Casellas, A. (Aina)
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- Nebulized ivermectin for COVID‑19 and other respiratory diseases, a proof of concept, dose‑ranging study in rats(Springer Link, 2020) Martinez-Galan, F. (Fernando); Aldaz, A. (Azucena); Hammann, F. (Felix); Chaccour, C.J. (Carlos J.); Gil, A.G. (Ana Gloria); Irigoyen-Barrio, A. (Angel); Casellas, A. (Aina); Abizanda-Sarasa, G. (Gloria)Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.
- BOHEMIA: Broad One Health Endectocide-based Malaria Intervention in Africa -a phase III cluster-randomized, open-label, clinical trial to study the safety and efficacy of ivermectin mass drug administration to reduce malaria transmission in two African settings(2023) Schürch, R. (Roger); Mrema, S. (Sigilbert); Xia, K. (Kang); Montaña-López, J. (Julia); Hammann, F. (Felix); Selvaraj, P. (Prashant); Sacoor, C. (Charfudin); Lyimo, I. (Issa); Marathe, A. (Achla); Rabinovich, N.R. (N. Regina); Elobolobo, E. (Eldo); Jones, C. (Caroline); Chaccour, C.J. (Carlos J.); Nicolas, P. (Paula); Maia, M. (Marta); Ruiz-Castillo, P. (Paula); Duthaler, U. (Urs); Casellas, A. (Aina); Mael, M. (Mary); Kakolwa, M. (Mwaka); Rist, C. (Cassidy); Okumu, F. (Fredros); Saute, F. (Francisco)Background Residual malaria transmission is the result of adaptive mosquito behavior that allows malaria vectors to thrive and sustain transmission in the presence of good access to bed nets or insecticide residual spraying. These behaviors include crepuscular and outdoor feeding as well as intermittent feeding upon livestock. Ivermectin is a broadly used antiparasitic drug that kills mosquitoes feeding on a treated subject for a dose-dependent period. Mass drug administration with ivermectin has been proposed as a complementary strategy to reduce malaria transmission.Methods A cluster randomized, parallel arm, superiority trial conducted in two settings with distinct eco-epidemiological conditions in East and Southern Africa. There will be three groups: human intervention, consisting of a dose of ivermectin (400 mcg/kg) administered monthly for 3 months to all the eligible population in the cluster (> 15 kg, non-pregnant and no medical contraindication); human and livestock intervention, consisting human treatment as above plus treatment of livestock in the area with a single dose of injectable ivermectin (200 mcg/kg) monthly for 3 months; and controls, consisting of a dose of albendazole (400 mg) monthly for 3 months. The main outcome measure will be malaria incidence in a cohort of children under five living in the core of each cluster followed prospectively with monthly RDTsDiscussion The second site for the implementation of this protocol has changed from Tanzania to Kenya. This summary presents the Mozambique-specific protocol while the updated master protocol and the adapted Kenya-specific protocol undergo national approval in Kenya. BOHEMIA will be the first large-scale trial evaluating the impact of ivermectin-only mass drug administration to humans or humans and cattle on local malaria transmission.
- Burden and risk factors of snakebite in Mopeia, Mozambique: leveraging larger malaria trials to generate data of this neglected tropical disease(2023) O'Bryan, E. (Emma); Nicolas, P. (Patricia); Munguambe, H. (Humberto); Montaña-López, J. (Julia); Sacoor, C. (Charfudin); Rabinovich, N.R. (N. Regina); Elobolobo, E. (Eldo); Chaccour, C.J. (Carlos J.); Jamisse, E. (Edgar); Ruiz-Castillo, P. (Paula); Imputiua, S. (Saimado); Casellas, A. (Aina); Saute, F. (Francisco)Background: Snakebite is a neglected disease that disproportionally affects the rural poor. There is a dearth of evidence regarding incidence and risk factors in snakebite-endemic countries. Without this basic data, it will be impossible to achieve the target of a 50% reduction of snakebite morbidity and mortality by 2030 as set by the World Health Organization. Methods: This was a descriptive analysis nested in a 2021 community-based demographic survey of over 70,000 individuals conducted in Mopeia, Mozambique, in preparation for a cluster randomized trial to test an intervention for malaria. We describe the incidence rate, demographics, socioeconomic indicators and outcomes of snakebite in this population. Findings: We found the incidence of self-reported snakebite in Mopeia to be 393 bites per 100,000 person-years at risk, with 2% of households affected in the preceding 12 months. Whilst no fatalities were recorded, over 3,000 days of work or school days were lost with an individual household economic impact higher than that of uncomplicated malaria. 1 in 6 of those affected did not fully recover at the time of the study. We found significant relationships between age older than 15, use of firewood for household fuel, and animal possession with snakebite. Conclusions: This study exposes higher than expected incidence and burden of snakebite in rural Mozambique. Whilst snakebite elimination in Mozambique seems unattainable today, it remains a preventable disease with manageable sequelae. We have shown that snakebite research is particularly easy to nest in larger studies, making this a practical and cost-effective way of estimating its incidence.
- Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats(2020) Martinez-Galan, F. (Fernando); Aldaz, A. (Azucena); Hammann, F. (Felix); Chaccour, C.J. (Carlos J.); Gil, A.G. (Ana Gloria); Irigoyen-Barrio, A. (Angel); Casellas, A. (Aina); Abizanda-Sarasa, G. (Gloria)Ivermectin is a widely used antiparasitic drug with known efcacy against several single-strain RNA viruses. Recent data shows signifcant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80–90 mg/kg), higher dose (110–140 mg/kg) or ethanol vehicle only. A toxicology profle including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profle of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.
- Bohemia a cluster randomized trial to assess the impact of an endectocide-based one health approach to malaria in Mozambique: baseline demographics and key malaria indicators(2023) Nicolas, P. (Patricia); Munguambe, H. (Humberto); Montaña-López, J. (Julia); Deng, X. (Xinwei); Sacoor, C. (Charfudin); Marathe, A. (Achla); Rabinovich, N.R. (N. Regina); Elobolobo, E. (Eldo); Chaccour, C.J. (Carlos J.); Jamisse, E. (Edgar); Ruiz-Castillo, P. (Paula); Imputiua, S. (Saimado); Casellas, A. (Aina); Materrula, F. (Felisbela); Xie, K. (Kexin); Saute, F. (Francisco)BackgroundMany geographical areas of sub-Saharan Africa, especially in rural settings, lack complete and up-to-date demographic data, posing a challenge for implementation and evaluation of public health interventions and carrying out large-scale health research. A demographic survey was completed in Mopeia district, located in the Zambezia province in Mozambique, to inform the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) cluster randomized clinical trial, which tested ivermectin mass drug administration to humans and/or livestock as a potential novel strategy to decrease malaria transmission.MethodsThe demographic survey was a prospective descriptive study, which collected data of all the households in the district that accepted to participate. Households were mapped through geolocation and identified with a unique identification number. Basic demographic data of the household members was collected and each person received a permanent identification number for the study.Results25,550 households were mapped and underwent the demographic survey, and 131,818 individuals were registered in the district. The average household size was 5 members and 76.9% of households identified a male household head. Housing conditions are often substandard with low access to improved water systems and electricity. The reported coverage of malaria interventions was 71.1% for indoor residual spraying and 54.1% for universal coverage of long-lasting insecticidal nets. The median age of the population was 15 years old. There were 910 deaths in the previous 12 months reported, and 43.9% were of children less than 5 years of age.ConclusionsThe study showed that the district had good coverage of vector control tools against malaria but sub-optimal living conditions and poor access to basic services. The majority of households are led by males and Mopeia Sede/Cuacua is the most populated locality in the district. The population of Mopeia is young (< 15 years) and there is a high childhood mortality. The results of this survey were crucial as they provided the household and population profiles and allowed the design and implementation of the cluster randomized clinical trial.Trial registration NCT04966702.