Subacute ivermectin-induced affective dysregulation: Evidence for hippocampal microglial and astrocytic activation.

Rhipicephalus microplus infestation in sheep from Yucatán, Mexico, and its toxicological response to coumaphos, cypermethrin, and ivermectin.

Improving the dissolution and solubility of poorly water-soluble drugs remains a major challenge in drug development. Solid dispersion (SD) techniques offer an effective strategy by which to enhance the bioavailability of BCS Class II drugs such as ivermectin (IVM). This study aimed to develop and validate stability-indicating analytical methods for the quantification of IVM and to evaluate the performance of the formulated SDs. A novel RP-HPLC and a UV spectrophotometric method were developed and validated in accordance with ICH guidelines. IVM SDs were prepared via physical mixing (PM), solvent evaporation (SE), and melt fusion (MF) using Poloxamer 188, Kollicoat® IR, and PEG 6000 at respective ratios of 1:1, 1:3, and 1:5. Dissolution studies showed a marked enhancement in drug release from SDs prepared by SE and MF methods compared with pure IVM. Among all formulations, the Poloxamer 188-based binary SD prepared by the SE method at a 1:5 ratio exhibited the highest dissolution (98.55% at 60 min), with release kinetics following anomalous (non-Fickian) transport (n = 0.681) according to the Korsmeyer–Peppas model. Solid-state characterization evidenced by FTIR, DSC, TGA, and SEM confirmed the transformation of IVM from its crystalline form to an amorphous state. Future studies will focus on the in vivo evaluation of the optimized IVM SD formulations.

Clinical characteristics and treatments of imported loiasis patients with microfilaraemia diagnosed in France, 2000-2022.

Ivermectin (IVM) is a cornerstone of nematode control. However, its efficacy is increasingly compromised by emerging resistance in target parasites. P-glycoproteins (Pgps), which mediate drug efflux, and amphid neuron defects, characterized by a dye-filling defective (Dyf) phenotype, may both contribute to IVM resistance in Caenorhabditis elegans, but their respective roles and potential connection remain to be clarified. Here, we investigated these mechanisms in three independently evolved Caenorhabditis elegans lineages exposed to stepwise IVM selection. These populations, although distinct, converged over time to a comparable and stabilized high level of IVM resistance. Endpoint transcriptomes revealed fluctuations in the expression of several pgp, overexpressed in one lineage only, suggesting that sustained pgp upregulation is not a conserved feature of stable resistance. Consistently, neither short-term exposure to IVM nor long-term drug pressure selection elicited strong transcriptional induction. Nevertheless, we uncovered a transient surge of several pgp transcripts during the early selection process of the worms exposed to low doses of IVM. We speculate this relates to an early pgp-dependent tolerance mechanism in the dynamic adaptation program to IVM. Beyond an initial pgp-based response, our expanded RNA-seq analysis across lineages revealed a conserved enrichment for ciliary/neuronal pathways including genes expressed in amphid/phasmid, indicating remodeling of the chemosensory/ciliary network as resistance intensifies. All resistant lines also converged on the Dyf phenotype that emerged during selection at stages coinciding with sharp gains in IVM tolerance, implicating amphid structure/function in the establishment of durable resistance. Together, these data reconcile heterogeneous literature on PGPs by decoupling transient, context-dependent pgp activation from long-term maintenance of resistance, and are consistent with previous work showing ciliary pathways as common denominators of IVM resistance. We propose a two-phase associative model in which early PGP-mediated tolerance precedes the emergence of ciliary/amphidial signatures and a Dyf phenotype during selection that durably reduces susceptibility.

Ivermectin (IVM) is used as antiparasitic drug in veterinary medicine and it is also the only avermectin approved in humans in several parasitic infestations. We examined this substance because potential critical issues associated with the use were highlighted. Moreover, criticisms related to the ecological-environmental sphere, as well as food contamination arise. Nevertheless, current in vitro studies are lacking. This study aimed to investigate the direct impact of IVM on reproductive function using swine granulosa cells as reproductive cell model. The results show that progesterone, ATP and free radicals' levels significantly increased (p < 0.05). Non-enzymatic defense systems as well as autophagy did not show significant differences. On the contrary, cell proliferation, estradiol levels, and enzymatic defense systems significantly decreased (p < 0.05) after IVM treatment. Since results show that the normal function of these cells is compromised by IVM the normal reproductive functions of the entire organism could be disrupted.

Borneol-caprylic acid deep eutectic solvent (DES) based microemulsion gel for improved topical delivery of ivermectin.

The control of vector-borne diseases is increasingly challenged by insecticide resistance widespread. Therefore, innovative vector control tools with alternative modes of action are urgently needed to support existing ones. Ivermectin (IVM), a broad-spectrum endectocide has been shown to exert lethal effects on mosquitoes, including Anopheles and Aedes species following blood meals taken from treated humans or livestock. In this study, we assessed the effect of IVM at concentrations equivalent to human plasma levels following mass drug administration (MDA), on the survival and fecundity of An. coluzzii and Ae. aegypti in Burkina Faso. The present study provides new insights into how IVM may impact differentially both malaria and arbovirus vectors, contributing to develop integrated strategies of vectors control. Two laboratory experiments were conducted using 3-5-days old wild-derived female An. coluzzii and Ae. aegypti. Each experiment included four replicates per IVM concentration and was performed on separate dates. Mosquitoes were membrane fed with rabbit blood treated with five IVM concentrations (C = 112 ng/mL, C2 = 29 ng/mL, C3 = 15 ng/mL, C4 = 6.5 ng/mL, C5 = 2.5ng/mL), corresponding to the mean human plasma levels at 2, 4, 7, 14, and 28 days post-MDA with IVM at a dose of 3x300 µg/kg. A negative control with free-IVM (0.0 ng/mL) was also included. Mosquito mortalities were recorded daily for 7 days. Fecundity was measured by counting both laid and developed eggs (via ovary dissection). IVM significantly reduced the survival of An. coluzzii compared to the control group (p < 0.001), with the risk of death increasing from 4.2-fold at the lowest concentration (2.5 ng/mL) to 64.2-fold at the highest (112 ng/mL). In contrast, IVM had no significant effect on Ae. aegypti (p > 0.05), and the survival rate of control group did not differ from that of treatment groups. Additionally, for An. coluzzii, IVM significantly reduced both egg laying and egg development (p < 0.0001 and p < 0.001, respectively), whereas no significant impact on fecundity was observed in Ae. aegypti (all p > 0.80). IVM concentrations typically achieved in human plasma during MDA campaigns were sufficient to significantly reduce both survival and fecundity of wild type An. coluzzii, but had no measurable effect on Ae. aegypti. These findings highlight the species-specific response to IVM and support its potential role in integrated vector control strategies targeting malaria vectors in Africa.

West Nile virus (WNV) is maintained in an enzootic cycle between reservoir host birds and Culex (Cx.) spp. mosquitoes. This relationship presents a potential target for vector control strategies. Ivermectin (IVM), an endectocidal drug that selectively affects invertebrates while remaining safe at high concentrations in mammals and birds, can be delivered to Culex tarsalis via blood meals from birds fed IVM-treated bird feed. In this study, we evaluated the safety, efficacy, and utility of IVM-treated bird feed as a novel vector control strategy by assessing its impact on multiple bird species and mosquitoes. Mosquitoes were collected during peak WNV transmission season in Northern Colorado and DNA extracted from blood meals to determine host species. Chickens, pigeons, zebra finches, and house sparrows were fed different formulations of IVM-treated bird feed and observed for clinical signs, and their sera were fed to Cx. tarsalis mosquitoes to evaluate mosquitocidal efficacy. Feeding rates and IVM serum concentrations in birds were analyzed using unpaired t-tests and one-way ANOVA, and mosquito survivorship was analyzed using Kaplan-Meier curves and compared using paired log-rank tests. IVM serum concentration and mosquito survivorship were compared using Spearman correlation. Speciation analyses conducted on blood meals from Cx. tarsalis collected during peak WNV transmission season in Northern Colorado determined that they feed primarily on songbird species that commonly visit bird feeders, with house sparrows representing the most frequent blood meal host. In laboratory experiments using multiple formulations and doses of IVM, chickens, pigeons, zebra finches, and house sparrows ate comparable amounts of IVM-treated bird feed compared to untreated feed, had similar weight gain, and exhibited no clinical signs of toxicity. Both colony-reared and locally captured Cx. tarsalis showed significant mortality after feeding on sera from IVM-treated birds compared to controls. These results suggest that targeting songbirds with IVM-treated bird feed should be safe for wildlife and may elicit high rates of IVM-induced mortality by reaching a large proportion of WNV vector mosquitoes via their proclivity for feeding on passerine birds.

Helminth infections in grazing ruminants are of major concern for animal welfare and cause substantial economic losses, prompting the widespread use of ivermectin (IVM). The emergence of IVM resistance, driven by complex and poorly understood mechanisms, increasingly compromises treatment efficacy. Drug efflux transporters, particularly P-glycoproteins (PGPs), are suspected to contribute to resistance. Yet, the study of their individual and functional role is hindered by their diversity in nematodes. This study aimed to dissect the role of specific PGPs in mediating IVM resistance. Thus, the Caenorhabditis elegans strain IVR10, selected for IVM resistance and reported to overexpress pgps, was used as a model. We generated different IVR10 strains each lacking one of six key pgps, and assessed changes in IVM tolerance. Remarkably, only the deletion of pgp-9 significantly increased IVM sensitivity. Furthermore, transgenic expression of Haemonchus contortus pgp-9.1 rescued the resistant phenotype, demonstrating a conserved function across species. To explore drug dynamics, we developed a fluorescent IVM analog, which revealed reduced drug accumulation in IVR10, a phenotype reversed by pgp-9 deletion. Altogether, these findings show that nematode PGP-9 modulates IVM tolerance in IVR10 by controlling drug efflux and highlight it as a potential therapeutic target.

Multiple myeloma (MM) is an incurable tumor of malignant plasma cells. Importin α4, also known as KPNA3, is a component of the importin α/β system, which contributes to the cytosol-to-nucleus trafficking of cellular substances. In this study, we discovered that KPNA3 was highly expressed in MM and that its expression level inversely correlated with patient prognosis. Both in vitro and in vivo experiments demonstrated that the knockdown of KPNA3 inhibited the proliferation of MM cells, promoted their apoptosis and increased their drug sensitivity. Mechanistic investigations also revealed that the knockdown of KPNA3 inhibited ALDH2 transcription and downregulated the activity of the hedgehog pathway. Additionally, we demonstrated the direct binding of ivermectin (IVM) to KPNA3, a functional component of the importin α/β system. IVM can significantly reduce KPNA3 protein levels and promote apoptosis in MM cells. Finally, both in vitro and in vivo experiments revealed that IVM and selinexor exhibited synergistic anti-MM activities. Overall, our study reveals the role of KPNA3 in MM and suggests that targeting its nuclear import is a promising MM treatment.

Innovative naringin-ivermectin combination for improved scabies management and dermal healing in rabbits.

Genetic survey of Ivermectin-resistance markers in head lice from Jazan, Saudi Arabia.

A physiologically based pharmacokinetic (PBPK) modeling approach was used to explore potential reasons for the unexpected in vivo/in vitro inconsistencies previously observed in an investigation exploring the comparative oral bioavailability and in vitro dissolution of three experimental treatments. All treatments contained two poorly soluble drugs: ivermectin (IVM) and praziquantel (PRZ). The purpose of that investigation was identification of alternative (non-terminal animal studies) pathways for assessing the bioequivalence (BE) of non-systemically available, locally acting oral formulations. Treatment differences in gastrointestinal (GI) IVM and PRZ in vivo dissolution and absorption were examined using the GastroPlus PBPK software. Drug models included Michaelis Menten kinetics and canine-specific relative abundances of the primary metabolizing enzyme and efflux transporter. Individual dog predictions were generated using a top-down approach where a double or triple Weibull function was fitted to the previously generated in vivo data (27 dogs × 3 treatments = 81 profiles per drug). By examining the predicted treatment differences in in vivo performance, it was possible to exclude several previously proposed reasonsfor the unexpected poor performance ofone of the treatments (e.g., IVM precipitation or intestinal efflux, unintended excipient effects, and rapid dissolution increasing PRZ exposure to enterocyte Cyp3a12) for the unexpected poor performance for one of the treatments. The top-down approach provided insights into the intestinal location of in vivo dissolution and absorption, eliminating previously proposed causes and raising alternative possibilities for theobserved in vivo/in vitro disparities (indirectly related to the granule diameters of the three treatments). It also helped identify in vitro test procedures worthy of future consideration.

This study investigates the interactions between ivermectin (IVM) and lipid membranes with varying cholesterol contents by using a combined molecular dynamics (MD) and experimental approach. DOPC bilayers containing 0, 10, 20, or 30% cholesterol were simulated, and SPC liposomes were employed for experimental validation. Mass density profiles indicated that the membrane thickness increased from 4.16 nm (0% cholesterol) to 4.60 nm (30% cholesterol), while ivermectin was most deeply embedded in membranes with 10% cholesterol with an average distance of 1.09 nm from the bilayer center. van der Waals interaction energies were most favorable at 10% cholesterol (-333.13 kJ/mol), correlating with an increased hydrogen-bond lifetime (2.10 ns) between IVM and lipid molecules. Mean square displacement (MSD) analysis revealed that ivermectin exhibited the lowest mobility (0.0019 × 10-5 cm2/s) in membranes with 10% cholesterol. ESR spectroscopy of 5-DSA-labeled SPC liposomes demonstrated a progressive increase in 2A|| values with increasing cholesterol content, with additional increases following IVM incorporation. IVM capture experiments showed that liposomes containing 10% cholesterol achieved the highest drug association, consistent across saline and plasma environments. These findings provide a mechanistic basis for the rational design of liposomal systems with high ivermectin-binding capacity, with potential implications for future applications requiring the sequestration of this compound in biological environments.

Background: Albendazole, mebendazole, and ivermectin are effective against adult Trichinella spiralis but show limited efficacy against encapsulated muscle stage larvae. This limitation highlights the need for improved experimental approaches to evaluate anthelmintic activity at this stage and to identify alternative therapeutic candidates. Methods: Seven antiparasitic drugs, albendazole (ABZ), miltefosine (MLT), ivermectin (IVM), tribendimidine (TBD), praziquantel (PZQ), artesunate (ART), and mefloquine (MEQ), were evaluated for in vitro activity against T. spiralis muscle larvae. Larval viability was quantified using a tetrazolium salt XTT assay to determine IC50 values and compare with microscopic assessments. Based on in vitro activity, TBD was selected for in vivo evaluation in a mouse model, where efficacy was assessed by muscle larval burden and histopathological changes. Results: TBD, MEQ, IVM, and ABZ exhibited measurable in vitro efficacies against T. spiralis larvae, with TBD showing the lowest IC50 value at 135.2 μM. XTT formazan absorbance correlated strongly with larval number and incubation time. In vivo, TBD treatment significantly reduced larval burdens in diaphragm and gastrocnemius muscles and was associated with reduced collagen capsule thickness, inflammation, and fibrosis compared with ABZ-treated controls. Conclusions: This study validated an assay for quantitative evaluation of T. spiralis muscle larvae and demonstrates robust in vitro and in vivo activity of TBD against this stage.

Ivermectin localization at the amphidial pore and dye-filling defects in the IVR-10 strain of Caenorhabditis elegans.

Integrated pharmacokinetic-pharmacodynamic analysis of macrocyclic lactones in sheep infested with resistant Psoroptes ovis.

ABSTRACTObjectiveLow‐intensity pulsed ultrasound (LIPUS) shows promising anti‐inflammatory and neuroprotective effects for different types of neurological disorders. This study aims to investigate the therapeutic effects of LIPUS on LPS‐induced depression‐like behavior and neuroinflammation and to elucidate the underlying molecular mechanisms.MethodsA depressive mouse model is established by intraperitoneal injection of LPS (1.0 mg/kg/day for 7 days). LIPUS is applied to the hippocampal region (30 min/day). Behavioral assessments include the open field test (OFT), forced swim test (FST), and tail suspension test (TST). Molecular analyses, including Western blotting, immunofluorescence, and qPCR, are performed to evaluate the expression of P2X4R, IBA1, inflammatory cytokines (IL‐1β, IL‐6, TNF‐α), BDNF/TrkB signaling pathway, and apoptosis‐related proteins (Bax, Bcl‐2). The involvement of P2X4R is further examined using ivermectin (IVM), a selective P2X4R agonist.ResultsLIPUS significantly alleviates the LPS‐induced depression‐like behavior, suppresses hippocampal pro‐inflammatory cytokine expression, inhibits microglial activation, and reduces neuronal apoptosis. Mechanistically, LIPUS downregulates P2X4R and IBA1, upregulates BDNF protein levels and TrkB phosphorylation, and modulates the Bax and Bcl‐2 expression. Co‐localization studies confirm that P2X4R is predominantly expressed in microglia, and LIPUS markedly reduces the overlap. Notably, the anti‐inflammatory, neuroprotective, and antidepressant effects of LIPUS are significantly attenuated by IVM, highlighting the critical role of P2X4R suppression in mediating therapeutic effects.ConclusionLIPUS mitigates LPS‐induced neuroinflammation, neuronal apoptosis, and depression‐like behavior by targeting microglial P2X4R and activating the BDNF/TrkB pathway. The findings provide mechanistic insights and demonstrate that LIPUS is a promising non‐pharmacological intervention for depression, underscoring the translational potential of P2X4R as a therapeutic target.

Metabolomic analysis of macrocyclic lactone susceptible and resistant isolates of Dirofilaria immitis.