Antiparasitic Research Articles

Ivermectin Inhibits Zika Virus Replication in Vitro But Does Not Prevent Zika Virus Infection in Rhesus Macaques (Macaca mulatta).

Zika virus (ZIKV) outbreaks occur sporadically in tropical and subtropical regions. At present, there are no licensed vaccines or specific treatments available for ZIKV. Ivermectin is approved for use in humans as an antiparasitic drug. In this study, we conducted invitro cell culture and invivo experiments in rhesus macaque hosts and Aedes aegypti vectors to investigate the potential of ivermectin as an inhibitor of ZIKV infection. In LLC-MK2 mammalian cells, ivermectin inhibited ZIKV growth invitro with 50% inhibitory concentration (IC50) values in the ranges of 7.4-21.3 µM and 4.0-11.6 µM for African and Asian genotypes, respectively. In C6/36 mosquito cells, ivermectin inhibited ZIKV growth invitro with IC50 values in the ranges of 10.1-17.4 µM and 8.0-15.6 µM for the African and Asian genotypes, respectively. Despite these invitro results, high-dose ivermectin prophylaxis (1.2 mg/kg for 3 consecutive days) failed to prevent ZIKV infection in rhesus macaque and did not alter ZIKV IgM antibody production. The secondary transfer of ivermectin from nonhuman primate blood to mosquito vectors at 3 days post-ZIKV inoculation and after the last dose of ivermectin administration showed no reduction in ZIKV replication in mosquitoes. However, mosquito survival rates were significantly (P <0.0001) lower after exposure to ivermectin, thereby potentially impacting ZIKV transmission through increased vector mortality. However, further investigation is needed to determine dosing regimens that may realize these effects invivo.

Genome alteration of Leishmania orientalis under Amphotericin B inhibiting conditions.

Amphotericin B (AmB) is a potent antifungal and antiparasitic medication that exerts its action by disrupting the cell membrane of the leishmanial parasite, leading to its death. Understanding the genetic alterations induced by Amphotericin B is crucial for gaining insights into drug resistance mechanisms and developing more effective treatments against Leishmania infections. As a new Leishmania species, the molecular response of Leishmania orientalis to anti-leishmanial drugs has not been fully explored. In this study, Leishmania orientalis strain PCM2 culture was subjected to AmB exposure at a concentration of 0.03 uM over 72 hours compared to the control. The genomic alteration and transcriptomic changes were investigated by utilising the whole genome and RNA sequencing methods, followed by the analysis of single nucleotide polymorphisms (SNPs), differential gene expression, and chromosomal copy number variations (CNVs) assessed using read depth coverage (RDC) values across the entire genome. The chromosomal CNV analysis showed no significant difference between L. orientalis from the control and AmB-treated groups. The distribution of SNPs displayed notable variability, with higher SNP incidence in the control group compared to the AmB-treated group. Gene ontology analysis unveiled functions of the SNPs -associated genes involved in transporter function, genetic precursor synthesis, and purine nucleotide metabolism. Notably, the impact of AmB treatment on the L. orientalis gene expression profiles exhibited diverse expressional alterations, particularly the downregulation of pivotal genes such as the tubulin alpha chain gene. The intricate interplay between SNPs and gene expression alterations might underscore the complex regulatory networks underlying the AmB resistance of L. orientalis strain PCM2.

Identification of Coumarin-Chalcone and Coumarin-Pyrazoline Derivatives as Novel Anti-Toxoplasma gondii Agents.

Toxoplasmosis, a zoonotic infection caused by the apicomplexan parasite Toxoplasma gondii, affects a significant portion of the global human population. This condition, particularly dangerous for pregnant women and immunocompromised individuals, currently lacks effective treatment options. Eighteen coumarin-based derivatives were synthesized, comprising coumarin-chalcone hybrids (5a-i) and coumarin-pyrazoline hybrids (6a-i). Cytotoxicity was evaluated using L929 mouse fibroblasts and Hs27human fibroblasts. Anti-T. gondii activity was assessed, and molecular docking studies were performed to predict binding modes with TgCDPK1. Pyrazoline hybrids (6a-i) showed lower toxicity than chalcone-bearing coumarins (5a-i), with CC30 values exceeding the highest tested concentration (500µg/mL) for most compounds. The synthesized molecules demonstrated strong anti-T. gondii activity, with IC50 values ranging from 0.66µg/mL to 9.05µg/mL. Molecular docking studies provided insights into potential binding mechanisms. This study highlights the potential of coumarin-based hybrids as anti-T. gondii agents. The findings should contribute to the growing arsenal of small molecules against T. gondii and underscore the value of molecular hybridization in drug design. Further studies to elucidate these compounds' mechanism of action and in vivo efficacy are warranted to fully realize their potential as anti-parasitic agents.

Bioprospecting of Metabolites from Actinomycetes and their Applications.

Actinomycetes are present in various terrestrial and aquatic habitats, predominantly in the soil rhizosphere, encompassing marine and freshwater ecosystems. These microorganisms exhibit characteristics that resemble both bacteria and fungi. Numerous actinomycetes exhibit a mycelial existence and undergo significant morphological transformations. These bacteria are widely recognized as biotechnologically significant microorganisms utilized for the production of secondary metabolites. In all, over 45% of all bioactive microbial metabolites are produced by actinomycetes, which are responsible for producing around 10,000 of them. The majority of actinomycetes exhibit substantial saprophytic characteristics in their natural environment, enabling them to effectively decompose a diverse range of plant and animal waste materials during the process of decomposition. Additionally, these organisms possess a sophisticated secondary metabolic system, which enables them to synthesize almost two-thirds of all naturally occurring antibiotics. Moreover, they can create a diverse array of chemical compounds with medical or agricultural applications, including anticancer, antiparasitic, and antibacterial agents. This review aims to provide an overview of the prominent biotechnological domains in which actinobacteria and their metabolites demonstrate noteworthy applicability. The graphical abstract provides a preview of the primary sections covered in this review. This paper presents a comprehensive examination of the biotechnological applications and metabolites of actinobacteria, highlighting their potential for patent innovations.

Lipid-Based Niclosamide Delivery: Comparative Efficacy, Bioavailability, and Potential as a Cancer Drug

Niclosamide, an FDA-approved anti-parasitic drug, has demonstrated significant potential as a repurposed anti-cancer agent due to its ability to interfere with multiple oncogenic pathways. However, its clinical application has been hindered by poor solubility and bioavailability. Lipid-based nanocarrier systems such as liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid nanoemulsions (LNE), along with lipid prodrugs, have successfully been employed by researchers to overcome these limitations and improve niclosamide’s pharmacokinetic profile. Lipids are the core organic compounds which serve as the foundation of these advanced drug delivery methods and in turn play a critical role in enhancing niclosamide’s therapeutic efficacy through improving drug solubility and bioavailability. Lipid-based nanoparticles encapsulate niclosamide, protect it from degradation, facilitate drug delivery and release, and may facilitate targeted delivery in the future. While niclosamide holds significant potential as an anticancer agent due to its multi-pathway inhibitory effects, the challenges associated with its poor bioavailability and rapid clearance underscore the need for innovative delivery methods and chemical modifications to unlock its full therapeutic potential. This review aims to present the latest instances of lipid-based delivery of niclosamide and to compile successful strategies which may be employed when aiming to develop effective anticancer therapies.

Retrospective study on Encephalitozoon cuniculi infections in 118 cat and 9 dog eyes.

This study aims to inform about the clinical image, diagnostic possibilities, and treatment options for cats and dogs diagnosed with ocular encephalitozoonosis. Medical records of 7 dogs and 75 cats with ocular encephalitozoonosis presented at the Clinical Unit of Ophthalmology of the University of Veterinary Medicine Vienna between 08/2006 and 02/2022 have been compiled. Diagnosis was based on the presence of cataracts and positive antibody titer against Encephalitozoon cuniculi. Patient history, details on the characteristics of the cataracts, level of antibody titers, and the treatment regimen were summarized, as are the results of histological stainings of surgical samples to determine the presence of Encephalitozoon cuniculi, as well as PCR analyses to identify its sub-strains. Our analysis of the clinical data shows that focal cortical anterior cataracts often associated with anterior uveitis and lesions in the fundus are the most prevalent manifestation of ocular encephalitozoonosis in cats and dogs. Serological testing and PCR analysis of lens material are the most important diagnostic tools. Timely phacoemulsification with adjuvant anti-inflammatory and antiparasitic medication is the most promising therapy for Encephalitozoon cuniculi-induced cataracts.

Mebendazole nano-medication which incorporation nano-chitosan decorated by zinc oxide nanoparticles for intestinal murine trichinellosis through a drug delivery system

The objective is to develop the drug system of mebendazole (MBZ) as an antiparasitic drug via the self-assembly of MBZ with nano chitosan (Cs) and zinc oxide nanoparticles (ZnO NPs). The method of nanocomposite was fabricated by the precipitation method. Sixty male Swiss albino mice (25–30 g) were used, equally divided into six groups; group 1 (G1) included the negative control, and the other five groups (G2, G3, G4, G5, and G6) were infected with 200 Trichinella spiralis (T. spiralis) larvae. G2 refers to the positive control (infected without treatment), G3 is treated with 200 mg/kg/day of MBZ, while G4, G5, and G6 were treated with Cs@MBZ (400 mg/kg/day), Cs-MBZ@ZnO full dose of MBZ, and Cs-MBZ@ZnO half dose of MBZ starting from the 3rd dpi for three successive days for the treatment of the intestinal phase of infection. Results of the adult worm counts in all treated groups showed the highest percent (96.4%) reduction in G5 and G6. Improvement of the intestinal histopathological changes and the lowest intensity of vascular endothelial growth factor (VEGF) expression in the intestinal tissue were observed in groups G5 and G6 compared to the control group. The conclusion of biochemical results showed a significant increase in levels of aspartate transferase (AST), alanine transaminase (ALT), and globulin in the infected control group and a decrease in all treated groups. We recommended using the modified drug MBZ as an alternative drug to MBZ for trichinellid treatment, but the results need to be applied clinically.

Assessing Antiparasitic Compounds Persistence in Cattle Hair by DART-MS.

This study introduces an alternative strategy for evaluating antiparasitic persistence compounds in cattle hair by Direct Analysis in Real Time Mass Spectrometry (DART-MS). The developed DART-MS method aimed to determine fenthion, chlorpyrifos, and cypermethrin in cattle hair samples. DART-MS analyses were performed in positive ion mode, and parameters related to the DART source were evaluated. The analytical performance demonstrated the efficiency of the optimized DART-MS method for fenthion, chlorpyrifos, and cypermethrin quantification in the evaluated samples, meeting criteria for precision, accuracy and limits of detection. Overall, the DART-MS method provided a fast and efficient analysis for determination of antiparasitic agents in cattle hair, which contributes to the evaluation of drug administration protocols and dosage intervals, and aids the safety and advancement of the livestock sector.

Albumin and Polysorbate-80 Coated Sterile Nanosuspensions of Mebendazole for Glioblastoma Therapy.

The scarcity of existing and novel therapies for brain cancer has significantly affected the survival rate of glioblastoma patients. Mebendazole (MBZ), an antiparasitic agent demonstrated promising activity against brain cancer. However, poor solubility, multiple polymorphs, and insufficient permeability through blood-brain barrier (BBB) restricts its therapeutic efficacy through parenteral administration. The current study aimed to develop, optimize, and characterize sterile, injectable nanosuspension of mebendazole using parenterally acceptable stabilizers. Albumin and polysorbate 80 (PS-80) coated MBZ Nanosuspension (NS) was prepared using wet media milling technique. Design of experiment (DoE) approach was used to understand effect of drug loading versus stabilizer concentration. The optimized MBZ NS showed hydrodynamic diameter of 208.36 ± 0.24 nm with a poly dispersibility index (PDI) of 0.210 ± 0.03 and zeta potential of -20.41 ± 0.36 mV. The IC50 value of MBZ NS in U-87 MG and LN-229 cell lines were found to be 0.49 ± 0.02 μM and 0.48 ± 0.05 μM, respectively. Additionally, MBZ NS demonstrated a 2.65-fold decrease in colony-forming efficiency and a 1.16-fold reduction in migration of the bridging area compared to MBZ. In 3D spheroids of the U-87 MG glioma cell line, MBZ NS exhibited a 50% reduction in tumor growth and increased cell apoptosis compared to the control. MBZ NS formulations were sterilized by gamma irradiation and tested as per the USP sterility test. Albumin-PS 80 coated NS is rendered to be useful parenteral delivery of mebendazole for the treatment of brain cancer.

Ivermectin as a promising therapeutic option for onchocerciasis-associated epilepsy.

Onchocerciasis, commonly known as river blindness, is a neglected tropical disease caused by the parasite Onchocerca volvulus. It can lead to blindness and visual impairment. Studies have also demonstrated a link between onchocerciasis and epilepsy, with there being a correlation between onchocerciasis endemicity and epilepsy prevalence. Onchocerciasis-associated epilepsy (OAE) emerges predominantly in individuals aged 3-18, with a notable prevalence in regions where onchocerciasis transmission persists. These areas exhibit elevated rates of epilepsy, underscoring the significant impact of ongoing onchocerciasis on the incidence of epilepsy, particularly within the specified age range. Both epilepsy prevalence and incidence have evolved over the past three decades in a Tanzanian area endemic for onchocerciasis. Researchers have studied the effects of the antiparasitic drug ivermectin on OAE. About one third of Ugandan patients saw reduced seizure frequency or intensity after one 150 μg/kg dose. Clinical research in the Congo among infected epileptics on anti-seizure medications (ASMs) suggested ivermectin may decrease seizure frequency following oral administration of ivermectin tablets (3 mg). Beyond its antiparasitic properties, ivermectin has demonstrated anticonvulsant effects against clonic and tonic-clonic seizures, likely through modulation of GABAA receptor and neuroinflammation. There is evidence of synergistic effects when combined with GABAergic ASMs like diazepam. As neuroinflammation plays a key role in OAE, ivermectin's anti-inflammatory properties by inhibiting cytokines like TNF-α and IL-1β are also relevant. While certain other antiparasitic drugs can interact with ASMs and have side effects like seizures, no such interactions or side effects have been reported for ivermectin. However, there is a need for more randomized controlled trials specifically evaluating ivermectin's impact on seizures in O. volvulus-infected epileptics on ASMs. Given its efficacy against parasites, limited side effects, and potential anticonvulsant mechanisms, ivermectin could be a favorable first-line treatment option, but further research is warranted to confirm benefits for OAE. PLAIN LANGUAGE SUMMARY: This article explores the potential benefits of ivermectin, a drug commonly used to treat parasitic infections, for reducing seizures in people with epilepsy linked to onchocerciasis, also known as river blindness. Research shows that ivermectin not only targets the parasitic cause of the disease but may also help reduce brain inflammation, which plays a key role in epilepsy. While early results are promising, more research is needed to confirm whether ivermectin can be a reliable treatment for epilepsy in people affected by this condition.

Echinacea purpurea and its nanoformulation as antiparasitic agents in experimental cryptosporidiosis

Echinacea purpurea and its nanoformulation as antiparasitic agents in experimental cryptosporidiosis

Ivermectin inhibits the growth of ESCC by activating the ATF4-mediated endoplasmic reticulum stress-autophagy pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common forms of malignancy worldwide. However, there is currently a lack of effective chemotherapeutic drugs for ESCC. Ivermectin is a broad-spectrum antiparasitic drug with notable antitumor activity. However, the cellular and molecular mechanisms by which ivermectin inhibits cancer growth remain unclear. In this study, we elucidate the role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy pathways. In transcriptome analyses, we find that activating transcription factor 4 (ATF4) and DNA damage inducible transcript 3 (DDIT3) are involved in the activation of ER stress by ivermectin. Moreover, ivermectin treatment suppresses the growth of ESCC xenograft tumors in nude mice. Taken together, our results establish the antitumor molecular role of ivermectin in targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug candidate for the treatment of ESCC.

Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with Toxoplasma gondii.

The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion of Toxoplasma gondii is essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes. The synthesis of the isoprenoid unit is essential for cell growth and is inhibited by lipophilic bisphosphonates, which inhibit the parasite growth. In this work, we investigated the effect of lipophilic bisphosphonates on the chronic stages of T. gondii. We discovered that three lipophilic bisphosphonates (BPH-1218, BPH-1236, and BPH-1238), effective for the acute infection, were also effective in controlling the development of chronic stages. We showed effectiveness by testing them against in vitro cysts and in vivo derived tissue cysts and, most importantly, these compounds reduced the cyst burden in the brains of chronically infected mice. We monitored the activity of infected mice non-invasively and continuously with a novel device termed the CageDot. A decrease in activity accompanied the acute phase, but mice recovered to normal activity and showed signs of hyperactivity when the chronic infection was established. Moreover, treatment with atovaquone or BPH-1218 ameliorated the hyperactivity observed during the chronic infection.IMPORTANCETreatment for toxoplasmosis is challenged by a lack of effective drugs to eradicate the chronic stages. Most of the drugs currently used are poorly distributed to the central nervous system, and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Bisphosphonates (BPs) are analogs of inorganic pyrophosphate and are used for the treatment of bone disorders. BPs target the isoprenoid pathway and are effective against several experimental parasitic infections. Some lipophilic BPs can specifically inhibit the mitochondrial activity of Toxoplasma gondii by interfering with the mechanism by which ubiquinone is inserted into the inner mitochondrial membrane. In this work, we present the effect of three lipophilic BPs against T. gondii chronic stages. We also present a new strategy for the monitoring of animal activity during disease and treatment that is non-invasive and continuous.

Isolated hydatid cyst in the medial rectus muscle: unveiling a rare orbital occurrence

BackgroundOrbital hydatid disease, while rare, should be included in the differential diagnosis of unilateral proptosis, particularly in endemic areas. Accurate diagnosis and comprehensive management are essential for effective treatment and favorable long-term outcomes.Case PresentationA 12-year-old boy presented with a one-month history of diplopia and left-sided proptosis. A CT scan revealed a cystic mass within the left medial rectus muscle. Surgical intervention confirmed the presence of a hydatid cyst following cyst rupture and irrigation with hypertonic saline. The patient underwent a two-month course of albendazole therapy. Initially, the patient experienced persistent exotropia and diplopia, but at the three-year follow-up, he exhibited no diplopia or proptosis and only mild residual exotropia.ConclusionThis case underscores the importance of considering orbital hydatid cysts in the differential diagnosis of unilateral proptosis in endemic regions. Heightened awareness, accurate diagnosis, and a tailored therapeutic approach, including surgical removal and antiparasitic treatment, are crucial for successful management and improved long-term outcomes.

Abstract 4137919: Electrical Storm Caused by Chagasic Cardiomyopathy Successfully Treated with Ventricular Aneurysmectomy

Introduction: Chronic Chagasic cardiomyopathy (CCC) is a serious complication of Chagas disease that can manifest as LV dysfunction, ventricular aneurysms, and ventricular arrhythmias. Management of the electrical storm in CCC is challenging, especially when it is refractory to catheter ablation. Case Presentation: A 59-year-old woman from southern Peru presented to the ED with palpitations and dyspnea for 1 week. Physical exam was normal. ECG showed Q waves in III and AVF leads. TTE revealed an LVEF of 45% with an inferolateral LV aneurysm. Coronary angiography showed no lesions. CCC was suspected and serology was ordered, which was positive for T. cruzi . Cardiac MRI confirmed the presence of a 32x22mm basal inferolateral LV aneurysm. During hospitalization, she experienced 4 episodes of unstable monomorphic ventricular tachycardia (VT) within 24 hours, requiring defibrillation with 200J, vasopressor support, and invasive mechanical ventilation. The diagnosis of electrical storm secondary to CCC was proposed, for which amiodarone infusion was started until complete impregnation was achieved. Additionally, support was provided with IABP and specific antiparasitic treatment with benznidazole. Electrophysiology determined that the probable focus of the VT was situated at the level of the LV aneurysm. Therefore, ablation with endocardial-epicardial mapping was performed. However, the patient continued to experience recurrent episodes of VT. Consequently, in a multidisciplinary discussion, it was decided to perform a ventricular aneurysmectomy, which was successful. The patient's clinical progress was favorable, with initiation of GDMT and placement of a single-chamber ICD for secondary prevention. After one year of outpatient follow-up, the patient remains free of VT recurrences. Conclusion: Ventricular aneurysmectomy is a successful management approach for patients with CCC who present with electrical storm refractory to antiarrhythmic drugs and catheter ablation, and whose VT is believed to originate from the aneurysm. The diagnosis of CCC is highly arrhythmogenic and should be suspected at an early stage, given the patient's demographics and the presence of LV aneurysm in the absence of coronary artery disease.

Moxidectin elevates Candida albicans ergosterol levels to synergize with polyenes against oral candidiasis

Candida albicans, the most common opportunistic pathogenic fungus, is also the main pathogenic organism for oral candidiasis. This condition is particularly prevalent among the elderly, children, and individuals undergoing radiotherapy or suffering from HIV. The lack of new antifungal drugs, and drug resistance coupled with the side effects of current antifungal agents have increased the challenges of clinical antifungal therapies. Polyenes, including amphotericin B and nystatin, are clinical fungicidal drugs, however, their side effects and low solubility have limited their clinical applications. Here, we identified that moxidectin, a novel approved antiparasitic agent, could synergize with both amphotericin B and nystatin to inhibit the growth and biofilm formation of Candida albicans including 60 clinical isolates. The transcriptome and RT-PCR analysis indicated that moxidectin activated the biosynthesis pathway of ergosterol, the direct target of polyenes, further being verified by the loss of the synergistic activities with polyenes against ergosterol pathway mutants, including Δ/Δerg3, Δ/Δerg11 and Δ/Δerg3 Δ/Δerg11. Moxidectin was then confirmed to elevate the ergosterol biosynthesis levels of C. albicans and enhance the binding between cells and polyenes. In a mouse oral candidiasis model, moxidectin combined with low dosages of polyenes to significantly reduce the infection area, colonization of C. albicans and the inflammatory degree of tongue mucosa. Our study originally demonstrated that moxidectin could activate the ergosterol biosynthesis then elevate the ergosterol contents to enhance the antifungal effects of polyenes against C. albicans and its infections. Moxidectin can serve as the candidate potentiator of polyenes for further clinical practice.Key points• Moxidectin synergized with polyenes against Candida albicans.• Moxidectin activated the ergosterol biosynthesis of Candida albicans.• Moxidectin combined with polyenes to effectively combat oral candidiasis in mice.

The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation.

The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug-drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug-drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4's role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide's regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug-drug interactions and hinder the hepatic metabolism of ivermectin.

Synergistic effects of elevated temperature with pesticides on reproduction, development and survival of dung beetles.

In times of global change, high temperatures can increase the negative effects of pesticides and other stressors. The goal of this study was to evaluate, under controlled laboratory conditions, the effect of a moderate increase in temperature in combination with ivermectin (an antiparasitic medication used in cattle that is excreted in dung), an herbicide, and parasitic pressure, on the reproductive success, development time and adult survival of dung beetles Euoniticellus intermedius. Whereas high temperature increased the number and proportion of emerged offspring, it had synergistic negative effects in combination with the ivermectin, herbicide and parasite treatments. Moreover, high temperature in combination with ivermectin and with parasitism caused a synergistic increase of adult offspring mortality and, in combination with the herbicide, it synergistically accelerated development. These results indicate that high temperatures can enhance the negative effects of other stressors and act synergistically with them, harming dung beetles, a group with high ecological and economic value in natural and productive ecosystems. Although adult sex ratio was not affected by experimental treatments, contrasting responses were found between males and females, supporting the idea that both sexes use different physiological mechanisms to cope with the same environmental challenges. The effects that combined stressors have on insects deepen our understanding of why we are losing beneficial species and their functions in times of drastic environmental changes.

Changes in lipid abundance are associated with disease progression and treatment response in chronic Trypanosoma cruzi infection

BackgroundChagas disease, caused by the parasite Trypanosoma cruzi, is a zoonosis that affects more than seven million people. Current limitations on the diagnosis of the disease hinder the prognosis of patients and the evaluation of treatment efficacy, slowing the development of new therapeutic options. The infection is known to disrupt several host metabolic pathways, providing an opportunity for the identification of biomarkers.MethodsThe metabolomic and lipidomic profiles of a cohort of symptomatic and asymptomatic patients with T. cruzi infection and a group of uninfected controls were analysed using liquid chromatography/mass spectrometry. Differences among all groups and changes before and after receiving anti-parasitic treatment across those with T. cruzi infection were explored.ResultsThree lipids were found to differentiate between symptomatic and asymptomatic participants: 10-hydroxydecanoic acid and phosphatidylethanolamines PE(18:0/20:4) and PE(18:1/20:4). Additionally, sphinganine, 4-hydroxysphinganine, hexadecasphinganine, and other sphingolipids showed post-treatment abundance similar to that in non-infected controls.ConclusionsThese molecules hold promise as potentially useful biomarkers for monitoring disease progression and treatment response in patients with chronic T. cruzi infection.Graphical

Drug repurposing for hard-to-treat human alveolar echinococcosis: pyronaridine and beyond.

Human alveolar echinococcosis is a hard-to-treat and largely untreated parasitic disease with high associated health care costs. The current antiparasitic treatment for alveolar echinococcosis relies exclusively on albendazole, which does not act parasiticidally and can induce severe adverse effects. Alternative, and most importantly, improved treatment options are urgently required. A drug repurposing strategy identified the approved antimalarial pyronaridine as a promising candidate against Echinococcus multilocularis infections. Following a 30-day oral regimen (80 mg kg−1 day−1), pyronaridine achieved an excellent therapeutic outcome in a clinically relevant hepatic alveolar echinococcosis murine model, showing a significant reduction in both metacestode size (72.0%) and counts (85.2%) compared to unmedicated infected mice, which revealed significantly more potent anti-echinococcal potency than albendazole treatment at an equal dose (metacestode size: 42.3%; counts: 4.1%). The strong parasiticidal activity of pyronaridine was further confirmed by the destructive damage to metacestode tissues observed morphologically. In addition, a screening campaign combined with computational similarity searching against an approved drug library led to the identification of pirenzepine, a gastric acid-inhibiting drug, exhibiting potent parasiticidal activity against protoscoleces and in vitro cultured small cysts, which warranted further in vivo investigation as a promising anti-echinococcal lead compound. Pyronaridine has a known drug profile and a long track record of safety, and its repurposing could translate rapidly to clinical use for human patients with alveolar echinococcosis as an alternative or salvage treatment.