Formulation Of Ivermectin Research Articles

Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use.

Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient-friendly orodispersible tablet formulation designed for pediatric use (CHILD-IVITAB) has been developed and is entering early phase clinical trials. To inform the pediatric program of CHILD-IVITAB, 16 healthy adults were enrolled in a phase I, single-center, open-label, randomized, 2-period, crossover, single-dose trial which aimed to compare palatability, tolerability, and bioavailability and pharmacokinetics of CHILD-IVITAB and their variability against the marketed ivermectin tablets (STROMECTOL) at a single dose of 12 mg in a fasting state. Palatability with CHILD-IVITAB was considerably enhanced as compared to STROMECTOL. Both ivermectin formulations were well tolerated and safe. Relative bioavailability of CHILD-IVITAB compared to STROMECTOL was estimated as the ratios of geometric means for Cmax, AUC 0-∞, and AUC0-last, which were 1.52 [90% CI: 1.13-2.04], 1.27 [0.99-1.62], and 1.29 [1.00-1.66], respectively. Maximum drug concentrations occurred earlier with the CHILD-IVITAB formulation, with a median Tmax at 3.0 h [range 2.0-4.0 h] versus 4.0 h [range 2.0-5.0 h] with STROMECTOL (P =.004). With CHILD-IVITAB, variability in exposure was cut in half (coefficient of variation: 37% vs 70%) compared to STROMECTOL. Consistent with a more controlled absorption process, CHILD-IVITAB was associated with reduced variability in drug exposure as compared to STROMECTOL. Together with a favorable palatability and tolerability profile, these findings motivate for further clinical studies to evaluate benefits of such a patient-friendly ODT formulation in pediatric patients with a parasitic disease, including infants and young children <15 kg.

Pharmacometrics to Evaluate Dosing of the Patient-Friendly Ivermectin CHILD-IVITAB in Children ≥ 15 kg and

The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h-1 (CV 19%) for CHILD-IVITAB vs. 1.56 h-1 (CV 43%) for STROMECTOL®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.

Ecotoxicological effects of the emerging contaminant ivermectin on Rhinella arenarum: A comparative study of active ingredient and commercial formulation

Ivermectin (IVM) is a broad-spectrum veterinary antiparasitic used worldwide in cattle breeding. The aim of this study was to evaluate the lethal effects of the active ingredient and a commercial formulation of IVM (1 % active ingredient) in the embryonic stage (S. 4–6) and larval stage (S. 25) of the South American amphibian Rhinella arenarum through chronic standardized bioassays. Also, behavior analysis and oxidative stress and cholinergic effects biomarkers were analyzed at 1, 10 and 100 μg IVM/L concentrations. For the embryonic stage, the active ingredient (96 h- LC50: 15900 μg/L) was more toxic than the commercial formulation (96 h-LC50: 51230 μg/L) during the acute period, while at chronic exposure the commercial formulation was more toxic (504 h-LC50: 10.25 μg/L), compared to the active ingredient (504 h-LC50: 312.80 μg/L). For the larval stage, in acute exposure, the active ingredient (96 h-LC50: 800 μg/L) was more toxic than the commercial formulation (96 h-LC50: 1550 μg/L). In the chronic exposure, the commercial formulation (504 h-LC50: 77.33 μg/L) was more toxic than the active ingredient (504 h-LC50: 195.25 μg/L). Overall, larvae exhibited greater sensitivity to both the active ingredient and the commercial formulation. However, during chronic exposure, embryos were more sensitive to the commercial formulation than larvae. The commercial formulation primarily induced oxidative stress, and both forms of the compound affected behavior and cholinergic effect biomarkers, even at low environmentally relevant concentrations (1 μg/L). These results highlight the potential impact of IVM on aquatic ecosystems.

Lethal and sublethal impacts of membrane-fed ivermectin are concentration dependent in Anopheles coluzzii.

Ivermectin is a well-tolerated anthelminthic drug with wide clinical and veterinary applications. It also has lethal and sublethal effects on mosquitoes. Mass drug administration with ivermectin has therefore been suggested as an innovative vector control tool in efforts to curb emerging insecticide resistance and reduce residual malaria transition. To support assessments of the feasibility and efficacy of current and future formulations of ivermectin for vector control, we sought to establish the relationship between ivermectin concentration and its lethal and sublethal impacts in a primary malaria vector. The in vitro effects of ivermectin on daily mortality and fecundity, measured by egg production, were assessed up to 14 days post-blood feed in a laboratory colony of Anopheles coluzzii. Mosquitoes were fed ivermectin in blood meals delivered by membrane feeding at one of six concentrations: 0ng/ml (control), 10ng/ml, 15ng/ml, 25ng/ml, 50ng/ml, 75ng/ml, and 100ng/ml. Ivermectin had a significant effect on mosquito survival in a concentration-dependent manner. The LC50 at 7days was 19.7ng/ml. The time to median mortality at ≥ 50ng/ml was ≤ 4days, compared to 9.6days for control, and 6.3-7.6days for ivermectin concentrations between 10 and 25ng/ml. Fecundity was also affected; no oviposition was observed in surviving females from the two highest concentration treatment groups. While females exposed to 10 to 50ng/ml of ivermectin did oviposit, significantly fewer did so in the 50ng/ml treatment group compared to the control, and they also produced significantly fewer eggs. Our results showed ivermectin reduced mosquito survival in a concentration-dependent manner and at ≥ 50ng/ml significantly reduced fecundity in An. coluzzii. Results indicate that levels of ivermectin found in human blood following ingestion of a single 150-200μg/kg dose would be sufficient to achieve 50% mortality across 7days; however, fecundity in survivors is unlikely to be affected. At higher doses, a substantial impact on both survival and fecundity is likely. Treating human populations with ivermectin could be used as a supplementary malaria vector control method to kill mosquito populations and supress their reproduction; however strategies to safely maintain mosquitocidal blood levels of ivermectin against all Anopheles species require development.

Impact of ivermectin components on Anopheles dirus and Anopheles minimus mosquito survival

BackgroundIvermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. Racemic ivermectin is composed of two components, namely a major component (> 80%; ivermectin B1a), which has an ethyl group at C-26, and a minor component (< 20%; ivermectin B1b), which has a methyl group at C-26. There is no difference between the efficacy of ivermectin B1a and ivermectin B1b efficacy in nematodes, but only ivermectin B1b has been reported to be lethal to snails. The ratios of ivermectin B1a and B1b ratios in ivermectin formulations and tablets can vary between manufacturers and batches. The mosquito-lethal effects of ivermectin B1a and ivermectin B1b have never been assessed. As novel ivermectin formulations are being developed for malaria control, it is important that the mosquito-lethal effects of individual ivermectin B1a and ivermectin B1b compounds be evaluated.MethodsRacemic ivermectin, ivermectin B1a or ivermectin B1b, respectively, was mixed with human blood at various concentrations, blood-fed to Anopheles dirus sensu stricto and Anopheles minimus sensu stricto mosquitoes, and mortality was observed for 10 days. The ivermectin B1a and B1b ratios from commercially available racemic ivermectin and marketed tablets were assessed by liquid chromatography-mass spectrometry.ResultsThe results revealed that neither the lethal concentrations that kills 50% (LC50) nor 90% (LC90) of mosquitoes differed between racemic ivermectin, ivermectin B1a or ivermectin B1b for An. dirus or An. minimus, confirming that the individual ivermectin components have equal mosquito-lethal effects. The relative ratios of ivermectin B1a and B1b derived from sourced racemic ivermectin powder were 98.84% and 1.16%, respectively, and the relative ratios for ivermectin B1a and B1b derived from human oral ivermectin tablets were 98.55% and 1.45%, respectively.ConclusionsThe ratio of ivermectin B1a and B1b does not influence the Anopheles mosquito-lethal outcome, an ideal study result as the separation of ivermectin B1a and B1b components at scale is cost prohibitive. Thus, variations in the ratio of ivermectin B1a and B1b between batches and manufacturers, as well as potentially novel formulations for malaria control, should not influence ivermectin mosquito-lethal efficacy.Graphical abstract

An ecotoxicological view on malaria vector control with ivermectin-treated cattle

Malaria remains an enduring challenge in sub-Saharan Africa, affecting public health and development. Control measures can include the use of insecticides that target adult Anopheles mosquitoes transmitting the malaria-causing Plasmodium parasite. Such mosquitoes can also bite livestock, allowing vector populations to be maintained at levels that enable parasite transmission. Thus, one way to control the spread of malaria includes the use of endectocide-treated livestock which renders the blood of cattle toxic to such mosquito populations. Here we present an ecotoxicological perspective on malaria vector control, using cattle treated with the endectocide ivermectin to target zoophagic and opportunistic Anopheles coluzzii mosquitoes. Our study employs an innovative, long-acting injectable ivermectin formulation with over 6 months of sustained mosquitocidal activity. Robust vector population modelling underscores its promising field effectiveness. Environmental implications (soil sorption and dissipation) of excreted ivermectin and potential ecotoxicological risks to non-target dung organisms in West Africa are discussed, in addition to actionable, locally inspired risk mitigation measures to protect sub-Saharan soils and agroecosystems from chemical pollution. We highlight how ecotoxicology and environmental chemistry improve livestock-based vector control with ivermectin for effective and more sustainable malaria management.

Synergistic interactions between the emerging contaminant ivermectin and the ubiquitous pesticide glyphosate at an environmentally relevant ratio on Rhinella arenarum larvae

Glyphosate (GLY) is a widely used broad-spectrum herbicide, and ivermectin (IVM) is a commonly used antiparasitic in livestock farming. Both substances can be found in water bodies from agricultural areas and can have negative impacts on ecosystems. The aim of this study was to evaluate the lethal and sublethal toxicity individually and in combination of a glyphosate-based herbicide (GBH) and an ivermectin commercial formulation (ICF). Groups of 10 larvae were exposed for 504 h, in triplicate to a concentration gradient of the commercial formulation of glyphosate and ivermectin, individually, and to a series of dilutions of a non-equitoxic mixture of both compounds based on environmental concentrations. Additionally, biomarkers of oxidative stress (catalase, glutathione S-transferase, and reduced glutathione) and neurotoxicity (acetylcholinesterase and butyrylcholinesterase) were evaluated at sublethal and environmental concentrations of ivermectin (0.00125 mg/L) and glyphosate (0.7 mg/L) individually and in mixture. The ICF (LC50-504h: 0.047 mg ai IVM/L) was more toxic to larvae than the GBH (LC50-504h: 24.73 mg ae GLY/L). In terms of lethality, exposure to the mixture was synergistic at all exposure times. Both compounds separately caused alterations in the biomarkers of oxidative stress and neurotoxicity. Regarding sublethal effects in organisms exposed to the mixture, potentiation was observed in acetylcholinesterase. The simultaneous exposure to both substances in water bodies can have synergistic and negative effects on aquatic organisms.

Impact of blood meals taken on ivermectin-treated livestock on survival and egg production of the malaria vector Anopheles coluzzii under laboratory conditions.

Treatment of livestock with endectocides such as ivermectin is viewed as a complementary vector control approach to address residual transmission of malaria. However, efficacy of this treatment may vary between animal species. Hence, our purpose was to investigate the effects of ivermectin treatments of common livestock species on life history traits of the opportunistic malaria vector Anopheles coluzzii. Sheep, goats and pigs were treated using injectable veterinary ivermectin formulation at the species-specific doses (recommended dose for all species and high dose in pig). Mosquito batches were exposed to treated and control (not injected) animals at different days after treatment. Daily mosquito mortality was recorded and fecundity assessed through the count of gravid females and the number of eggs they developed. The recommended dose of ivermectin induced a significant decrease in mosquito survival for up to 7 days after injection (DAI), with a decrease of 89.7%, 66.7%, and 48.4% in treated pigs, goats and sheep, respectively, compared to control animals. In treated pigs, the triple therapeutic dose decreased mosquito survival of 68.97% relatively to controls up to 14 DAI. The average number in gravid females Anopheles that survived after feeding on treated animals were reduced when blood-meals were taken on sheep (2.57% and 42.03% at 2 and 7 DAI), or on goats (decrease of the 28.28% and 73.64% respectively at 2 and 7 DAI). This study shows that ivermectin treatments to animals negatively impacts An. coluzzii life history traits and could reduce vector densities in areas where livestock live near humans. However, due to short-term efficacy of single dose treatments, repeated treatments and potentially increased dosages would be required to span the transmission season. The use of long-acting ivermectin formulations is discussed as a mean for extending efficacy while remaining cost effective.

Comparative Pharmacokinetics and Bioequivalence of Pour-On Ivermectin Formulations in Korean Hanwoo Cattle.

This study aimed to conduct a bioequivalence study of applying three pour-on ivermectin formulations at a dose of 1 mg/kg on the back of Korean native beef cattle (Hanwoo). To conduct bioequivalence testing, the pharmacokinetics of three groups (control Innovator, test Generic A, and test Generic B) of five clinically healthy Korean Hanwoo cattle (average weight 500 kg) were studied. After topical application to the skin, blood samples were drawn at the indicated times. These blood samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The time required to reach the maximum concentration (Tmax), the maximum concentration (Cmax), and the area under the curve (AUClast) of each pharmacokinetic parameter were compared for bioequivalence. The results showed that the control had a Tmax of 41 ± 1.24 h, a Cmax of 0.11 ± 0.01 μg/mL, and an AUClast of 9.33 ± 0 h*μg/mL). The comparator Generic A had a Tmax of 40 ± 1.14 h, a Cmax of 0.10 ± 0.01 (μg/mL, and an AUClast of 9.41 ± 0.57 h*μg/mL, while Generic B had a Tmax of 40 ± 2.21 h, a Cmax of 0.10 ± 0.01 μg/mL, and an AUClast of 9 h*μg/mL. The values of the bioequivalence indicators Cmax, Tmax, and AUC were all within the range of 80% to 120%, confirming that all three tested formulations were bioequivalent. In conclusion, the study showed that the two generic products were bioequivalent to the original product in Hanwoo cattle.

Preparation and Physicochemical Evaluation of Topical Cream Ivermectin 1% for Treatment of Rosacea

Background: Rosacea is a prevalent disease throughout the world. Various studies have shown that the hair follicle mites Demodex has a key role in the rosacea pathogenesis. The current study aims to formulate a formulation of ivermectin 1% for rosacea treatment. Methods: The researchers sought an ivermectin topical cream in following a stable preparation for the treatment of rosacea. Investigation of the active ingredient in the formulation was conducted according to standards. The formulation was monitored as an ICH guideline within six months. Results: The resulting formula did not show any physical instability during accelerated stability studies, and the appearance of the formula did not change. During the storage period, the preparation displayed no significant changes in density, viscosity, pH, and uniformity. Additionally, no microbial contamination was occurred in this formulation. Conclusion: The study data indicated that the proper o/w cream produced from the active ingredient Ivermectin. Administration of ivermectin topical dosage form reduces the chronic use of antibiotic in the rosacea treatment. Our data can aid physicians to prescribe high potential formulation for rosacea treatment. This topical ivermectin with the standard formulation assessments showed the preparation was sufficiently stable and can use in the treatment of rosacea.

Off-label drug use during the COVID-19 pandemic in Africa: topic modelling and sentiment analysis of ivermectin in South Africa and Nigeria as a case study.

Although rejected by the World Health Organization, the human and even veterinary formulation of ivermectin has widely been used for prevention and treatment of COVID-19. In this work we leverage Twitter to understand the reasons for the drug use from ivermectin supporters, their source of information, their emotions, their gender demographics, and location information, in Nigeria and South Africa. Topic modelling is performed on a Twitter dataset gathered using keywords 'ivermectin' and 'ivm'. A model is fine-tuned on RoBERTa to find the stance of the tweets. Statistical analysis is performed to compare the stance and emotions. Most ivermectin supporters either redistribute conspiracy theories posted by influencers, or refer to flawed studies confirming ivermectin efficacy in vitro. Three emotions have the highest intensity, optimism, joy and disgust. The number of anti-ivermectin tweets has a significant positive correlation with vaccination rate. All the provinces in South Africa and most of the provinces of Nigeria are pro-ivermectin and have higher disgust polarity. This work makes the effort to understand public discussions regarding ivermectin during the COVID-19 pandemic to help policy-makers understand the rationale behind its popularity, and inform more targeted policies to discourage self-administration of ivermectin. Moreover, it is a lesson to future outbreaks.

Pharmacokinetics of macrocyclic lactone endectocides in indigenous Zebu cattle and their insecticidal efficacy on Anopheles arabiensis

Outdoor biting, outdoor resting, and early evening biting of Anopheles arabiensis is a challenge in current malaria control and elimination efforts in Africa. Zooprophylaxis using livestock treated with macrocyclic lactones is a novel approach to control zoophilic vectors. Therefore, the present study aimed to investigate the pharmacokinetics and insecticidal efficacy of ivermectin (IVER), doramectin (DORA), and moxidectin (MOXI) subcutaneous (SC) formulations in treated calves. The study was conducted using indigenous (Bos indicus) calves treated with SC formulation at a dosage of 0.5, 0.2 or 0.05 mg/kg body weight (BW) IVER or DORA and 0.2 or 0.05 mg/kg BW MOXI. Direct skin feeding of mosquitoes and animal blood sampling were performed at 4, 8, 12, and 24 h and on days 2, 3, 5, 7, 10, 14, 21, 28, and 35 post treatment. The survival of fully fed A. arabiensis mosquitoes was monitored for 10 days. Plasma samples were analyzed using UHPLC-MS/MS. A. arabiensis mortality percentages in the 0.5 mg/kg BW DORA and IVER groups were 65.74% (95% CI: [54.98; 76.50]) and 64.53% (95% CI: [53.77; 75.29]), respectively, over 35 days post treatment. At the recommended dose (0.2 mg/kg BW), promising overall A. arabiensis mortality rates of 61.79% (95% CI: [51.55; 72.03]) and 61.78% (95% CI: [51.02; 72.54]) were observed for IVER and DORA, respectively. In contrast, A. arabiensis mortality in the MOXI group was 50.23% (95% CI: [39.87, 60.58]). At 0.2 mg/kg BW dose, area under the plasma concentration versus time curve (AUC0−inf) values for IVER, DORA, and MOXI were 382.53 ± 133.25, 395.41 ± 132.12, and 215.85 ± 63.09 ng day/mL, respectively. An extended elimination half-life (T1/2el) was recorded for DORA (4.28 ± 0.93 d), at 0.2 mg/kg BW dose level, compared to that for IVER (3.16 ± 1.47 d). The T1/2el of MOXI was 2.17 ± 0.44 day. A maximum plasma concentration (Cmax) was recorded earlier for MOXI (10 h) than for IVER (1.6 days) and longer for DORA (3.0 days). For DORA and IVER, significant differences were found in T1/2el (P<0.05), Cmax (P<0.01), and AUC0−inf (P<0.01) between the higher 0.5 mg/kg BW and the lower 0.05 mg/kg BW doses. The T1/2el and AUC0−inf of DORA and IVER in the present study were significantly (p < 0.05) correlated with the observed insecticidal efficacy against A. arabiensis mosquitoes at 0.2 mg/kg a dose. Therefore, treating cattle with IVER or DORA could complement the malaria vector control interventions, especially in Ethiopia, where the zoophilic malaria vector A. arabiensis majorly contribute for residual malaria transmission.

Physical and pharmacokinetic characterization of Soluvec™, a novel, solvent-free aqueous ivermectin formulation.

Purpose: To describe application of the Quicksol™ solvent-free approach to solubilize ivermectin (IVM). Methods: Lyophilized IVM complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD) was resolubilized in aqueous polysorbate-80, generating Soluvec™. Lyophilizate was examined by Fourier-transform infrared spectroscopy and differential scanning calorimetry; Soluvec, by dynamic light scattering. Pharmacokinetics was evaluated in dogs allocated to subcutaneous (SC) or intramuscular (IM) Soluvec or oral IVM. Results: IVM in Soluvec was tightly bound by HPβCD, forming nearly monodisperse 28nm particles with solubility ∼2500-times that of free IVM. SC and IM Soluvec increased IVM exposure, peak IVM and extended duration of IVM exposure, versus oral dosing. Conclusion: The Quicksol method generated Soluvec, a concentrated aqueous parenteral IVM formulation with pharmacokinetic properties suitable for veterinary or human use.

Synthesis and Clinical Examination of Novel Formulations of Ivermectin, Albendazole and Niclosamide for the Treatment of Equine Gastrointestinal Helminthoses.

This study aimed to develop new complex preparations of ivermectin, niclosamide and albendazole based on solid-phase mechanochemical technology, and to evaluate their efficacy against equine nematodosis and cestodosis. Novel formulation of antiparasitic paste were prepared using joint mechano-chemical treatment of ivermectin (0.2 mg/kg bodyweight; BW), niclosamide (10 mg/kg BW) and albendazole (3, 5, 10 mg/kg BW) substances with polyvinylpyrrolidone and arabinogalactan. For the evaluation of activity of different doses of formulations against gastrointestinal tract helminths a total of 151 adult horses of the Novoaltai breed weighing 450-500 kg naturally infected with strongyles (>150 egg per gram of faeces, EPG), Parascaris spp. (>20 EPG) and Anoplocephala spp. (>10 EPG) were selected. Antiparasitic pastes were orally fed to the horses and faecal egg count reduction counts were compared prior to and 14 days after the treatment. Pastes with mechanically modified ivermectin showed 91.4-100% efficacy against strongyles and Parascaris. Pastes with modified albendazole and niclosamide were also effective against Anoplocephala in all tested dosages i.e. 78.6-100%. In particular, treatment with two formulations containing i) 0.2 mg ivermectin, 10 mg albendazole, 10 mg niclosamide, and ii) 0.2 mg ivermectin, 3 mg albendazole showed 100% efficacy against strongyles, Parascaris and Anoplocephala. Solid-phase mechanochemical technology could be applied in equine anthelminthics production. It is suggested that future studies focus on plasma concentration-time profile of these highly effective pastes.

Proof-of-concept study for a long-acting formulation of ivermectin injected in cattle as a complementary malaria vector control tool

BackgroundDomesticated animals play a role in maintaining residual transmission of Plasmodium parasites of humans, by offering alternative blood meal sources for malaria vectors to survive on. However, the blood of animals treated with veterinary formulations of the anti-helminthic drug ivermectin can have an insecticidal effect on adult malaria vector mosquitoes. This study therefore assessed the effects of treating cattle with long-acting injectable formulations of ivermectin on the survival of an important malaria vector species, to determine whether it has potential as a complementary vector control measure.MethodsEight head of a local breed of cattle were randomly assigned to either one of two treatment arms (2 × 2 cattle injected with one of two long-acting formulations of ivermectin with the BEPO® technology at the therapeutic dose of 1.2 mg/kg), or one of two control arms (2 × 2 cattle injected with the vehicles of the formulations). The lethality of the formulations was evaluated on 3–5-day-old Anopheles coluzzii mosquitoes through direct skin-feeding assays, from 1 to 210 days after treatment. The efficacy of each formulation was evaluated and compared using Cox proportional hazards survival models, Kaplan–Meier survival estimates, and log-logistic regression on cumulative mortality.ResultsBoth formulations released mosquitocidal concentrations of ivermectin until 210 days post-treatment (hazard ratio > 1). The treatments significantly reduced mosquito survival, with average median survival time of 4–5 days post-feeding. The lethal concentrations to kill 50% of the Anopheles (LC50) before they became infectious (10 days after an infectious blood meal) were maintained for 210 days post-injection for both formulations.ConclusionsThis long-lasting formulation of ivermectin injected in cattle could complement insecticide-treated nets by suppressing field populations of zoophagic mosquitoes that are responsible, at least in part, for residual malaria transmission. The impact of this approach will of course depend on the field epidemiological context. Complementary studies will be necessary to characterize ivermectin withdrawal times and potential environmental toxicity.Graphical

Comment on 'Oral ivermectin to treat scabies: a comparison of two different regimens'.

Current guidelines recommended the use of oral ivermectin (taken with food) 200 µg kg–1 as two doses 1-week apart as the first-line treatment option; however, the drug package of the ivermectin formulation recently approved for the Italian market recommends a single dose. In this context, we read with great interest the article recently published by Balestri et al. comparing two regimens of oral ivermectin. Similarly, we performed a retrospective analysis at our Dermatological Clinic of Mycology and Parasitosis and report our results.

Comparative assessment of different ivermectin and doramectin formulations for mange control in grazing steers

Psoroptic mange causes relevant losses of productivity in cattle. Macrocyclic lactones are one of the main pharmacological tools recommended for controlling it. The aim of the current work was to compare the relationship between the pharmacokinetic behavior and the effectiveness of both ivermectin (IVM) and doramectin (DRM) following their administration as either the traditional (1 %) or long-acting (3.15–3.5 %) injectable formulations to cattle naturally infected with Psoroptes ovis. The overall work involved three trials (1, 2 and 3) carried out on commercial beef cattle farms (grazing systems). In Trial 1, 20 grazing steers with active mange infection were allocated into 2 groups (n = 10) and treated subcutaneously (SC) with either IVM (1 %) or DRM (1%) at 0.2 mg/kg. In Trial 2, 16 grazing steers with active mange divided in 2 groups (n = 8) were treated SC with either IVM 1 % (0.2 mg/kg) or IVM 3.15 % long-acting (0.63 mg/kg). In Trial 3, 2 groups of mange infected steers (n = 8) were treated SC with either IVM 3.15 % (0.63 mg/kg) or DRM 3.5 % (0.7 mg/kg). Blood samples were collected of each experimental group and the drug systemic availability was estimated by measuring of IVM/DRM concentrations by HPLC. Skin scraping samples were collected from each animal and mites were counted at 14, 21 and 28 days post-treatment. In Trial 1, the mite density score on day 14 was significantly lower for DRM (0.60) compared to IVM (1.80) (P = 0.019). Based on the number of animals clinically cured (negative to the presence of mites), the efficacy of DRM was higher (80 %) than that obtained for IVM (10 %) (P < 0.05). DRM systemic exposure measured as AUC was 1.37-fold higher compared to IVM. In Trial 2, even though IVM exposure was significantly greater after the long-acting (3.15 %) compared to the traditional formulation (1 %), none of the treatments significantly reduced the mite density score, with a percentage of animals cured between 0 % and 37.5 % after both IVM treatments. In Trial 3, the 100 % of cured animals were achieved at day 21 (IVM 3.15 %) and at day 28 (DRM 3.5 %) post-treatment. In conclusion, DRM treatment could offer some therapeutic advantages in field situations where IVM fails to control mange. Depending on the level of susceptibility of the mite population, long-acting pharmaceutical formulations can be useful to control Psoroptic mange in cattle. The use of macrocyclic lactones for mange control in cattle should be based on appropriate diagnosis on each individual farm.

Characteristics of ivermectin toxicity in patients taking veterinary and human formulations for the prevention and treatment of COVID-19

Background US poison control centers reported increased cases of ivermectin toxicity during the COVID-19 pandemic. Previous descriptions of ivermectin toxicity have evaluated heterogeneous groups with a variety of ivermectin sources and dosage patterns. We sought to compare the clinical effects of ivermectin toxicity in patients taking human- vs. veterinary-formulations and acute- vs. chronic-ingestion patterns. Methods We performed a retrospective analysis of cases from the Oregon Poison Center of ivermectin exposures for the prevention or treatment of COVID-19 that resulted in a healthcare visit over a 24-week period (14 August 2021 − 31 January 2022). Results We identified 37 cases of ivermectin toxicity. The median age of patients was 64 years, and most patients were male. The majority of patients were hospitalized (21) or treated in an emergency department (13). A minority were treated in an outpatient setting (3) and one patient died. Seventeen ingested veterinary formulations and fifteen ingested prescription tablets. Patients reported taking ivermectin for treatment (23) and prevention (14) of COVID-19. Clinical effects included neurotoxicity (30), gastrointestinal symptoms (14), and musculoskeletal complaints (7). Patients taking veterinary products took higher doses of ivermectin and had higher rates of altered mental status than those taking prescription tablets. Patients taking ivermectin chronically took smaller doses (daily dose of 13.5 mg) over a prolonged period (median 3.8 weeks) and developed toxicity that was milder than those with acute ingestions. Conclusion Ivermectin toxicity developed in predominantly male patients >60 years old who ingested higher than recommended doses and developed neurologic symptoms. Patients who took a veterinary formulation of ivermectin ingested large single doses or large daily doses for several days and developed rapid onset of neurotoxicity. Patients with chronic toxicity developed milder symptoms and tended to take typical therapeutic doses, but continued therapy for weeks rather than days.

Repurposing Potential of the Antiparasitic Agent Ivermectin for the Treatment and/or Prophylaxis of COVID-19.

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials, novel nasal formulations of IVM were explored with the hope of an improved optimized effect.

Zebrafish behavioral response to ivermectin: insights into potential neurological risk

Ivermectin is a well-known and widely used anti-parasitic drug. Recently, in vitro data suggest anti-viral efficacy of the drug, albeit at much higher concentrations than currently approved. Despite warnings by several governing bodies, the (uncontrolled) human use of ivermectin has significantly increased during the COVID-19 epidemic. This study thus aimed to elucidate potential neurological risk of particularly the veterinary formulation of ivermectin in comparison to pure ivermectin. Zebrafish eggs (1hpf) and larvae (4dpf) were exposed to a range of concentrations of either pure ivermectin (IVM) or a veterinary formulation (V-IVM) for a period of 24 hours. Behavioral responses to both treatments were assessed at various timepoints using the pentylenetetrazol assay, the light–dark assay and a 5-day teratogenesis protocol. In addition, dissolution rates were calculated for both treatments. Acute responses of larvae at 4–<5dpf was similar for both treatments – a transient hyperlocomotion was followed by a general hypolocomotion (ANOVA dose effect, P < 0.01). Both IVM and V-IVM-treated larvae showed significant dose-dependent (ANOVA dose effect, P < 0.0001) decreases in responsiveness to repeated light–dark transitions, which again was more pronounced in IVM. These effects were maintained after 24 hours of exposure. In contrast, when ivermectin was administered prior to establishment of the blood brain-barrier in the teratogenesis protocol, V-IVM treatment was linked to more severe activity decline on <5dpf. Differences in dissolution rates cannot account for these differences. In conclusion, current data suggest significantly higher neurological risk of a veterinary formulation of ivermectin under conditions of penetration across the blood brain-barrier.