Efficacy and safety of oral ivermectin in the treatment of mild to moderate Covid-19 patients: a multi-centre double-blind randomized controlled clinical trial.

BACKGROUND: Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19. TRIAL DESIGN AND METHODS: A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups. RESULTS: Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 - 20,500) with ivermectin (n = 80) and 4,100 copies/mL (1,000-65,600) with placebo (n = 81, p = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively (p = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load. CONCLUSION: Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms. TRIAL REGISTRATION NUMBER: SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021.

Comprehensive analysis of gastrointestinal side effects in COVID-19 patients undergoing combined pharmacological treatment with azithromycin and hydroxychloroquine: a systematic review and network meta-analysis.

During the COVID-19 pandemic, several drugs were repositioned and combined to quickly find a way to mitigate the effects of the infection. However, the adverse effects of these combinations on the gastrointestinal tract are unknown. We aimed investigate whether Hydroxychloroquine (HD), Azithromycin (AZ), and Ivermectin (IV) used in combination for the treatment of COVID-19, can lead to the development of gastrointestinal disorders. This is a systematic review and network meta-analysis conducted using Stata and Revman software, respectively. The protocol was registered with PROSPERO (CRD42023372802). A search of clinical trials in Cochrane Library databases, Embase, Web of Science, Lilacs, PubMed, Scopus and Clinicaltrials.gov conducted on November 26, 2023. The eligibility of the studies was assessed based on PICO criteria, including trials that compared different treatments and control group. The analysis of the quality of the evidence was carried out according to the GRADE. Six trials involving 1,686 COVID-19 patients were included. No trials on the association of HD or AZ with IV met the inclusion criteria, only studies on the association between HD and AZ were included. Nausea, vomiting, diarrhea, abdominal pain and increased transaminases were related. The symptoms of vomiting and nausea were evaluated through a network meta-analysis, while the symptom of abdominal pain was evaluated through a meta-analysis. No significant associations with these symptoms were observed for HD, AZ, or their combination, compared to control. Low heterogeneity and absence of inconsistency in indirect and direct comparisons were noted. Limitations included small sample sizes, varied drug dosages, and potential publication bias during the pandemic peak. This review unveils that there are no associations between gastrointestinal adverse effects and the combined treatment of HD with AZ in the management of COVID-19, as compared to either the use of a control group or the administration of the drugs individually, on the other hand, highlighting the very low or low certainty of evidence for the evaluated outcomes. To accurately conclude the absence of side effects, further high-quality randomized studies are needed.

Efficacy and safety of ivermectin for treatment of non-hospitalized COVID-19 patients: A systematic review and meta-analysis of 12 randomized controlled trials with 7,035 participants.

INTRODUCTION: We systematically assessed benefits and harms of the use of ivermectin in non-hospitalized patients with early COVID-19. METHODS: Five databases were searched until October 17, 2023, for randomized controlled trials (RCTs) in adult patients with COVID-19 treated with ivermectin against standard of care (SoC), placebo, or active drug. Primary outcomes were hospitalization, all-cause mortality, and adverse events (AEs). Secondary outcomes included mechanical ventilation (MV), clinical improvement, clinical worsening, viral clearance, and severe adverse events (SAEs). Random effects meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Pre-specified subgroup analyses (ivermectin dose, control type, risk of bias, follow-up, and country income) and trial sequential analysis (TSA) were performed. RESULTS: Twelve RCTs (n = 7,035) were included. The controls were placebo in nine RCTs, SoC in two RCTs, and placebo or active drug in one RCT. Ivermectin did not reduce hospitalization (relative risk [RR], 0.81, 95% confidence interval [95% CI] 0.64-1.03; 8 RCTs, low QoE), all-cause mortality (RR 0.98, 95% CI 0.73-1.33; 9 RCTs, low QoE), or AEs (RR 0.89, 95% CI 0.75-1.07; 9 RCTs, very low QoE) vs. controls. Ivermectin did not reduce MV, clinical worsening, or SAEs and did not increase clinical improvement and viral clearance vs. controls (very low QoE for secondary outcomes). Subgroup analyses were mostly consistent with main analyses, and TSA-adjusted risk for hospitalization was similar to main analysis. CONCLUSIONS: In non-hospitalized COVID-19 patients, ivermectin did not have effect on clinical, non-clinical or safety outcomes versus controls. Ivermectin should not be recommended as treatment in non-hospitalized COVID-19 patients.

Onchocerca volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia.

BACKGROUND: After ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with high Onchocerca volvulus microfilaridermia (microfilariae/mg skin, SmfD). Assuming long-term ivermectin use led to < 5 SmfD with little or no eye involvement, DEC + ivermectin + albendazole treatment a few months after ivermectin was proposed. In 2018, the US FDA approved moxidectin for treatment of O. volvulus infection. The Phase 3 study evaluated SmfD, microfilariae in the anterior chamber (mfAC) and adverse events (AEs) in ivermectin-naïve individuals with ≥ 10 SmfD after 8 mg moxidectin (n = 978) or 150 µg/kg ivermectin (n = 494) treatment. METHODS: We analyzed the data from 1463 participants with both eyes evaluated using six (0, 1-5, 6-10, 11-20, 21-40, > 40) mfAC and three pre-treatment (< 20, 20 to < 50, ≥ 50) and post-treatment (0, > 0-5, > 5) SmfD categories. A linear mixed model evaluated factors and covariates impacting mfAC levels. Ocular AEs were summarized by type and start post-treatment. Logistic models evaluated factors and covariates impacting the risk for ocular AEs. RESULTS: Moxidectin and ivermectin had the same effect on mfAC levels. These increased from pre-treatment to Day 4 and Month 1 in 20% and 16% of participants, respectively. Six and 12 months post-treatment, mfAC were detected in ≈5% and ≈3% of participants, respectively. Ocular Mazzotti reactions occurred in 12.4% of moxidectin- and 10.2% of ivermectin-treated participants without difference in type or severity. The risk for ≥ 1 ocular Mazzotti reaction increased for women (OR 1.537, 95% CI 1.096-2.157) and with mfAC levels pre- and 4 days post-treatment (OR 0: > 10 mfAC 2.704, 95% CI 1.27-5.749 and 1.619, 95% CI 0.80-3.280, respectively). CONCLUSIONS: The impact of SmfD and mfAC levels before and early after treatment on ocular AEs needs to be better understood before making decisions on the risk-benefit of strategies including DEC. Such decisions should take into account interindividual variability in SmfD, mfAC levels and treatment response and risks to even a small percentage of individuals.

Ivermectin ameliorates bleomycin-induced lung fibrosis in male rats by inhibiting the inflammation and oxidative stress.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a pulmonary fibrotic disease characterized by a poor prognosis, which its pathogenesis involves the accumulation of abnormal fibrous tissue, inflammation, and oxidative stress. Ivermectin, a positive allosteric modulator of GABAA receptor, exerts anti-inflammatory and antioxidant properties in preclinical studies. The present study investigates the potential protective effects of ivermectin treatment in rats against bleomycin-induced IPF. MATERIALS AND METHODS: The present study involved 42 male Wistar rats, which were divided into five groups: control (without induction of IPF), bleomycin (IPF-induced by bleomycin 2.5 mg/kg, by intratracheal administration), and three fibrosis groups receiving ivermectin (0.5, 1, and 3 mg/kg). lung tissues were harvested for measurement of oxidative stress [via myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione (GSH)] and inflammatory markers (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], and transforming growth factor-ß [TGF-ß]). Histological assessments of tissue damage were performed using hematoxylin-eosin (H&E) and Masson's trichrome staining methods. RESULTS: The induction of fibrosis via bleomycin was found to increase levels of MPO as well as TNF-α, IL-1ß, and TGF-ß while decrease SOD activity and GSH level. Treatment with ivermectin at a dosage of 3 mg/kg was able to reverse the effects of bleomycin-induced fibrosis on these markers. In addition, results from H&E and Masson's trichrome staining showed that ivermectin treatment at this same dose reduced tissue damage and pulmonary fibrosis. CONCLUSION: The data obtained from this study indicate that ivermectin may have therapeutic benefits for IPF, likely due to its ability to reduce inflammation and mitigate oxidative stress-induced toxicity.

Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand.

BACKGROUND: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. METHODS: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. RESULTS: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). CONCLUSIONS: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).

Development and validation of analytical methods by HPLC for quality control of avermectins and milbemycins in bulk samples

This work aims to develop analytical methods using high-performance liquid chromatography with a diode array detector (HPLC-DAD) for analysis and quantification of avermectins (AVMs) and milbemycins (MBMs) in bulk samples. First, the methods were optimized and some parameters such as temperature, flow rate, injection volume and mobile phase with different proportions of solvents were evaluated. The best chromatographic conditions were obtained using the Phenomenex® C18 (150 × 4.60 mm, 5 µm) column at a temperature of 20 °C, flow rate of 1.2 mL min-1, injection volume of 20 µL, and detection at 250 nm. Acetonitrile: ultrapure water (87: 13, v/v) was used as mobile phase for moxidectin and eprinomectin, and acetonitrile: methanol: ultrapure water (53: 35: 12, v/v/v) for abamectin and ivermectin. Under these conditions satisfactory results were obtained, with appropriate limits of detection and quantification, acceptable linearity, precision, accuracy, and robustness. These methods satisfy the need for analytical methods for the multi-determination of MBMs and the B1a and B1b forms of AVMs by HPLC-DAD, which can be considered simple, effective, innovative and should aid in the development of the fiel

Sales of "COVID kit" drugs and adverse drug reactions reported by the Brazilian Health Regulatory Agency / Vendas de "kit-COVID" e reações adversas a esses medicamentos relatadas pela Agência Nacional de Vigilância Sanitária / Ventas de medicamentos del "kit-COVID" y reacciones adversas a los medicamentos notificadas por la Agencia Nacional de Vigilancia Sanitaria

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

No Brasil, o uso off label de azitromicina, hidroxicloroquina e ivermectina (o "kit-COVID") foi sugerido para tratar COVID-19 sem que tivéssemos evidências clínicas ou científicas de sua eficácia. Estas drogas têm causado reações adversas (RA) em quem as tomam. Este estudo almejou analisar se a venda dos medicamentos que compõem o "kit-COVID" correlaciona-se com o número relatado de RAs após o início da pandemia da COVID-19. Os dados sobre vendas e RA associados a azitromicina, hidroxicloroquina e ivermectina foram obtidos no site da Agência Nacional de Vigilância Sanitária (Anvisa) para todos os estados brasileiros. Comparamos o período entre março de 2019 e fevereiro de 2020 (antes da pandemia) ao de março de 2020 a fevereiro de 2021 (durante a pandemia). Ajustamos tendências para os dados de séries temporais e as análises de correlação cruzada para investigar a correlação entre vendas e RA em um mesmo mês (lag 0) e nos seguintes (lag 1 e 2). O coeficiente de correlação de Spearman foi utilizado para avaliar a magnitude das correlações. Após o início da pandemia, as vendas de todos os medicamentos investigados aumentaram significativamente (69,75% para azitromicina, 10.856.481,39% para hidroxicloroquina e 12.291.129,32% para ivermectina). Os níveis de RAs de todos os medicamentos (com exceção de azitromicina) eram zero antes da pandemia mas aumentaram após seu início. A análise de correlação cruzada foi significativa no lag 1 para todas as drogas em todo o país. A correlação de Spearman foi moderada para azitromicina e hidroxicloroquina, mas ausente para ivermectina. Os dados devem ser interpretados com cautela, uma vez que não realizamos uma busca ativa por RA. Nossos resultados mostram que o uso aumentado e indiscriminado do "kit-COVID" durante a pandemia se correlaciona com uma ocorrência aumentada de RAs.

Se ha sugerido el uso fuera de lo establecido de azitromicina, hidroxicloroquina e ivermectina (el "kit-COVID") para el tratamiento de la COVID-19 en Brasil sin evidencia clínica o científica de su eficacia. Estos medicamentos tienen reacciones adversas (RAM) conocidas. Este estudio pretendía analizar si las ventas de medicamentos del "kit-COVID" están correlacionadas con el número de reacciones adversas notificadas tras el inicio de la pandemia de COVID-19. Los datos se obtuvieron del sitio web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) sobre las ventas y las RAM notificadas para la azitromicina, la hidroxicloroquina y la ivermectina para todos los estados brasileños. Se comparó el periodo de marzo de 2019 a febrero de 2020 (antes de la pandemia) con el de marzo de 2020 a febrero de 2021 (durante la pandemia). Se realizó un ajuste de tendencia para los datos de las series de tiempo y un análisis de correlación cruzada para investigar la correlación entre las ventas y la RAM dentro del mismo mes (lag 0) y en los meses siguientes (lag 1 y lag 2). Se utilizó el coeficiente de correlación de Spearman para evaluar la magnitud de las correlaciones. Tras el inicio de la pandemia, las ventas de todos los medicamentos investigados aumentaron significativamente (69,75% para la azitromicina, 10.856.481,39% para la hidroxicloroquina y 12.291.129,32% para la ivermectina). Los niveles de RAM de todos los medicamentos, excepto la azitromicina, eran nulos antes de la pandemia, pero aumentaron tras su inicio. El análisis de correlación cruzada fue significativo en el lag 1 para todos los medicamentos a nivel nacional. La correlación de Spearman fue moderada para la azitromicina y la hidroxicloroquina, pero no para la ivermectina. Los datos deben interpretarse con cautela, ya que no se realizó una búsqueda activa de RAM. Nuestros resultados muestran que el uso creciente e indiscriminado del "kit-COVID" durante la pandemia se correlaciona con una mayor aparición de las RAM.

Recomendación sobre uso de ivermectina en el tratamiento de COVID-19 / Recommendation Regarding the Use of Ivermectin as a Treatment for COVID-19, 22 June 2020 / Recomendação sobre o uso de ivermectina no tratamento de COVID-19, 22 de junho de 2020

Un estudio reciente (1) informó que la ivermectina se utilizó con éxito in vitro para el tratamiento del SARS-CoV-2 en células infectadas experimentalmente y dos publicaciones preimpresas (2,3) sobre estudios clínicos observacionales informaron la aparente utilidad de la ivermectina para tratar pacientes con COVID-19 que requirieron ventilación mecánica. Sin embargo, ninguno de estos estudios fue revisado por pares ni publicado formalmente y uno de ellos (3) fue retirado posteriormente.

A recent study reported that ivermectin was successfully used in vitro for the treatment of SARS-CoV-2 in experimentally infected cells, and two preprint publications reported observational clinical studies on the apparent utility of ivermectin to treat patients with COVID-19 needing mechanical ventilation. However, none of these studies was peer-reviewed nor formally published and one study was later retracted. The Pan American Health Organization (PAHO) compiled an evidence database of potential COVID-19 therapeutics for which a rapid review was conducted of all COVID-19 in vitro (lab) and in vivo (clinical) human studies published from January to May 2020. The review concluded that the studies on ivermectin were found to have a high risk of bias, very low certainty of the evidence, and that the existing evidence is insufficient to draw a conclusion on benefits and harms. Though the effectiveness of ivermectin is currently being evaluated in various randomized clinical trials, the World Health Organization (WHO) excluded ivermectin from its co-sponsored Solidarity Trial for COVID-19 treatments, a global effort to find an effective treatment for COVID-19. The Mectizan® (ivermectin) Expert Committee Statement on Potential Efficacy of Ivermectin on COVID-19 emphasized that the laboratory results showing efficacy of ivermectin to reduce viral loads in laboratory cultures, at dosage levels far beyond those approved by the FDA for treatment of parasitic diseases in humans, are not sufficient to indicate that ivermectin will be of clinical benefit to reduce viral loads in COVID-19 patients. Chaccour et al. caution against using in vitro findings as more than a qualitative indicator of potential efficacy and emphasize that "due diligence and regulatory review are needed before testing ivermectin in COVID-19.

Um estudo recente informou que a ivermectina foi usada com êxito, in vitro, para o tratamento do vírus SARS-CoV-2 em células infectadas experimentalmente. Duas publicações preprint sobre estudos clínicos observacionais relataram aparente utilidade da ivermectina no tratamento de pacientes com COVID-19, em ventilação mecânica. Nenhum desses estudos teve revisão por pares, nem foi publicado formalmente, e um deles se retratou depois. A Organização Pan-Americana da Saúde (OPAS) compilou um banco de dados de evidências sobre potenciais tratamentos para COVID-19, e fez uma revisão rápida de todos os estudos realizados em humanos, in vitro (laboratórios) ou in vivo (clínicos), publicados de janeiro a maio de 2020. A revisão concluiu que os estudos sobre ivermectina tinham um alto risco de viés, muito pouca certeza de evidências, e as evidências existentes eram insuficientes para se chegar a uma conclusão sobre benefícios e danos. Apesar da efetividade da ivermectina estar sendo avaliada atualmente em diversos ensaios clínicos randomizados, deve-se enfatizar que a Organização Mundial da Saúde (OMS) excluiu a ivermectina de seu ensaio "Solidarity Trial" para tratamentos da COVID-19, uma iniciativa co-patrocinada, para encontrar um tratamento efetivo para COVID-19.

Efficacy and safety of topical eprinomectin to control Myocoptes musculinus infestation in mice / Eficácia e segurança da eprinomectina tópica para controlar a infestação Myocoptes musculinus em camundongos

Myocoptes musculinus is the most common fur mite identified among laboratory mice; infested mice, in addition to dermatological signs, may also be prone to secondary infections, affecting the outcome of a research trial. This trial was conducted in order to assess the safety and efficacy of a single topical administration of eprinomectin (5mg/kg BW) in a naturally infested laboratory mice colony. A safety trial was conducted on 20 uninfested pregnant females assigned to two groups, receiving eprinomectin and mineral oil, respectively. The mice were examined daily for signs of illness or toxicity; nests were individually weighted at 21 and 28 days postpartum. No acute toxicity was observed, all treated females gave full term delivery and number and mean weight of newborns ranged in the physiological values. To evaluate the efficacy, 20 naturally infested non-pregnant females were divided into two groups, treated as in the safety trial. Animals were observed daily for 15 min until 21 days post-treatment (DPT) and a “pruritus index” (PI: scratching and gnawing acts/mouse/min) was calculated. Pelage examination was performed on DPT 7, 14, 21 and 50. The “PI” was significantly lower in the treated group and mites were eradicated from all infested animals. A single topical administration of eprinomectin at a (high) dosage of 5mg/kg BW was safe and effective to control M. musculinus in mice.

Myocoptes musculinus é o ácaro de pele mais comum identificado entre camundongos de laboratório. Camundongos infestados, além de sinais dermatológicos, também podem ser propensos a infecções secundárias, interferindo no resultado de um ensaio de pesquisa. Este estudo foi realizado para avaliar a segurança e eficácia de uma única administração tópica de eprinomectina (5mg / kg PV) em uma colônia de camundongos de laboratório naturalmente infestada. Um estudo de segurança foi realizado em 20 fêmeas prenhes sadias, divididas em dois grupos, recebendo eprinomectina e óleo mineral, respectivamente. Os camundongos foram examinados diariamente para detectar quaisquer sinais da doença ou toxicidade; camundongos recém-nascidos foram pesados individualmente aos 21 e 28 dias pós-parto. Nenhuma toxicidade aguda foi observada. Todas as fêmeas tratadas chegaram ao parto, o número e peso dos recém-nascidos variaram dentro de parâmetros fisiológicos. Para avaliar a eficácia, 20 camundongos não prenhes, naturalmente infestados, foram divididos em dois grupos: tratado e grupo controle não tratado. Os animais foram observados diariamente durante 15 minutos até os 21 dias pós- tratamento (DPT) e um índice de prurido (IP) - arranhões e ato de roer / camundongo / min) foi calculado. Exame da pelagem foi realizado em DPT 7, 14, 21 e 50. O IP foi significativamente menor no grupo tratado, e os ácaros foram erradicados de todos os animais infestados. Uma única administração tópica de eprinomectina, na dose de 5mg / kg de peso corporal, foi segura e eficaz no controle de M. musculinus em camundongos.

Impact of ivermectin-resistant gastrointestinal nematodes in feedlot cattle in Argentina / Impacto de nematódeos gastrointestinais ivermectina-resistentes em bovinos em confinamento na Argentina

The aim was to evaluate for 75 days the impact on production of the remaining burden of ivermectin (IVM)-resistant parasites in naturally infected feedlot calves. The herds came from tick-infested areas of cattle breeding where the systematic use of IVM to control tick increases the gastrointestinal parasites resistant to this drug. This investigation was carried out in two commercial feedlots in Buenos Aires province. In feedlot A, two groups of 35 animal each received IVM 1% and the other received ricobendazole (RBZ) 10% respectively. The same was done in feedlot B. On day 0, two groups of 35 animals were made in feedlots A and B. Fecal samples were taken on days 0, 22, 54 and 75 pos-treatment (PT), and body weight was registered, from each animal. Fecal samples were processed for individual count of eggs per gram (EPG) and pooled fecal culture was carried out for identification of the parasite genus in each sampling. Fecal egg count reduction test (FECR) was calculated on day 22 PT. The study design used was a totally randomized block, with commercial feedlot and sex as block variables. For data analysis, a mixed model of the SAS statistical program was used. The FECR average on day 22 was 28.4% in the IVM group, and 94,2 % in the RBZ group . From this date on, significant differences in EPG were kept until day 54. EPG counts were only equal near the end of the trial, on day 75 (p=0.16). In both commercial feedlots, especially in the IVM group, Cooperia spp. was the most prevalent parasite in the fecal cultures. Significant differences in weight (P<0.01) on post-treatment day 75 was found between the average weight in the RBZ and the IVM group (246 vs. 238 kg respectively), what means a difference of 8.3% in gains. The importance for production in the antiparasite failure treatment in commercial feedlots was demonstrated, and the need of pos-treatment controls to evaluate the efficacy of the antiparasitic administered is emphasized.

O objetivo deste trabalho foi avaliar durante 75 dias o impacto sobre a produção da carga de parasita-ivermectina (IVM) resistentes remanescentes em bezerros naturalmente infectados no confinamento. Os rebanhos são provenientes de áreas infestadas por carrapatos, onde o uso sistemático de IVM para o controle do carrapato aumenta a resistência de parasita gastrintestinais a esta droga. Este trabalho foi realizado em dois confinamentos comerciais na província de Buenos Aires. Na fazenda A, dois grupos de 35 animais cada receberam IVM 1% e ricobendazole (RBZ) 10%, respectivamente. O mesmo foi feito no confinamento B. No dia 0, dois grupos de 35 animais foram feitos nas fazendas A e B. As amostras fecais foram tomadas nos dias 0, 22, 54 e 75 pós-tratamento (PT) e o peso corporal foi registrado, de cada animal. Amostras fecais foram processadas para a contagem individual de ovos por grama (EPG). Amostras fecais foram agrupadas para a identificação do gênero parasitária. O teste de redução de ovos fecais (TROF) foi calculado no dia 22 PT. O desenho do estudo utilizado foi aquele dos blocos inteiramente randomizados, sendo confinamento comercial e sexo as variáveis de bloco. Para a análise dos dados, um modelo misto do programa estatístico SAS foi utilizado. A média TROF no dia 22 foi de 28,4% no grupo IVM e 94,2% no grupo RBZ. A partir desta data, diferenças significativas na EPG foram mantidas até o dia 54. Contas de OPG só foram iguais perto do fim do estudo, no dia 75 (p=0,16). Em ambos os confinamentos comerciais, especialmente no grupo IVM, Cooperia spp. foram os parasitos mais prevalentes nas culturas fecais. Diferenças significativas no peso (P<0,01) 75 dias pós-tratamento foram encontradas entre o peso médio nos grupos RBZ e IVM (246 vs 238 kg, respectivamente), o que significa uma diferença de 8,3% nos ganhos. A importância para a produção no tratamento da insuficiência antiparasitários em confinamento comercial foi demonstrada, bem como a necessidade de controles pós-tratamento para avaliar a eficácia dos antiparasitários administrados é enfatizada.

Adverse reactions from community directed treatment with ivermectin (CDTI ) for onchocerciasis and loiasis in Ondo State, Nigeria

Onchocerciasis is an endemic disease in Ondo state, Nigeria. Community directed distribution of ivermectin is currently on-going in some local government areas of the state. Randomly selected persons (2 331 males and 2 469 females) were interviewed using a modified rapid assessment procedure for Loa loa (RAPLOA) to assess community directed treatment with ivermectin. The retrospective study evaluated the coverage, impacts and adverse reactions to the drug treatment. A questionnaire was administered by house-to-house visit in six local government areas, implementing community directed treatment with ivermectin (CDTI) in this bioclimatic zone. A total of 2,398 respondents were reported to have participated in the treatment. The overall ivermectin coverage of 49.96% was recorded (range 0 - 52% in different communities). Adverse reactions from ivermectin administration were experienced in 38% of individuals. Diverse adverse reactions experienced included predominantly itching (18.50%); oedema, especially of the face and the limbs (8.2%); rashes (3.4%) and body weakness (2.4%). Expulsion of intestinal worms occurred in 0.96% of the respondents. The occurrence of adverse reactions in relation to age categories was statistically significant. Neither fatal nor severe adverse reactions were reported by respondents. Significantly, despite experienced adverse reactions, continued participation, acceptability and compliance to ivermectin treatment was expressed by the various communities. This attitude is in consonance with the African Programme for Onchocerciasis Control (APOC) objectives. Rev. Biol. Trop. 56 (4): 1635-1643. Epub 2008 December 12.

La oncocercosis es endémica en el estado Ondo, Nigeria. Se seleccionaron 4 800 personas al azar para evaluar con encuesta retrospectiva la cobertura, efectos y reacciones al tratamiento farmacológico con ivermectina administrado por la misma comunidad. La cobertura global de ivermectina fue 50 % con reacciones adversas en 38 % de los individuos. Estas fueron comezón picazón (18%), edema, especialmente de la cara y las extremidades (8%), erupciones cutáneas (3%) y debilidad (2%); dependieron de la edad y no hubo reacciones más graves. La expulsión de las lombrices intestinales se produjo en 96% de los encuestados. A pesar de las reacciones adversas, hubo continuidad, aceptación y cumplimiento del tratamiento con ivermectina, en consonancia con los objetivos del Programa Africano para el Control de Oncocercosis (APOC).

Market survey of loiasis: prevalence and adverse reactions to ivermectin using a rapid procedure for loiasis / Encuesta de mercado de loiasis: prevalencia y reacciones adversas a la ivermectina usando un procedimiento rápido para la loiasis

OBJECTIVES: 1. To assess the levels of endemicity of loiasis in a total of 30 selected villages covering an area of 5.2 sq km in Owo, Akure North, Akure South, Ondo East, Ondo West and Ifedore local governments in Ondo State, Nigeria, using Rapid Assessment for loiasis technique. 2. To obtain information on adverse reactions which occurred during previous administrations of the drug ivermectin used for the treatment of loiasis and onchocerciasis in the study area. METHODS: Consent was obtained from the chairman of each local government village head and individuals were co-opted into the study. A total of 480 individuals were interviewed, 80 from each of the six local governments, during the regular scheduled community market days. Survey for Loa loa was carried out according to specifications in "Guidelines for rapid Assessment of Loa loa (TDR, 2002). RESULTS: Among the 480 respondents, 80 (16.7%) reported having had a history of loiasis while 11 (2.3%) had recent occurrence of the disease. The local name given to the disease in all the villages studied is "aran oju". Respondents in Ondo East local government had an eyeworm history of 23 (28.8%) and occurrence of loiasis was 02 (2.5%), these were the highest figures recorded. Using the SPSS version 10 package for data analysis, demographic factors of age and gender were not significant determinants of prevalence (> 0.05). Ondo East and Ifedore local governments had significant levels of loiasis prevalence (p < 0.05). Adverse reactions from the retrospective ivermectin administration was 04 (0.83%). This was statistically insignificant (p > 0.05). CONCLUSION: Market surveys in rural communities were considered to be cost effective and rapid in the determination of prevalence of any disease. Since less than 40% of the respondents in the study area reported having had a history of eyeworm, the entire area was classified as "low risk" as regards the administration of ivermectin.

OBJETIVOS: 1. Evaluar los niveles de endemicidad de loiasis en un total de 30 poblados seleccionados, que abarcan un area de 5.2 sq km in Owo, Akure North, Akure South, Ondo East, Ondo West y los gobiernos locales de Ifedore in Ondo State, Nigeria, usando una evaluación rápida para técnica de loiasis. 2. Obtener información acerca de las reacciones adversas que ocurrieron durante las administraciones previas del medicamento invermectina usado para el tratamiento de loiasis y onchocerciasis en el área de estudio. MÉTODOS: Se obtuvo el consentimiento del presidente de cada uno de los gobiernos locales de los poblados de cabecera, así como de los individuos cooptados para la realización del estudio. Se entrevistaron un total de 480 individuos, 80 de cada uno de los seis gobiernos locales, durante los días de mercado regularmente programados para la comunidad. Se llevó a cabo una encuesta de Loa loa de acuerdo con las especificaciones de las "Guías para la evaluación rápida de Loa loa". RESULTADOS: De los 480 encuestados, 80 (16.7%) reportaron haber tenido una historia de loiasis, mientras que 11 (2.3%) tuvieron padecimientos recientes de esta enfermedad. El nombre local dado a esta enfermedad en todos los poblados estudiados es "aran oju". Los encuestados en el gobierno local de Ondo East local tenían antecedentes de gusano ocular de 23 (28.8%) y la manifestación de loiasis fue 02 (2.5%). Estas fueron las cifras más altas registradas. Usando el paquete SPSS versión 10 para el análisis de datos, se observó que los factores demográficos de edad y sexo no fueron significativamente determinantes de la prevalencia (> 0.05). Los gobiernos locales de Ondo East y de Ifedore tuvieron niveles significativos de prevalencia de loiasis (p < 0.05). Las reacciones adversas de la administración de ivermectina retrospectiva fue 04 (0.83%). Esto fue estadísticamente significativo (p > 0.05). CONCLUSIÓN: Las encuestas de mercado en las comunidades rurales fueron consideradas costo-efectivas y rápidas en la determinación de la prevalencia de cualquier enfermedad. Puesto que menos del 40% de los encuestados en el área de estudio reportaron haber tenido una historia de gusano ocular, toda el área fue clasificada como de "bajo riesgo" en relación con la administración de la invermectina.

Identification of ivermectin and doramectin-resistant Cooperia punctata (LINSTOW, 1907) in a dairy herd in the State of Rio de Janeiro, Brazil / Identificação de Cooperia punctata (LINSTOW, 1907) resistente a ivermectina e doramectina em um rebanho leiteiro no Estado do Rio de Janeiro, Brasil

Anthelmintic resistance is a potential problem to nematodes controlin cattle and may cause economic loss in the dairy and beef cattle industries. The objetive of this study was to determinate the efficacy of ivermectin, doramectin and abamectin in naturally and experimentally infected calves for Cooperia punctata in a brazilian dairy herd. Faecal egg count reduction tests were carried out employing naturally infected calves that were treated with injectable solutions of ivermectin, doramectin and abamectin. Faecal samples were collectedon the day of the treatment, day 0, and at 7 and 14 days after treatmentand larvae culture were made in the positive samples. A control test was carried out using 18 artificially infected calves, alocatted in three groups with six animals each: Group I - control, no treatment; GroupII – ivermectin, injectable solution, 200 μg/kg; Group III –doramectin, injectable solution, 200 μg/kg. Faecal samples were collected on day of the treatment, day 0, and at 3, 7, 9 and 14 days after treatment. On days 14, 15 and 16, two animals of each group weres laughtered and their lung and gastrointestinal parasite burdens determined...

Resistência antihelmíntica é um problema potencial para o controlede nematodas em bovinos e pode causar perdas econômicas na indústria de bovinos leiteiros e de cortes. O objetivo deste estudo foi determinar a eficácia da ivermectina, doramectna e abamectina em bezerros infectados naturalmente e experimentalmente para Cooperia punctata em um rebanho bovino leiteiro. Testes de redução da contagem de ovos fecais foram conduzidos em bezerros infectados naturalmente que foram tratados com soluções injetáveis de ivermectina, doramectina e abamectina. Amostras fecais foram colhidas no dia do tratamento, dia 0, e nos dias 7 e 14 após o tratamento e cultura de larvas foram feitas nas amostras positivas. Um teste controlado foi realizado usando 18 bezerros infectados artificialmente, alocados em três grupos com seis animais cada: Grupo I - controle,sem tratamento; Grupo II – ivermectina, solução injetável,200μg/kg; Grupo III – doramectina, solução injetável, 200μg/kg. Amostras fecais foram colhidas no dia do tratamento, dia 0, e nos dias 3, 7, 9 e 14 após o tratamento. Nos dias 14, 15 e 16, dois animais de cada grupo foram eutanaziados e cargas de parasitos pulmonares e gastrintestinais foram determinados. Os resultados dos testes de redução da contagem de ovos fecais em bezerros infectados naturalmente mostraram redução no dia 14 após o tratamento de –4,45 a 11,49% para ivermectina; 32.31 a 60.40% para doramectina e 85,05% para abamectina...

Efeito da ivermectina sobre a ciclicidade, gestação e desenvolvimento neonatal em ratos / Effects of ivermectin on parameters of the estrous cycle, gestation and lactation of rats

O objetivo do presente trabalho foi avaliar o ciclo estral, gestação e lactação de ratas tratadas com ivermectina. 82 ratas albinas foram divididas em sete grupos. Os animais receberam água destilada (GI) ou diferentes doses de ivermectina, por via oral (GII=0,5; GIII=1,0; GIV=2,0; GV=4,0; GVI=8,0 e GVII=10,0 mg/kg). Os animais foram tratados por 45 dias, com ivermectina a cada três dias, totalizando 15 aplicações. Após esse período foi realizado exame colpocitológico durante 15 dias consecutivos. Ao final, quatro animais de cada grupo foram sacrificados e ovários e úteros retirados e processados para avaliação histológica. Os animais restantes foram acasalados e tratados com ivermectina, nas doses correspondentes a cada grupo, no 1º, 4º, 7º, 10º, 13º e 16º dias de gestação. Ao nascimento, os neonatos foram contados, analisados quanto à existência de defeitos congênitos, mortalidade e pesados até o 15º dia de lactação...

This work evaluates the estrous cycle, gestation and lactation of rats treated with ivermectin. Control (GI) rats received distilled water; and the remaining were treated during 45 days with ivermectin (GII=0.5; GIII=1.0; GIV=2.0; GV=4.0; GVI=8.0 and GVII=10.0 mg/kg) by the oral route, the drug being administered every three day, in a total of 15 administrations. Colpocytological examinations were then performed during 15 consecutive days. Four animals from each group were euthanized, and samples of ovaries and uteri were taken for histological evaluations. The remaining animals were mated and treated throughout the gestation period and further until the 15th postpartum day. Colpocytologic examinations revealed that the animals of groups II, III, IV, V, VI and VII presented a higher incidence of the estrus phase, in comparison with the control group (group I). Histopathologic studies showed that the groups treated with ivermectin presented an increased concentration of hyperplasic endometrial glands, where as the morphology of the ovary was not altered. The treatment did not affect the gestation lenght, the number of newborns nor did it caused congenital mortality or newborns malformations. During lactation, there was a significant slowering of the body weight gain of the litter. It is concluded that the treatment of female rats with ivermectin increases the incidence of the estrus phase. In addition, a definite deleterious effect is exerted on nursing animals as revealed by the reduced body weight gain of the litter.

Validación de un método analítico y determinación de residuos de invermectina en tejidos de ovino / Validation of an analytical method and determination of invermectin residues in sheep tissues

Se realizó un estudio con el objetivo de validar un método analítico sensible y confiable para la detección de residuos de ivermectina (IVM) en muestras de hígados, riñón, músculo y grasa, junto con determinar las concentraciones del fármaco en tejidos de ovinos tratados por vía subcutánea. Muestras de tejidos libres de fármaco fueron sobrecargadas con concentraciones de IVM entre 1 y 50 ng/g (hígado, riñón y músculo); 5 a 200 ng/g (grasa), luego fueron sometidas a extracción en fase sólida y analizados por cromatografía líquida de alta eficiencia (HPLC). Para el estudio de residuos se utilizaron 12 ovinos Suffolk Down de 27,8 ± 1,3 kg de peso, los que fueron tratados con 0,2 mg/kg de IVM vía subcutánea, luego se sacrificaron grupos de 3 animales a los 1,5; 7; 14 y 21 días post tratamiento. La ausencia de interferencias y una adecuada simetría de los cromatogramas indica una buena especificidad del método analítico empleado para la detección de IVM en los tejidos analizados. Los porcentajes de recuperación fluctuaron entre 70 a 93,2 por ciento. El límite de cuantificación se estableció en hígado: 0,48 ng/g; riñón: 1,02 ng/g; músculo:0,18ng/g y grasa: 2,65ng/g. La validación de la metodología analítica demostró adecuados valores de sensibilidad, presición y axactitud que permiten obtener resultados confiables para la detección y cuantificación de residuos de IVM en tejidos de ovinos. En los ovinos tratados con IVM, las mayores concentraciones de residuos fueron observadas a los 1,5 días post tratamiento en hígado (281,7 ± 116,95 ng/g) y grasa (248,67 ± 90,85 ng/g), los que persistieron hasta el día 21 con concentraciones de 0,63 ± 0,2 ng/g y 4,07 ± 2,25 ng/g, respectivamente. Las menores concentraciones de residuos de IVM fueron observadas en las muestras de músculo.

A study was undertaken in order to validate a precise and reliable analytical method for the detection of ivermectin’s (IVM) tissue residues in sheep, and to know the patterns of the drug concentrations depletion in edible tissues such as liver, kidney, muscle and fat, from treated animals by subcutaneous route. Drug free tissue samples were fortified with increasing concentrations of IVM (1 to 50 ng IVM/g for liver, kidney and muscle; and 5 to 200 ng IVM/g for adipose tissue) and then were subjected to solid phase extraction and analyzed by high performance liquid chromatography (HPLC). Twelve sheep weighing 27.8 ± 1.3 kg, were treated with 0.2 mg/kg of IVM by subcutaneous route, and then were slaughtered in groups of three animals at 1.5, 7.0, 14.0, and 21.0 days post treatment. The specificity of the method was demonstrated by the absence of interferences and the adequate symmetry of chromatograms. The percentage of recovery ranged from 70 to 93.2% for all tissues analyzed and different drug concentrations. The limit of quantification of the method was established in 0.48 ng/g for liver; 1.02 ng/g for kidney; 0.18 ng/g for muscle and 2.65 ng/g for adipose tissue. The validated analytical methodology showed satisfactory results of sensitivity, precision and accuracy that allow it use for the detection and quantification of tissue residues of IVM in sheep. From the tissues samples of sheep treated with IVM, the higher concentrations were found in liver (281.7 ± 116.95 ng/g) and adipose tissue (248.67 ± 90.85 ng/g) at 1.5 days, and the drug concentrations in both tissues were maintained for a period of 21 days post treatment with 0.63 ± 0.2 ng/g and 4.07 ± 2.25 ng/g respectively. The lowest concentrations of IVM in tissues were observed in muscle samples.

Avaliação histomorfométrica do parênquima testicular de ratos adultos tratados com diferentes doses de ivermectina / Histomorphometric evaluation of testicular parenchyma of adult rats treated with different dosages of ivermectin

Avaliou-se o efeito da ivermectina sobre o parênquima testicular através da produção espermática diária e da eficiência da espermatogênese em ratos Wistar adultos tratados com diferentes dosagens (200, 400 e 600æg/kg). Pela avaliação histomorfométrica, o parênquima testicular e o processo espermatogênico dos ratos Wistar não sofreram qualquer efeito deletério da aplicação de ivermectina, o que foi confirmado pela manutenção da produção espermática diária por testículo, pelo rendimento intrínseco da espermatogênese (PED/g/t) e pela manutenção da estrutura do parênquima testicular. Com base nos resultados quantitativos e qualitativos da espermatogênese, é possível concluir que a ivermectina não tem efeito tóxico-degenerativo sobre o parênquima testicular de ratos Wistar adultos.

The aim of this work was to evaluate the ivermectin effect on the testicular parenchyma through the daily spermatic production and the efficiency of the spermatogenesis in adult Wistar rats treated with different dosages (200, 400 and 600æg/kg) of ivermectin. Based on the histomorfometric evaluation, ivermectin had no deleterious effect on the testicular parenchyma and spermatogesis, which one was confirmed through the maintenance of the daily spermatic input and intrinsic income of spermatogenesis (PED/g/t), as well as by the maintenance of the testicular parenchyma structure. Based on the quantitative and qualitative results of spermatogenesis, it is possible to conclude that ivermectin does not have toxic-degenerative effect on the testicular parenchyma of adult Wistar rats.