies of their toxicity, mechanisms and structure-activity relationship to assess more fully their potential as drugs.

Triclabendazole for the treatment of fascioliasis.

Fascioliasis is a neglected tropical disease that is commonly caused by flatworms affecting both domestic ruminants and humans. Fascioliasis currently affects roughly 17 million people globally with additional 180 million people at risk of developing infection. Despite the gigantic patient pool, clinicians typically have very few treatment options available. In this context, triclabendazole (Fasinex, Egaten) is the only medication approved by the Food and Drug Administration (FDA) for the treatment of fascioliasis. The FDA approval has been granted in 2019 although the drug was already utilized in the veterinary setting. Recently, three hits from the Pathogen Box have been identified in vitro as exhibiting potent anti-fascioliasis activity in an effort to identify other drugs active against fascioliasis.