Epidemiology of epilepsy in Wulu County, an onchocerciasis-endemic area in South Sudan.

Background: We sought to investigate the epidemiology of epilepsy in Wulu County (Lakes State, South Sudan), and document the onchocerciasis transmission status in the study villages. Methods: In February 2024, a community-based epilepsy study was conducted Wulu County and participants were surveyed via a door-to-door approach in five villages, namely: Kombi, Makundi Center, Tonjo, War-Pac, and Woko. All village residents were asked about ivermectin intake during the 2023 round of community-directed treatment with ivermectin (CDTI). In addition, children aged 3-9 years were tested for Ov16 antibodies using a rapid diagnostic test. Epilepsy diagnosis in screened individuals was confirmed by a physician. Results: We surveyed 1355 persons in the five study sites. The overall CDTI coverage in 2023 was 67.4 %. Fifty-five persons with epilepsy (PWE) were identified (prevalence 4.1 %) and a history of nodding seizures was noted in 11/55 (20 %) PWE. The mean age of PWE was 21.5 ± 9.6 years, with 32 (58.2 %) being males. Epilepsy onset frequently occurred under 5 years of age (38.6 % of cases). In two PWE, seizure onset occurred during the past 12 months (annual incidence: 147.6 per 100,000 persons). Twenty-nine PWE (52.7 %) were taking anti-seizure medicines, but only five were taking them daily. Overall, Ov16 seroprevalence in children aged 3-9 years (n = 119) was 15.1 % and differed across villages, peaking at 30.9 % in Woko village where epilepsy prevalence was also highest (7.1 %). Of the 35 recorded deaths during the past two years, 9 (25.7 %) occurred in PWE. Annual estimates for epilepsy mortality and fatality rates were 323.7 per 100,000 persons and 7031.3 per 100,000 PWE, respectively. Conclusion: High epilepsy prevalence was found in Wulu, particularly in villages with persistent onchocerciasis transmission. Frequent epilepsy onset among under-fives suggests that perinatal/early childhood etiologies are common. Appropriate measures should be instituted to prevent and treat epilepsy in Wulu villages.

Cutaneous larva migrans, a neglected tropical disease (NTD) of skin, with severe secondary eczematization at an unusual location.

Cutaneous larva migrans (CLM), commonly referred to as creeping eruption, is an infectious condition caused by various types of hookworms. It primarily affects the superficial layers of the skin owing to the absence of hyaluronidases and proteases. Typically, the distal lower extremities are the most commonly affected areas. The presence of distinctive lesions characterized by erythematous, winding, or serpentine tracks, slightly elevated from the skin surface, is indicative of the condition. Diagnosis primarily relies on clinical observation. Dermoscopy reveals multiple segmented yellowish-linear regions corresponding to pustules along the larval path. Treatment typically involves the use of topical and oral ivermectin, oral albendazole, and topical thiabendazole cream.

A comparative field efficacy trial of three treatment programs against endo- and ectoparasites in naturally infected dogs.

Introduction: Tropical climates in remote Aboriginal and Torres Strait Islander communities in northern Australia are conducive to the transmission of canine helminths such as hookworms, as well as ectoparasites such as fleas and ticks. In addition to their veterinary importance, these parasites may present a zoonotic risk either directly, or as potential vectors for bacterial pathogens. These factors necessitate efficacious and effective antiparasitic treatment programs for community dogs. Methods: A cluster-randomised trial was performed on three islands in the Torres Strait to examine the short-term efficacy and medium-term effectiveness of three treatment programs. Treatments administered included oral oxibendazole/praziquantel (Paragard®) and oral afoxolaner (Nexgard®); topical moxidectin/imidacloprid (Advocate®) and imidacloprid/flumethrin collars (Seresto®); and off-label oral ivermectin (Bomectin®). Canine faecal samples were collected and examined for endoparasites by faecal flotation and real-time PCR at baseline, 7-11 days after treatment and 6 months later. Results: The proportion of dogs positive for Ancylostoma caninum at baseline and negative at day 7-11 was 9% (95% CI 4.4-17.4) for dogs treated with oxibendazole, 56.4% (95% CI 41-70.7) for moxidectin, and 89.7% (95% CI 73.6-96.4) for ivermectin. Faecal flotation results showed a greater than 90% egg reduction in 29.2% (95% CI 19.9-40.5) of dogs treated with oxibendazole, 79.4% (95% CI 63.2-89.7) for moxidectin, and 95% (95% CI 76.4-99.1) for off-label ivermectin. Elimination of ectoparasite infestation was observed at day 7-11 in 69.9% (95% CI 56.7-80.1) of dogs treated with afoxolaner, 80% (95% CI 60.9-91.1) with imidacloprid/flumethrin collars, and 0% (95% CI 0-11.7) for off-label ivermectin. Mixed effects modelling revealed only treatment group to be significantly associated with outcome measures. Discussion: Based on these study results, the poor efficacy of oxibendazole against A. caninum renders it inept for treatment, while ivermectin and moxidectin were suitable. Ivermectin was unsuitable for ectoparasite treatment due to its poor efficacy, while afoxolaner and imidacloprid/flumethrin collars appear suitable.

Ivermectin-based products in the context of green pharmaceutical analysis.

BACKGROUND: Ivermectin (IVE), a broad-spectrum antiparasitic, is used in human and animal health. Analytical methods for evaluating IVE in pharmaceutical products are found in the literature and in official compendiums. However, the vast majority of them do not have an eco-friendly approach. OBJECTIVE AND METHOD: The aim of this review is to present an overview of existing analytical methods for evaluating IVE in pharmaceutical matrices in the context of Green Analytical Chemistry (GAC) and show possibilities for increasing their greenness. RESULTS: GAC is a current alternative to promote sustainable development in laboratories and chemical-pharmaceutical industries, therefore, through its principles, such as reducing the use of aggressive solvents, it is possible to make processes more ecological. However, the vast majority of analytical methods available in the literature and official compendiums do not present an eco-friendly approach. 70% of the methods are by HPLC. Among the various pharmaceutical matrices, the most evaluated are tablets (37%). Of all the solvents used in HPLC, UPLC, HPLC-MS/MS, UV and TLC methods, the combination of methanol and acetonitrile is the most chosen, accounting for more than 50% of occurrences. CONCLUSIONS: Analytical methods for evaluating IVE-based products can be leveraged within the scope of GAC, bringing sustainable work opportunities to analytical development laboratories around the world. HIGHLIGHTS: This review shows an overview of the analytical methods present in the literature and official compendiums to evaluate pharmaceutical IVE matrices, in the context of green analytical chemistry.

Revitalizing common drugs for antibacterial, quorum quenching, and antivirulence potential against Pseudomonas aeruginosa: in vitro and in silico insights.

In the post-antibiotic era, antivirulence therapies are becoming refractory to the clinical application of existing antimicrobial regimens. Moreover, in an attempt to explore alternate intervention strategies, drug repurposing is gaining attention over development of novel drugs/antimicrobials. With the prevalence of multidrug resistance and high medical burden associated with Pseudomonas aeruginosa, there is an urgent need to devise novel therapeutics to combat this bacterial pathogen. In this context, the present study was undertaken to scrutinize the anti-quorum sensing (QS) and antivirulence potential of commonly consumed drugs such as fexofenadine (FeX), ivermectin (IvM), nitrofurantoin (NiT), levocetrizine (LvC), atorvastatin (AtS), and aceclofenac (AcF), against P. aeruginosa. The methodology involved assessment of antibacterial activity against P. aeruginosa PAO1 and quorum quenching (QQ) potential using Agrobacterium tumefaciens NTL4 biosensor strain. The antivirulence prospects were investigated by estimating the production of hallmark virulence factors in P. aeruginosa accompanied by molecular docking to predict drug associations with the QS receptors. Interestingly, all the drugs harbored antibacterial, anti-QS, and antivirulence potential in vitro, which consequently disrupted QS circuits and attenuated pseudomonal virulence phenotypically by significantly lowering the production of pyocyanin, hemolysin, pyochelin, and total bacterial protease in vitro. Moreover, the findings were validated by computational studies that predicted strong molecular interactions between the test drugs and QS receptors of P. aeruginosa. Hence, this study is the first to suggest the prospect of repurposing FeX, IvM, NiT, LvC, AtS, and AcF against P. aeruginosa.

Mosquitocidal efficacy and pharmacokinetics of single-dose ivermectin versus three-day dose regimen for malaria vector control in comparison with albendazole and no treatment: an open-label randomized controlled trial.

OBJECTIVES: When malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations (MDA). However, questions remain regarding the optimal dosing. This study aimed at comparing the mosquitocidal effect and pharmacokinetics of two dose regimens of ivermectin for malaria vector control. DESIGN: We conducted an open-label randomized control trial in Kenya staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random sequence generation, unstratified, with one block of six pharmacokinetic only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n=12), three daily doses (three-day regimen 300 mcg/kg, n=6), albendazole (400 mg, n=6), or no treatment (negative control, n=6).Our primary outcome was Anopheles gambiae survival (time-to-event (days)) post blood feeding up to 10-days after drug administration. We also evaluated pharmacokinetics (Cmax, AUC, Tmax, Thalf) up to 7 days post treatment. RESULTS: A total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion with 2 participants not attending visit on day 28. All drug regimens were well tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10-days post treatment single dose presented superior longevity of effect (aHR(adjusted hazard ratio)=3.91; 95% CI=1.93- 7.93; p<0.001) compared to triple dose (aHR=1.79; 95% CI=0.88-3.62; p=0.0.11). Albendazole had overall no mosquitocidal effect. CONCLUSIONS: It is unclear why a single dose led to increased bio-efficacy compared to triple dose. We recommend trials investigating ivermectin MDA for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared to a three-day regimen leading to improved programmatic suitability.

The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

PURPOSE: Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies. METHODS: Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared. RESULTS: In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome. CONCLUSIONS: The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.

P-glycoproteins in anthelmintic safety, efficacy, and resistance.

P-glycoprotein (PGP) is a pivotal transmembrane transporter governing the cellular flux of diverse substances shielding mammals from toxics. It can thwart the effectiveness of medicines such as ivermectin (IVM) and other macrocyclic lactone (ML) anthelmintics, undermining therapeutic efforts. We analyze the role of PGPs in limiting the toxicity of these drugs in hosts, and their potential contribution to anthelmintic resistance in nematodes. Targeting nematode PGPs to increase drug sensitivity to MLs seems interesting, but is hampered by the lack of selective inhibitors. The nuclear hormone receptor (NHR)-8 should be seriously considered as a target because it upregulates multiple PGPs involved in anthelmintic resistance and it is specific to nematodes. This would advance our understanding of host-pathogen dynamics and foster innovative therapeutic strategies.

Comparative effect of ivermectin and amitraz on cellular architecture of ovaries, synganglion and Gené's organ of Rhipicephalus microplus (Acari: Ixodidae).

The present study investigated the effect of ivermectin and amitraz on the cellular architecture of vital organs of Rhipicephalus microplus. Adult female ticks were treated with lethal concentrations (LC95) of ivermectin and amitraz, and the ovaries, synganglion, and Gené's organ were processed 48 h post treatment. In both the treatment groups, the ultra-thin sections of ovary exhibited deformed oocytes, irregular plasmic membrane and chorion layer, extensive vacuolation in the cytoplasm mainly at periphery of the cell and oocyte-pedicel junction. Marked vacuolations in the cortex and neuropile region with significant structural disorganization of the neural fibers were common alterations observed in the synganglion of ticks exposed to ivermectin and amitraz. The tissue sections of Gené's organ revealed deformed tubular glands with severe loss of cellular limit of secretory epithelium and cytoplasmic vacuolations in the ivermectin treated ticks whereas, the alterations were comparatively less severe in amitraz exposed ticks. The cellular deformities in these vital organs probably impaired reproductive function, nerve signal transmission and metabolic activities and thus affected fecundity and survivability of the treated ticks. The findings suggested that the action of ivermectin and amitraz are not restricted to the nervous system of ticks, but also on other vital organs, ovary and Gené's organ affecting the oviposition. The study provided insights into the development of targeted interventions for tick control strategies.

Ivermectin toxicokinetics in rainbow trout (Oncorhynchus mykiss) following P-glycoprotein inhibition.

Changes to ivermectin (IVM [22,23-dihydro avermectin B1a + 22,23-dihydro avermectin B1b]) toxicokinetics (TK) with and without P-glycoprotein (P-gp) inhibition by cyclosporin A (CsA) were examined in rainbow trout (Oncorhynchus mykiss). Rainbow trout were injected with 175 µg/kg 3H-IVM (8.6 µCi/mg IVM) with or without co-administration of 480 µg/kg CsA into the caudal vasculature. Fish were sacrificed at various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) for organ and tissue sampling (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad, and fat) which were analyzed for IVM-derived radioactivity. The IVM concentration decreased over time in blood, liver, kidney, and gill, while concentrations in other tissues remained constant. The highest maximum IVM concentration (Cmax) was found in kidney, followed by liver; the lowest Cmax was found in eye, followed by brain and adipose tissue. The highest % of the administered dose was found in the blood 15 min post-IVM administration, followed by the intestine at 60 min post-IVM administration. P-gp inhibition by CsA did not significantly affect calculated TK parameters (AUC [7.33 ± 0.73 - 11.5 ± 2.5 mg•h/kg], mean residence time [84.7 ± 21 - 125 ± 55 h], T1/2 [58.7 ± 15 - 86.8 ± 38 h], clearance rate [0.0152 ± 0.0033 - 0.0239 ± 0.0024 L/kg•h], or volume of distribution [1.91 ± 0.47 - 2.02 ± 0.33 L/kg]), but resulted in small but significant changes in the % administered dose found in blood and medulla. These results suggest that P-gp plays a limited role in overall IVM TK, and that its role in xenobiotic protection may be much less robust in fish than it is in mammals.

Ivermectin therapy for young children with scabies infection: a multicentre phase 2 non-randomized trial.

Background: Ivermectin, an effective treatment for scabies, is not licensed for children weighing <15 kg. Pharmacokinetic modelling has shown a 3 mg dose in young children (2-4 years, weighing 10-14 kg) achieves comparable drug exposure to a 200 µg/kg dose in children aged ≥5 years. This trial evaluated a 3 mg dose in young children. Methods: Multicentre, phase 2 trial in five health centres in Lao PDR. Children aged 2-4 years, weighing 10-14 kg with scabies received 3 mg ivermectin and had two plasma concentrations determined (Clinicaltrials.gov ID NCT05500326). On day 14, clinical outcomes and adverse effects were assessed, and a second dose given to complete treatment. The primary outcome was the mean plasma ivermectin exposure (AUC0-∞) after the first dose (compared to a historical control of Indigenous Australian children aged ≥5 years weighing ≥15 kg receiving 200 µg/kg). Secondary outcomes were clinical improvement and adverse effects. Findings: Overall, 100 children with a median age of 3.0 years (IQR 2.6-3.9) and weight of 11.9 kg (IQR 11.0-13.1) were enrolled. The mean observed ivermectin AUC0-∞ was comparable to the historical control group aged 5-11 years (815 µg h/L vs 953 µg h/L, p = 0.256). Complete resolution of scabies occurred in 90/99 children by day 14. Adverse effects were mild, occurring in 7/99. Interpretation: A 3 mg ivermectin dose in children aged 2-4 years and weighing 10-14 kg achieved a mean plasma AUC0-∞ comparable to older children, was highly effective in treating scabies and well tolerated. This study supports extending ivermectin treatment to younger children improving global efforts to control this neglected disease. Funding: Project funding provided by a Thrasher Foundation Early Career Research Award.

Factors Associated With Coverage in Community-directed Treatment With Ivermectin for Onchocerciasis Control in Savanah and Forest Areas in Central African Republic : A Cross- sectional Study.

Objectives: The aim of this study was to identify factors associated with coverage in community-directed treatment with ivermectin for onchocerciasis control in savannah and forest areas in the Central African Republic. Methods: A cross-sectional study was conducted in 2 districts where onchocerciasis is endemic. We employed a pretested and validated questionnaire that included questions about the sociodemographic characteristics of the respondents and variables relevant to coverage assessment. Multivariate logistic regression analyses were performed to identify the associations between surveyed mass drug administration (MDA) coverage and the variables considered, while accounting for potential confounding factors. A p-value <0.05 was considered statistically significant. Results: At the district level, the MDA program achieved a reach of 87.29% (95% CI, 86.03%-88.55%) in Bossangoa and 61.74% (95% CI, 59.56%-63.92%) in Kémo, compared to the reported rates of 90.02% and 91.70%, respectively. Women in both Bossangoa and Kémo were 1.28 times more likely to have taken ivermectin than men (95% CI, 1.12-1.47, p=0.008; 1.09-2.00, p=0.041, respectively). The age groups of 5-14, 15-24, and 25-34 were statistically associated with better distribution coverage in both districts. Individuals with knowledge of onchocerciasis were more likely to receive ivermectin compared to those without knowledge, with adjusted odds ratios of 1.41 (95% CI, 1.11-2.01, p=0.030) and 3.19 (95% CI, 2.91-4.08, p=0.001), respectively. Conclusions: The authors recommend implementing measures to improve MDA coverage in future campaigns. These measures should include allocating sufficient time for MDA activities, providing health education, and mobilising the entire population.

Maximizing the Use of Ivermectin Transethosomal Cream in the Treatment of Scabies.

In an effort to tackle the skin reactions frequently observed with topical application of ivermectin (IVM), a study was conducted to develop and optimize transethosomes (TESMs) loaded with IVM for scabies treatment. A three-factor, two-level (23) full factorial design was employed. Soyabean phosphatidylcholine concentration (A), ethanol concentration (B) and Span 60 amount (C) were studied as independent factors, while entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and drug release after 6 h (Q6h) were characterized. The skin sensitivity of the optimized formulation was evaluated by skin irritation test and histopathological examination. The EE% ranged from 88.55 ± 0.576% to 94.13 ± 0.305%, PS was from 318.033 ± 45.61 nm to 561.400 ± 45.17 nm, PDI was from 0.328 ± 0.139 to 0.671 ± 0.103, ZP was from -54.13 ± 1.09 mV to -60.50 ± 2.34 mV and Q6h was from 66.20 ± 0.30% to 93.46 ± 0.86%. The IVM-loaded transethosomal cream showed lower skin irritation and a more intact epidermal layer with intact keratinocyte, compared to the marketed cream which showed severe destruction of the keratin layer. Therefore, patient compliance can be improved by encapsulating IVM within TESMs to minimize its skin reactions.

Inhaled Ivermectin-Loaded Lipid Polymer Hybrid Nanoparticles: Development and Characterization.

Ivermectin (IVM), a drug originally used for treating parasitic infections, is being explored for its potential applications in cancer therapy. Despite the promising anti-cancer effects of IVM, its low water solubility limits its bioavailability and, consequently, its biological efficacy as an oral formulation. To overcome this challenge, our research focused on developing IVM-loaded lipid polymer hybrid nanoparticles (LPHNPs) designed for potential pulmonary administration. IVM-loaded LPHNPs were developed using the emulsion solvent evaporation method and characterized in terms of particle size, morphology, entrapment efficiency, and release pattern. Solid phase characterization was investigated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Using a Twin stage impinger (TSI) attached to a device, aerosolization properties of the developed LPHNPs were studied at a flow rate of 60 L/min, and IVM was determined by a validated HPLC method. IVM-loaded LPHNPs demonstrated spherical-shaped particles between 302 and 350 nm. Developed formulations showed an entrapment efficiency between 68 and 80% and a sustained 50 to 60% IVM release pattern within 96 h. Carr's index (CI), Hausner ratio (HR), and angle of repose (θ) indicated proper flowability of the fabricated LPHNPs. The in vitro aerosolization analysis revealed fine particle fractions (FPFs) ranging from 18.53% to 24.77%. This in vitro study demonstrates the potential of IVM-loaded LPHNPs as a delivery vehicle through the pulmonary route.

Successful Treatment of Cutaneous Larva Migrans With Combined Albendazole and Ivermectin Therapy: A Report of Two Cases From Sudan.

Cutaneous larva migrans (CLM), caused by third-stage filariform larvae of cat and dog hookworms, presents as pruritic, serpiginous tracks upon skin penetration by larvae from contaminated soil. Herein, we report the successful treatment of two CLM patients using albendazole and ivermectin combination therapy. A 42-year-old man from Kordofan and a 38-year-old man from White Nile State presented with characteristic lesions on their lower extremities, resolving completely within one week post-treatment without recurrence. This report highlights the potential of combined albendazole-ivermectin therapy in managing CLM amid emerging antihelminthic resistance, suggesting that its broader application warrants further investigation.

In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.