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.

Clinical efficacy of a parasiticide formulation containing eprinomectin, esafoxolaner and praziquantel (NexGard® Combo) in the treatment of natural feline aelurostrongylosis and troglostrongylosis.

The metastrongyloids Aelurostrongylus abstrusus and Troglostrongylus brevior are primary causes of feline clinical respiratory disease. The present field trial evaluated the clinical efficacy of a spot-on formulation containing eprinomectin, esafoxolaner and praziquantel (NexGard® Combo) administered per label recommendations to cats affected with aelurostrongylosis and/or troglostrongylosis. Overall, 36 naturally infected cats were randomly assigned to Group 1 (G1) or Group 2 (G2) of 18 cats each. The two groups included 6 cats with A. abstrusus, T. brevior and mixed infection, each. All cats completed the study. Cats in G1 were treated on study Days (SDs) 0 and 28±2. Cats in G2 served as negative control until SD 56±2 and were then treated on SD 56±2 and 84±2. On SD 0/-7, 28±2 and SD 56±2 all cats were subjected to parasitological (quali-quantitative Baermann) and clinical examinations (physical exams and thoracic X-rays). Hematology and biochemistry analyses were performed on SD 0/-7 and SD 56±2. On SD 84±2 quali-quantitative Baermann, clinical examination and thorax radiography were performed on all G2 cats and on two G1 cats that still had radiographic alterations on SD 56±2. On SD 112±2 all G2 cats were subjected to parasitological and clinical evaluations and one cat from G1 that still had radiographic signs at SD 84±2 was clinically and radiographically evaluated. Efficacy criteria were the reduction of larval shedding in faeces and the clinical response in terms of pathological and radiographic scores after treatment compared to the baseline. An efficacy of 100 % based on LPG reduction was recorded after one (20/24 cats) or two (all 24 cats) treatments in cats with single infection by A. abstrusus or T. brevior. For cats with mixed infections, larval shedding was stopped after one (11/12 cats) or two (all 12 cats) treatments. Statistically significant clinical and radiographic improvement was evident in all study cats after 2 treatments. The present data show that two monthly treatments with NexGard® Combo stopped larval shedding and led to a significant clinical recovery and a complete resolution of radiographic abnormalities in cats infected with A. abstrusus and/or T. brevior.

Efficacy of a topical combination of esafoxolaner, eprinomectin and praziquantel against Amblyomma maculatum infestations in cats.

Amblyomma maculatum, the Gulf Coast tick, infests a wide range of vertebrate species including livestock, dogs, cats, and humans. It is a species of significant veterinary and public health importance, especially as a vector of diseases, for instance American canine hepatozoonosis or tidewater spotted fever. An experimental study was conducted to evaluate the efficacy of NexGard® Combo, a topical endectoparasiticide product for cats combining eprinomectin, praziquantel and esafoxolaner, against induced infestations of A. maculatum in cats. This Good Clinical Practice (GCP) study used a randomized, negative controlled, masked design. Ten cats were allocated to an untreated group and ten to a treated group, dosed once on Day 0 at the minimum label dose. On Days -2, 7, 14, 21, 28, 35, and 42, cats were infested with ~50 unfed adult A. maculatum. On Days 3, 10, 17, 24, 31, 38, and 45, i.e., 72 h after treatment and subsequent infestations, ticks were removed, counted and the numbers of live attached tick in each group were used for efficacy calculations. At each time-point, all untreated cats were adequately infested, demonstrating a vigorous tick population and an adequate study model. The curative efficacy after a single application against existing tick infestation, 72 h after treatment, was 98.7%. The preventive efficacy, 72 h after weekly infestations, over the following five weeks ranged from 93.8% to 99.4%.

Title: Efficacité d'une association topique d'esafoxolaner, d'éprinomectine et de praziquantel contre les infestations par Amblyomma maculatum chez le chat. Abstract: Amblyomma maculatum, la tique de la Gulf Coast, infeste un large éventail d'espèces de vertébrés, notamment le bétail, les chiens, les chats et les humains. Il s'agit d'une espèce d'importance significative en médecine vétérinaire et en santé publique, notamment en tant que vecteur de maladies, par exemple l'hépatozoonose canine américaine ou la fièvre pourprée des marées. Une étude expérimentale a été menée pour évaluer l'efficacité de NexGard® Combo, un produit endectoparasiticide topique pour chats associant éprinomectine, praziquantel et esafoxolaner, contre les infestations par A. maculatum provoquées chez le chat. Cette étude de bonnes pratiques cliniques (BPC) a utilisé une conception randomisée, contrôlée négativement et masquée. Dix chats ont été répartis dans un groupe non traité et dix chats dans un groupe traité, traités une fois au jour 0 à la dose minimale indiquée sur l'étiquette. Aux jours −2, 7, 14, 21, 28, 35 et 42, les chats ont été infestés par environ 50 A. maculatum adultes non nourris. Les jours 3, 10, 17, 24, 31, 38 et 45, c'est-à-dire 72 heures après le traitement et les infestations ultérieures, les tiques ont été retirées, comptées et le nombre de tiques vivantes attachées dans chaque groupe a été utilisé pour les calculs d'efficacité. À chaque instant, tous les chats non traités étaient correctement infestés, démontrant une population de tiques vigoureuse et un modèle d'étude adéquat. L'efficacité curative après une seule application contre une infestation de tiques existante, 72 heures après le traitement, était de 98,7%. L'efficacité préventive, 72 heures après les infestations hebdomadaires, au cours des cinq semaines suivantes, variait entre 93,8% et 99,4%.

Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia.

Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.

Fabrication and efficacy assessment of combination of brimonidine and ivermectin for treatment of papulopustular rosacea.

BACKGROUND & AIM: Rosacea is a chronic inflammatory, multifactorial disease for which combination therapy could be an effective treatment. In this study, we evaluate the effect of the combination therapy of brimonidine 0.33% and ivermectin 1% as a single cream for the treatment of papulopustular rosacea. METHOD: A stable and appropriate formulation was prepared by adding the aqueous phase to the lipid phase while being stirred. The stability and physicochemical properties of the formulation were evaluated under accelerated conditions. Twelve patients (36-60 years) with mild to moderate papulopustular rosacea and a Demodex count of five or more were treated with the combination of brimonidine 0.33% and ivermectin 1% cream. Clinician's Erythema Assessment (CEA), Patients Self-Assessment (PSA), skin erythema (ΔE) and lightness (ΔL), and skin biophysical parameters including transepidermal water loss (TEWL), skin hydration, pH, and sebum content, as well as erythema and melanin index and ultrasound parameters, were measured before treatment and 4 and 8 weeks after. Adverse drug reactions were also recorded. RESULTS: CEA and PSA decreased significantly from 3 to 2 after 8 weeks, respectively (p-value = 0.014 for CEA and 0.010 for PSA). ΔE and ΔL, as well as skin erythema index and TEWL improved after 8 weeks of treatment (p < 0.05). Two patients withdrew from the study in the first week because of local adverse effects; one developed flushing following treatment and left the investigation after 4 weeks and another patient withdrew from the study after 4 weeks due to deciding to become pregnant. CONCLUSION: Eight-week treatment with the combination of brimonidine 0.33% and ivermectin 1% was shown to be effective for improvement of erythema and inflammatory lesions in mild to moderate papulopustular rosacea.

Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Sarna costrosa: revisión sobre aspectos clínicos de una ectoparasitosis desatendida y de presentación infrecuente / Crusty scabies: review of the clinical aspects of a neglected and infrequent ectoparasitosis

En esta revisión de la literatura se describen aspectos epidemiológicos, fisiopatológicos, clínicos y terapéuticos sobre una presentación atípica y grave de escabiosis, la sarna costrosa o noruega. Esta presentación de escabiosis destaca por afectar principalmente a personas con condiciones de inmunodepresión o sociales que las hacen susceptibles de una alta carga parasitaria, además se asocia a un peor pronóstico y a riesgo de complicaciones. Desde el punto de vista terapéutico, sus estrategias difieren del manejo de la escabiosis clásica.(AU)

This literature review describes epidemiological, pathophysiological, clinical and therapeutic aspects of an atypical and severe presentation of scabies, Norwegian or crusty scabies. This presentation of scabies stands out because it mainly affects people with immunosuppressive or social conditions that make them susceptibleto a high parasite load, it is also associated with a worse prognosis and risk of complications. From a therapeutic point of view, their strategies differ from the management of classic scabies.(AU)

Proxy Responses for Mass Drug Administration Coverage Surveys: The Trends and Biases When Others are Allowed to Respond.

Coverage surveys for mass drug administration (MDA) rely on respondent recall and often permit proxy responses, whereby another household member is allowed to respond on behalf of an absent individual. In this secondary analysis of coverage surveys in Malawi, Burkina Faso, and Uganda, we explore the characteristics of individuals who require proxy responses and quantify the association between proxy responses and reported drug coverage. The adjusted logistic regression model found that men 11-39 years and women 11-18 years who were eligible for MDA had greater odds of requiring a proxy response compared with ineligible men and women in the same age groups. A hierarchical multivariable analysis found that proxy responses had 1.70 times the odds of reporting ingestion of MDA drugs compared with first-person responses, controlling for age and sex (95% CI: 1.17, 2.46). This finding is surprising, given that individuals absent during a coverage survey may also have been absent during the MDA, and suggests that proxy responses may be leading to an inflation of survey estimates of drug coverage. This study highlights the possibility for recall bias in proxy responses to MDA coverage; however, excluding absent individuals from coverage surveys would introduce a new bias. Further research is necessary to determine the best method for obtaining information on drug coverage when individuals are absent.

Repeated Ivermectin Treatment Induces Ivermectin Resistance in Strongyloides ratti by Upregulating the Expression of ATP-Binding Cassette Transporter Genes.

Ivermectin (IVM) is a widely used anthelmintic. However, with widespread use comes the risk of the emergence of IVM resistance, particularly in strongyloidiasis. Adenosine triphosphate (ATP)-binding cassette (ABC) transporter genes play an important role in the IVM-resistance mechanism. Here, we aimed to establish an animal experimental model of IVM resistance by frequent treatment of Strongyloides ratti with subtherapeutic doses of IVM, resistance being evaluated by the expression levels of ABC transporter genes. Rats infected with S. ratti were placed in experimental groups as follows: 1) untreated control (control); 2) treated with the mutagen ethyl methanesulfonate (EMS); 3) injected with 100 µg/kg body weight of IVM (IVM); 4) treated with a combination of EMS and IVM (IVM+EMS). Parasites were evaluated after four generations. Extent of IVM resistance was assessed using IVM sensitivity, larval development, and expression of ABC genes. By the F4 generation, S. ratti in the IVM group exhibited significantly higher levels of IVM resistance than did other groups according to in vitro drug-sensitivity tests and inhibition of larval development (IC50 = 36.60 ng/mL; 95% CI: 31.6, 42.01). Expression levels of ABC isoform genes (ABCA, ABCF, and ABCG) were statistically significantly higher in the IVM-resistant line compared with the susceptible line. In conclusion, IVM subtherapeutic doses induced IVM resistance in S. ratti by the F4 generation with corresponding upregulation of some ABC isoform genes. The study provides a model for inducing and assessing drug resistance in Strongyloides.

Mecanismos de acción de agentes propuestos para el tratamiento farmacológico específico de la infección por SARS-CoV-2 / Mechanisms of action of proposed agents for the specific pharmacological treatment of SARS-CoV-2 infection

Resumen Desde la notificación de la pandemia por SARS-CoV-2, agente patógeno responsable del COVID-19, muchos de los tratamientos dirigidos a su manejo han estado sometidos a estudios de manera constante, con el fin de comprobar su eficacia y seguridad. El conocimiento de su virología y etiopatogenia posibilitaría objetivar los pasos moleculares específicos que puedan ser blancos terapéuticos de variados fármacos actualmente disponibles. Esta experiencia proviene principalmente de las infecciones por SARS-CoV y MERS-CoV, con resultados variados 'in vitro' en el SARS-CoV-2, sin evidencia clínica que demuestre efectividad y seguridad de dichos tratamientos. A la fecha, no se ha podido concretar con claridad un esquema de tratamiento específico, debido a que la evidencia surgida ha puesto en jaque cada uno de los fármacos propuestos. Esto ha motivado a continuar en la búsqueda de una estrategia efectiva que permita manejar esta pandemia con la seguridad y eficacia necesaria para que el beneficio terapéutico esté por sobre los posibles efectos adversos que estos esquemas farmacológicos pudiesen presentar. La siguiente revisión pretende mostrar la evidencia disponible a la fecha, definiendo la actividad de cada fármaco en función de su mecanismo de acción.

Since the beginning of the pandemic by SARS-CoV-2, the pathogen responsible for COVID-19, many of the therapeutic options for its management have been under constant revision, in order to verify their safety and efficiency. Knowledge of the viral structure and pathogenesis make it possible to determine the molecular pathways that may be targeted with current available drugs. The experience with these drugs comes mainly from infections caused by SARS-CoV and MERS-CoV, in vitro studies with SARS-CoV-2 that yield variable results, and clinical experience that does not ensure effectiveness and safety of such drugs. To date, it has not been possible to elucidate a specific treatment scheme, because of the constant release of evidence that challenges the usefulness of the proposed drugs. This has motived us to continue seeking for an effective strategy that allows to manage this pandemic in a safe and efficient manner, so that therapeutic benefit surpasses the related adverse drug reactions that can occur. The following review aims to showcase the evidence available to date by defining the activity of each drug based on its mechanism of action.

Control of scabies in a tribal community using mass screening and treatment with oral ivermectin -A cluster randomized controlled trial in Gadchiroli, India.

BACKGROUND: Scabies is often endemic in tribal communities and difficult to control. We assessed the efficacy of a community-based intervention using mass screening and treatment with oral ivermectin in controlling scabies. METHODS/ FINDINGS: In this cluster randomised controlled trial, 12 villages were randomly selected from a cluster of 42 tribal villages in Gadchiroli district. In these villages, trained community health workers (CHWs) conducted mass screening for scabies. The diagnosis was confirmed by a physician. Six villages each were randomly allocated to the intervention and usual care arm (control arm). In the intervention arm (population 1184) CHWs provided directly observed oral ivermectin to scabies cases and their household contacts. In the usual care arm (population 1567) scabies cases were referred to the nearest clinic for topical treatment as per the standard practice. The primary outcome was prevalence of scabies two months after the treatment. Secondary outcomes were prevalence of scabies after twelve months of treatment and prevalence of impetigo after two and twelve months of treatment. Outcomes were measured by the team in a similar way as the baseline. The trial was registered with the clinical trial registry of India, number CTRI/2017/01/007704. In the baseline, 2 months and 12 months assessments 92.4%, 96% and 94% of the eligible individuals were screened in intervention villages and 91.4%, 91.3% and 95% in the usual care villages. The prevalence of scabies in the intervention and usual care arm was 8.4% vs 8.1% at the baseline, 2.8% vs 8.8% at two months [adjusted relative risk (ARR) 0.21, 95% CI 0.11-0.38] and 7.3% vs 14.1% (ARR 0.49, 95% CI 0.25-0.98) at twelve months The prevalence of impetigo in the intervention and usual care arm was 1.7% vs 0.6% at baseline, 0.6% vs 1% at two months (ARR 0.55, 95% CI 0.22-1.37) and 0.3% vs 0.7% at 12 months (ARR 0.42, 95% CI 0.06-2.74). Adverse effects due to ivermectin occurred in 12.1% of patients and were mild. CONCLUSIONS: Mass screening and treatment in the community with oral ivermectin delivered by the CHWs is superior to mass screening followed by usual care involving referral to clinic for topical treatment in controlling scabies in this tribal community in Gadchiroli.

Ivermectin reduces in vivo coronavirus infection in a mouse experimental model.

The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 µg/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases.

Intravenous lipid emulsion treatment in rabbits with ivermectin toxicosis.

OBJECTIVE: To determine the effect and safety of IV lipid emulsion in rabbits with acute ivermectin toxicosis. DESIGN: Randomized controlled trial. SETTING: University research facility. ANIMALS: Twenty-four healthy male adult New Zealand rabbits. INTERVENTIONS: Three groups of rabbits (IV, IV_RL, and IV_LE) received 80 mg/kg of ivermectin (8 mL/kg) through a nasogastric tube, and 1 group (LE) received an equivalent volume (8 mL/kg) of 0.9% sodium chloride. Group IV_RL was treated with Ringer's lactate (2 mL/kg bolus, followed by 0.25 mL/kg/min for 60 minutes), whereas groups IV_LE and LE received 20% lipid emulsion. The rabbits were submitted to clinical and neurological evaluation, and blood samples were collected for biochemical analysis. All animals were euthanized, and tissue samples were collected and processed for histopathological evaluation and ivermectin quantification. MEASUREMENTS AND MAIN RESULTS: All animals exposed to ivermectin manifested clinical changes consistent with toxicosis, but the ones that received IV lipid emulsion infusion showed no significant clinical improvement. Intense increase in serum glucose and triglyceride concentrations was seen after ivermectin exposure, along with increased urea and creatinine concentrations, but the last 2 remained within the reference range. Lipid emulsion caused an intense increase in triglycerides and cholesterol concentrations. No pathological abnormalities were seen in the organs sampled. Toxicological analysis showed greater ivermectin concentration in adipose tissue and liver, followed by kidney and, finally, brain. The treatments did not change ivermectin tissue concentration. CONCLUSIONS: When given to rabbits intoxicated with ivermectin, IV lipid emulsion was biochemically and histologically safe but was not effective in treating, delaying, or reversing clinical signs and progression, nor did it alter ivermectin tissue concentration.

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study.

BACKGROUND: Ivermectin is one among several potential drugs explored for its therapeutic and preventive role in SARS-CoV-2 infection. The study was aimed to explore the association between ivermectin prophylaxis and the development of SARS-CoV-2 infection among healthcare workers. METHODS: A hospital-based matched case-control study was conducted among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020. Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR. Exposure was defined as the intake of ivermectin and/or hydroxychloroquine and/or vitamin-C and/or other prophylaxis for COVID-19. Data collection and entry was done in Epicollect5, and analysis was performed using STATA version 13. Conditional logistic regression models were used to describe the associated factors for SARS-CoV-2 infection. RESULTS: Ivermectin prophylaxis was taken by 76 controls and 41 cases. Two-dose ivermectin prophylaxis (AOR 0.27, 95% CI, 0.15-0.51) was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Those involved in physical activity (AOR 3.06 95% CI, 1.18-7.93) for more than an hour/day were more likely to contract SARS-CoV-2 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with SARS-CoV-2 infection. CONCLUSION: Two-dose ivermectin prophylaxis at a dose of 300 µg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Chemoprophylaxis has relevance in the containment of pandemic.

Eficacia y Seguridad de Ivermectina para la prevención de la infección por SARS-CoV-2: (febrero del 2021) / Efficacy and Safety of Ivermectin for Prevention of SARS-CoV-2 infection: (February 2021)

INTRODUCCIÓN: Ivermectina, es un medicamento antiparasitario y autorizado en el país en su presentación oral para el tratamiento de estrongiloidiasis y oncocercosis, ha sido propuesto como potencial alternativa terapéutica y profiláctica para COVID-19 debido a su actividad antiviral in vitro sobre SARS-CoV-2, al observarse la inhibición de la replicación viral luego de su administración a células Vero hSLAM infectadas (1), a niveles de dosificación muy superiores a los aprobados para uso en humanos. Sin embargo, los estudios preclínicos no resultan suficientes para indicar que Ivermectina resultará un beneficio clínico en pacientes con riesgo de exposición al SARS-CoV2. Se ha elaborado la presente revisión a fin de identificar la evidencia disponible a la fecha, respecto a la efectividad y seguridad de Ivermectina como profilaxis para COVID-19. OBJETIVO: Resumir la evidencia disponible sobre la eficacia y seguridad de la Ivermectina para la prevención de la infección por SARS-CoV-2. METODOLOGÍA: La búsqueda sistemática se realizó en MEDLINE/Pubmed, EMBASE/Ovid, la Biblioteca Cochrane, medRxiv (un servidor de distribución de manuscritos aún no publicados, sin certificación de revisión por pares) y en la Plataforma Living Overview of the Evidence (L·OVE) de la Fundación Epistemonikos, incluyendo términos en lenguaje natural y lenguaje estructurado (Tesauros) para COVID-19 e Ivermectina según cada base de datos. A excepción de L·OVE, la búsqueda se restringió a partir de la última fecha de búsqueda de la Síntesis de Evidencia No 35-2020: "Efectividad y seguridad de Ivermectina en pacientes hospitalizados con COVID-19. Actualización al 25 de octubre de 2020", desde el 25 de octubre de 2020 hasta el 18 de enero de 2021. No se consideró incluir el periodo previo al 25 de octubre de 2020, ya que en la etapa de selección de las revisiones efectuadas previamente, no se identificó ningún estudio vinculado al uso de Ivermectina como profilaxis. Adicionalmente, se revisaron los estudios referenciados en la Revisión Rápida de opciones terapéuticas para COVID-19, actualizada al 29 de enero de 2021 por la Organización Panamericana de la Salud (2) y el listado de estudios citados por la página web https://ivmmeta.com al 29 de enero de 2021(3). RESULTADOS: Se seleccionaron 6 estudios, 4 fueron publicados (4­6) y 2 están disponibles en formato de pre-impresión (manuscritos no publicados ni certificados por revisión por pares (7,8). CONCLUSIONES: Se identificaron 2 ensayos clínicos, 3 cohortes prospectivas y un estudio caso control, realizados en Egipto, Argentina, Bangladesh e India. Tres estudios observacionales se realizaron en trabajadores de salud con la administración de Ivermectina bajo un entorno de profilaxis pre-exposición, un ensayo clínico administró Ivermectina como profilaxis post-exposición en contactos domiciliarios de casos de COVID-19 y un ensayo clínico adicional incluyó a ambos grupos de población. Cuatro estudios evaluaron el uso de Ivermectina sola o combinada con medidas preventivas estándares y dos de ellos evaluaron Ivermectina en combinación con Iota-carragenina. Existió variabilidad entre los estudios respecto a la dosis, frecuencia de administración y duración del tratamiento profiláctico con Ivermectina así como el periodo de seguimiento. Si bien la frecuencia de eventos de infección por SARS-CoV-2 (casos sintomáticos y asintomáticos) y de COVID-19 (enfermedad sintomática) fue menor en los grupos donde se administró Ivermectina, la calidad de la evidencia para estos desenlaces es muy baja debido al riesgo de sesgo e imprecisión en los resultados. Por consiguiente, existe incertidumbre respecto al efecto de Ivermectina en la prevención de la infección por SARS-CoV-2. La certeza global de la evidencia para la frecuencia de eventos adversos debido a la profilaxis con Ivermectina es muy Baja debido al riesgo de sesgo serio e imprecisión. En consecuencia, no se tiene seguridad en el estimado reportado por un estudio. La evidencia identificada hasta el momento resulta insuficiente para establecer que Ivermectina administrada como profilaxis pre-exposición o post-exposición, resulta efectiva y segura para prevenir la infección por SARS-CoV-2, siendo necesario contar con resultados de ensayos clínicos aleatorizados y adecuadamente conducidos.

Chemoprophylaxis against COVID-19 among health-care workers using Ivermectin in low- and middle-income countries: A systematic review and meta-analysis.

Coronavirus disease-2019 (COVID-19) is a novel viral infectious disease that the World Health Organization (WHO) has announced to be a pandemic. This meta-analysis was aimed at providing evidence for the use of ivermectin to prevent COVID-19 among hospital workers in low-resource countries. Medical databases including African Journals online, Google Scholar, PubMed, Cochrane library, EMBASE, COVID-19 research database (WHO), Clinicaltrials.gov, and SCOPUS were searched for studies on Ivermectin as a chemoprophylactic drug against COVID-19 among hospital personnel in settings with limited resources. Preprint servers such as bioRxiv and medRxiv as well as the gray literature were also searched. Studies adjudged to be eligible were identified using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses algorithm. Statistical analyses were done using Stata version 14.3. Seven studies were selected for the meta-analysis. The total sample size was 2652. There were two randomized controlled trials and five nonrandomized studies. Some studies dosed Ivermectin daily while some dosed it weekly. However, one of the studies dosed it monthly. The studies reported variable clinical benefits. I2 statistic was 92%, and random effect model was used. The pooled odd ratio was 0.11 (95% confidence interval 0.09-0.13). This implies that 89% of the participants benefited from taking Ivermectin as a form of preexposure chemoprophylaxis. Ivermectin has a significant clinical benefit as a preventive drug against COVID-19 for hospital personnel in settings with limited resources.

Scabies: Diagnostic and Therapeutic Update.

BACKGROUND: Scabies is globally ubiquitous and is a significant health issue for institutions, the economically disenfranchised, resource-poor areas, and for those with weakened immune systems. Topicals are usually effective, but are cumbersome and expensive to use in large populations and for those nonadherent to topicals. Oral ivermectin became available in Canada for the off-label treatment of scabies in the fall 2018. OBJECTIVES: To review the diagnosis and management of scabies. Dose schedules and concomitant management measures are outlined for scabies simplex and for crusted scabies. Ivermectin use is outlined. METHODS: Medline, colleague discussions, practice review, and experience from managing scabies in institutions. RESULTS: Oral ivermectin is safe, easier to use, cheaper, more effective, and more economical than topicals in widespread institutional scabies, for those nonadherent to topicals, and in crusted scabies. CONCLUSIONS: Oral ivermectin is the treatment of choice in large populations, the nonadherent, and for crusted scabies. Oral ivermectin is produced by Merck Canada as Stromectol 3 mg. The treatment dose for noncrusted scabies is 200 µg/kg, taken in a single dose with food. For example, 15 mg (5 tablets) for a 70 kg person. Retreat in 10-14 days to enhance effectiveness, and perhaps to reduce scabicide resistance.

Treatment of sarcoptic and chorioptic mange in an alpaca (Vicugna pacos) herd with a combination of topical amitraz and subcutaneous ivermectin.

Clinical history: An outbreak of intense pruritus and weight loss in a herd of 40 alpacas (Vicugna pacos) in the south-west of France was investigated after the death of 14 adults. One alpaca was referred to a veterinary teaching hospital for diagnosis and treatment but died soon after and one of the dead alpacas was submitted for necropsy. Clinical findings: The remaining alpacas were intensely pruritic with variably severe and extensive alopecia, erythema, lichenification and crusting on the face, ventral abdomen and distal limbs. Superficial skin scrapes from five animals revealed large numbers of Sarcoptes scabiei mites, and less frequent and numerous Chorioptes bovis mites. Coproscopic examinations revealed a median of 1,350 (min 500, max 8800) strongyle epg. The alpaca admitted for treatment was anaemic and hypoalbuminaemic. Skin scrapes revealed copious S. scabiei and C. bovis mites. The two alpacas examined post-mortem had similar skin lesions to those examined on-farm and were cachexic. One had lung lesions attributed to protostrongylid infestation and its liver contained numerous Dicrocoelium spp. adults. Diagnosis: Sarcoptic and chorioptic mange with secondary superficial bacterial skin infection, associated with severe internal parasitism and underfeeding. Treatment and outcome: All 25 alpacas were treated topically with a 3% chlorhexidine shampoo followed by a 0.025% amitraz wash at the initial visit and then 1, 2, 3, 7 and 9 weeks later. A systemic treatment with S/C 500 µg/kg ivermectin was administered at the initial visit and then 2, 7 and 9 weeks later. The alpacas were treated orally with 50 mg/kg praziquantel to control dicrocoeliosis. Nutritional measures, including increased pasture area and supplemental feeding were simultaneously implemented. Pruritus was reduced 1 week after the start of treatment and had resolved after 2 weeks. After 9 weeks, skin lesions were markedly improved. Six months after the initial visit, skin lesions entirely resolved and superficial skin scrapes, taken from half of the animals, were negative for mites. Clinical relevance: This is the first report of the use of two acaricides combined with a chlorhexidine shampoo to successfully treat simultaneous sarcoptic and chorioptic mange in alpacas.

Efficacy of Topical Ivermectin for the Treatment of Cutaneous and Ocular Rosacea.

Purpose: To investigate the efficacy of once-daily topical treatment of ocular and cutaneous rosacea with ivermectin 1% cream (Soolantra®, Galderma).Methods: Ten patients with rosacea were evaluated in a retrospective monocentric pilot study. Subjective symptoms (measured with the Ocular Surface Disease Index), skin findings, and ocular changes (blepharitis with telangiectasia and meibomian gland dysfunction, conjunctival redness, tear breakup time (TBUT), and fluorescein staining of the cornea) were evaluated. The follow-up was 8 months (range: 5-12 months).Results: The OSDI score decreased in the 8th week of treatment (38.5 ± 21.7, P = .004). After 16 weeks, blepharitis (P = .004), and conjunctival redness (P = .008) had strongly improved, and grade 1 was seen in all patients until the end of follow-up. Fluorescein staining of the cornea (P = .001) and TBUT (P = .016) showed significant improvement until the last follow-up visit. No side effects were observed. Conclusion: Topical ivermectin cream 1% given daily is an effective and safe therapy against rosacea.