Mother-to-child Chagas disease transmission: The challenge of detection and prevention in areas without the risk of vectorial transmission.

Chagas disease (CD) is caused by the parasite Trypanosoma cruzi. Although it is endemic in many Latin American (LA) countries, mother-to-child transmission has caused it to expand to other countries and continents. In places where vector transmission is controlled or absent, the epidemiological importance of T. cruzi transmission of the infected mother to her child during pregnancy or childbirth (i.e., perinatal CD) increases. In countries where CD is not endemic, CD screening should be performed in pregnant or fertile women who are native to LA countries or whose mothers are native to LA countries. Diagnosis is established by detecting anti-T. cruzi IgG antibodies in a serum or plasma sample. Antiparasitic treatment cannot be offered during pregnancy, and since the majority of infected newborns are asymptomatic at birth, a diagnosis is made by direct observation or concentration (microhematocrit) or by using molecular testing techniques. Once the infected child receives a diagnosis, it is essential to offer treatment (benznidazole/nifurtimox) as soon as possible, with good tolerance and effectiveness in the first year of life. Even if the diagnosis is negative at birth, the newborn must be followed up for at least the first 9 months of life.

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers.

Soil-transmitted helminths are intestinal worm diseases transmitted through the soil. Available treatments are albendazole and/or ivermectin. The co-administration of existing drugs is an appropriate strategy. A fixed-dose combination adds practical advantages mainly considering mass drug administration. The aim is to characterize pharmacokinetics and to evaluate the comparative bioavailability of an innovative fixed-dose combination of ivermectin/albendazole 18/400 mg compared with the marketed references. Seventy-eight healthy volunteers were included in this laboratory-blinded, randomized, three-treatment, three-period crossover study. Each subject received a single dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3 mg (6 tablets); and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysis were obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectin H2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysis and bioavailability compared through a bioequivalence analysis. Safety and tolerability were assessed throughout the study. Main pharmacokinetic parameters of the fixed combination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40 (30.42-39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530-1,678) ng·h/mL; tmax (median, min., and max.); 4.50 (2.50-5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89-111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65-507.78) ng·h/mL; tmax (median, min., and max.): 2.50 (1.00-12.00) h]. The 90% confidence interval of the geometric mean ratios demonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%-120.49%; AUC0-72: 110.46%-119.60%) but not in the case of albendazole (Cmax: 53.10%-70.34%; AUC0-72: 61.13%-76.54%). The pharmacokinetic profile of a new fixed-dose combination of ivermectin and albendazole was characterized. The bioequivalence versus the reference ivermectin was demonstrated, though bioequivalence versus albendazole was not shown. The three medications analyzed were well tolerated. The results allow the advancement to the next phase of the clinical program to demonstrate efficacy and safety in patients affected by soil-transmitted helminths. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search/, identifier Nr. 2020-003438-19.

Corrigendum to Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial [EClinicalMedicine 37 (2021) 100,959]".

[This corrects the article DOI: 10.1016/j.eclinm.2021.100959.].

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.

BACKGROUND: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. METHODS: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. FINDINGS: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. INTERPRETATION: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. FUNDING: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model.

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

Building an innovative Chagas disease program for primary care units, in an urban non- endemic city.

BACKGROUND: On an absolute basis, Argentina is the country with the largest affected population with Chagas Disease (ChD). This constitutes a significant public health issue. As a consequence of Argentina's migratory patterns, there has been a significant increase of affected population in urban centers. An innovative project for early diagnosis and timely treatment of ChD was designed for Municipal Primary Care Facilities of La Plata City, a non- endemic area, in line with a proposal from the Pan-American Health Organization. The project was a public -private intervention. The objectives of this study were to demonstrate the feasibility of the primary healthcare level for early diagnosis and timely treatment of ChD; to design and implement a tailor made program and to innovate in a public-private association. METHODS: The healthcare barriers for early diagnosis and timely treatment for the population with ChD of La Plata were analyzed. The four dimensions described by Peters et al. (Ann N Y Acad Sci 1136:161-71, 2008) were used. The baseline was measured during a previous pilot project and the same items were evaluated at the end of 2017. The model from Damschroder et al. (Implement Sci 4:50, 2009) was used during the implementation process. RESULTS: With all the information gathered during this investigation, a "patient-centered" model was designed. During the program, 17,894 people were serologically tested for ChD, 1,394 were positive and 1,035 were treated. Additionally, 3,750 children from 46 public schools were evaluated for risk factors of ChD. CONCLUSIONS: This project showed the feasibility of the primary healthcare level for early diagnosis and timely treatment of ChD. Tailor made programs and public-private associations should be considered for vulnerable populations in emerging economies in order to enhance efforts and obtain better results. This program may be replicated in other countries of Latin America were Chagas is a main public health issue and, with the corresponding adaptations, for other neglected diseases as well.

Reporting of adverse reactions to benznidazole: does medical expertise matter?

[ABSTRACT]. This study evaluated and compared follow-up and adverse drug reaction (ADR) reporting for Chagas disease (CD) patients treated with benznidazole (BZN) by two health teams with different levels of experience, using medical records for 204 patients participating in the first year of a scaled-up public health program for CD case detection and treatment conducted at all 46 primary health care centers in La Plata district, Buenos Aires, Argentina, in 2014. Both teams were experienced in CD patient management and trained in BZN administration, and included senior physicians, but one team had no experience in administering BZN while the other team had three years of experience due to their participation in the program’s pilot project. Patients with positive serology for CD were treated with 5 mg/kg/day of BZN for 60 days. Patients’ median age was 35 years and 84.3% were female. There was a statistically significant difference in the number of ADRs reported by the experienced versus the inexperienced health teams (18 versus 44 respectively; P < 0.001). Health team experience in administering BZN to CD patients, and treatment duration, were significantly associated with reporting of ADRs (adjusted odds ratios (aORs) 0.340 (95% confidence interval (CI): 0.177–0.652) and 0.967 (CI: 0.942–0.993) respectively). ADR reporting increased with patient age, occurring at the highest frequency (42.9%) in people 50+ years old. All treatment discontinuations (nine) occurred in patients followed up by the inexperienced health team. Level of experience in BZN administration to CD patients was significantly and inversely associated with frequency of ADR reports: inexperienced health team members tended to report more.

[RESUMEN]. El presente estudio evaluó y comparó el seguimiento y la notificación de reacciones adversas medicamentosas (RAM) en pacientes con enfermedad de Chagas tratados con benznidazol por dos equipos de salud con diferentes niveles de experiencia, mediante el uso de los expedientes médicos de 204 pacientes que participaron en el primer año de un programa de salud pública ampliado para la detección de casos de enfermedad de Chagas y su tratamiento, realizado en los 46 centros de atención primaria de salud del distrito de La Plata (Buenos Aires) en el 2014. Ambos equipos tenían experiencia en la atención de pacientes con enfermedad de Chagas, estaban capacitados en la administración de benznidazol e incluían médicos experimentados, pero uno de los equipos nunca había usado benznidazol, mientras que el otro tenía tres años de experiencia por su participación en el proyecto piloto del programa. Los pacientes con pruebas serológicas positivas para la enfermedad de Chagas recibieron 5 mg/kg/día de benznidazol durante 60 días. La mediana de edad de los pacientes era de 35 años y 84,3% eran mujeres. Hubo una diferencia estadísticamente significativa entre el número de reacciones adversas medicamentosas notificadas por el equipo de salud experimentado y el equipo sin experiencia (18 y 44, respectivamente; P<0.001). Tanto la experiencia de los equipos de salud en la administración de benznidazol a los pacientes con enfermedad de Chagas como la duración del tratamiento se asociaron significativamente con la notificación de reacciones adversas medicamentosas (razones de posibilidades ajustadas, 0,340; intervalo de confianza de 95% [IC]: 0,177–0,652; y 0,967, IC: 0,942–0,993, respectivamente). La notificación de reacciones adversas medicamentosas aumentó a mayor edad de los pacientes; la frecuencia máxima (42,9%) se observó en las personas mayores de 50 años. Todas las interrupciones del tratamiento (nueve) fueron en pacientes atendidos por el equipo de salud sin experiencia. El nivel de experiencia en la administración de benznidazol a los pacientes con enfermedad de Chagas mostró una asociación significativa e inversa con la frecuencia de notificación de reacciones adversas medicamentosas: los miembros del equipo de salud sin experiencia tendieron a notificar más reacciones.

[RESUMO]. Neste estudo foram analisados e comparados dados notificados de reação adversa medicamentosa e de acompanhamento de pacientes com doença de Chagas tratados com benznidazol (BZN) por dois grupos de profissionais da saúde com níveis de experiencia distintos. Os dados foram obtidos dos prontuários médicos de 204 pacientes que participaram do primeiro ano de um programa expandido de saúde pública para detecção de casos e tratamento da doença de Chagas implantado nas 46 unidades básicas de saúde do distrito de La Plata em Buenos Aires, Argentina, em 2014. Ambos os grupos eram formados por médicos mais graduados e profissionais com experiencia na conduta de pacientes com doença de Chagas e capacitados em administrar BZN, porém um dos grupos era inexperiente em administrar BZN enquanto o outro contava com experiência de três anos por ter participado do projeto-piloto do programa. Os pacientes com sorologia positiva para doença de Chagas foram tratados com 5 mg/kg/dia de BZN por 60 dias. A mediana de idade foi 35 anos e 84,3% dos pacientes eram do sexo feminino. Verificou-se uma diferença estatisticamente significativa no número de reações adversas medicamentosas notificadas pelo grupo experiente em relação ao grupo inexperiente (18 vs. 44, respectivamente; P < 0.001). Ter experiência em administrar BZN aos pacientes com doença de Chagas e a duração do tratamento foram fatores significativamente associados à notificação de reação adversa medicamentosa (razão de chances ajustada [aOR] 0,340, intervalo de confiança de 95% [IC 95%] 0,177–0,652 e aOR 0,967, IC 95% 0,942–0,993, respectivamente). A notificação de reação adversa medicamentosa aumentou de acordo com a idade do paciente, ocorrendo com maior frequência (42,9%) nos pacientes acima de 50 anos. Os 9 casos de interrupção do tratamento ocorreram em pacientes acompanhados pelo grupo inexperiente. O nível da experiência em administrar BZN aos pacientes com doença de Chagas teve uma associação significativa e inversa com a frequência de notificação de reação adversa medicamentosa: os integrantes do grupo inexperiente tenderam a notificar mais.

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150­200 µg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective. TRIAL REGISTRATION: ClinicalTrials.gov NCT03173742.

Reporting of adverse reactions to benznidazole: does medical expertise matter?

This study evaluated and compared follow-up and adverse drug reaction (ADR) reporting for Chagas disease (CD) patients treated with benznidazole (BZN) by two health teams with different levels of experience, using medical records for 204 patients participating in the first year of a scaled-up public health program for CD case detection and treatment conducted at all 46 primary health care centers in La Plata district, Buenos Aires, Argentina, in 2014. Both teams were experienced in CD patient management and trained in BZN administration, and included senior physicians, but one team had no experience in administering BZN while the other team had three years of experience due to their participation in the program's pilot project. Patients with positive serology for CD were treated with 5 mg/kg/day of BZN for 60 days. Patients' median age was 35 years and 84.3% were female. There was a statistically significant difference in the number of ADRs reported by the experienced versus the inexperienced health teams (18 versus 44 respectively; P < 0.001). Health team experience in administering BZN to CD patients, and treatment duration, were significantly associated with reporting of ADRs (adjusted odds ratios (aORs) 0.340 (95% confidence interval (CI): 0.177-0.652) and 0.967 (CI: 0.942-0.993) respectively). ADR reporting increased with patient age, occurring at the highest frequency (42.9%) in people 50+ years old. All treatment discontinuations (nine) occurred in patients followed up by the inexperienced health team. Level of experience in BZN administration to CD patients was significantly and inversely associated with frequency of ADR reports: inexperienced health team members tended to report more.

El presente estudio evaluó y comparó el seguimiento y la notificación de reacciones adversas medicamentosas (RAM) en pacientes con enfermedad de Chagas tratados con benznidazol por dos equipos de salud con diferentes niveles de experiencia, mediante el uso de los expedientes médicos de 204 pacientes que participaron en el primer año de un programa de salud pública ampliado para la detección de casos de enfermedad de Chagas y su tratamiento, realizado en los 46 centros de atención primaria de salud del distrito de La Plata (Buenos Aires) en el 2014. Ambos equipos tenían experiencia en la atención de pacientes con enfermedad de Chagas, estaban capacitados en la administración de benznidazol e incluían médicos experimentados, pero uno de los equipos nunca había usado benznidazol, mientras que el otro tenía tres años de experiencia por su participación en el proyecto piloto del programa. Los pacientes con pruebas serológicas positivas para la enfermedad de Chagas recibieron 5 mg/kg/día de benznidazol durante 60 días. La mediana de edad de los pacientes era de 35 años y 84,3% eran mujeres. Hubo una diferencia estadísticamente significativa entre el número de reacciones adversas medicamentosas notificadas por el equipo de salud experimentado y el equipo sin experiencia (18 y 44, respectivamente; P<0.001). Tanto la experiencia de los equipos de salud en la administración de benznidazol a los pacientes con enfermedad de Chagas como la duración del tratamiento se asociaron significativamente con la notificación de reacciones adversas medicamentosas (razones de posibilidades ajustadas, 0,340; intervalo de confianza de 95% [IC]: 0,177­0,652; y 0,967, IC: 0,942­0,993, respectivamente). La notificación de reacciones adversas medicamentosas aumentó a mayor edad de los pacientes; la frecuencia máxima (42,9%) se observó en las personas mayores de 50 años. Todas las interrupciones del tratamiento (nueve) fueron en pacientes atendidos por el equipo de salud sin experiencia. El nivel de experiencia en la administración de benznidazol a los pacientes con enfermedad de Chagas mostró una asociación significativa e inversa con la frecuencia de notificación de reacciones adversas medicamentosas: los miembros del equipo de salud sin experiencia tendieron a notificar más reacciones.

Neste estudo foram analisados e comparados dados notificados de reação adversa medicamentosa e de acompanhamento de pacientes com doença de Chagas tratados com benznidazol (BZN) por dois grupos de profissionais da saúde com níveis de experiência distintos. Os dados foram obtidos dos prontuários médicos de 204 pacientes que participaram do primeiro ano de um programa expandido de saúde pública para detecção de casos e tratamento da doença de Chagas implantado nas 46 unidades básicas de saúde do distrito de La Plata em Buenos Aires, Argentina, em 2014. Ambos os grupos eram formados por médicos mais graduados e profissionais com experiência na conduta de pacientes com doença de Chagas e capacitados em administrar BZN, porém um dos grupos era inexperiente em administrar BZN enquanto o outro contava com experiência de três anos por ter participado do projeto-piloto do programa. Os pacientes com sorologia positiva para doença de Chagas foram tratados com 5 mg/kg/dia de BZN por 60 dias. A mediana de idade foi 35 anos e 84,3% dos pacientes eram do sexo feminino. Verificou-se uma diferença estatisticamente significativa no número de reações adversas medicamentosas notificadas pelo grupo experiente em relação ao grupo inexperiente (18 vs. 44, respectivamente; P < 0.001). Ter experiência em administrar BZN aos pacientes com doença de Chagas e a duração do tratamento foram fatores significativamente associados à notificação de reação adversa medicamentosa (razão de chances ajustada [aOR] 0,340, intervalo de confiança de 95% [IC 95%] 0,177­0,652 e aOR 0,967, IC 95% 0,942­0,993, respectivamente). A notificação de reação adversa medicamentosa aumentou de acordo com a idade do paciente, ocorrendo com maior frequência (42,9%) nos pacientes acima de 50 anos. Os 9 casos de interrupção do tratamento ocorreram em pacientes acompanhados pelo grupo inexperiente. O nível da experiência em administrar BZN aos pacientes com doença de Chagas teve uma associação significativa e inversa com a frequência de notificação de reação adversa medicamentosa: os integrantes do grupo inexperiente tenderam a notificar mais.

Reporting of adverse reactions to benznidazole: does medical expertise matter? / Notificación de las reacciones adversas al benznidazol: ¿importa la pericia médica? / Notificação de reações adversas ao benznidazol: experiência médica faz diferença?

ABSTRACT This study evaluated and compared follow-up and adverse drug reaction (ADR) reporting for Chagas disease (CD) patients treated with benznidazole (BZN) by two health teams with different levels of experience, using medical records for 204 patients participating in the first year of a scaled-up public health program for CD case detection and treatment conducted at all 46 primary health care centers in La Plata district, Buenos Aires, Argentina, in 2014. Both teams were experienced in CD patient management and trained in BZN administration, and included senior physicians, but one team had no experience in administering BZN while the other team had three years of experience due to their participation in the program's pilot project. Patients with positive serology for CD were treated with 5 mg/kg/day of BZN for 60 days. Patients' median age was 35 years and 84.3% were female. There was a statistically significant difference in the number of ADRs reported by the experienced versus the inexperienced health teams (18 versus 44 respectively; P < 0.001). Health team experience in administering BZN to CD patients, and treatment duration, were significantly associated with reporting of ADRs (adjusted odds ratios (aORs) 0.340 (95% confidence interval (CI): 0.177-0.652) and 0.967 (CI: 0.942-0.993) respectively). ADR reporting increased with patient age, occurring at the highest frequency (42.9%) in people 50+ years old. All treatment discontinuations (nine) occurred in patients followed up by the inexperienced health team. Level of experience in BZN administration to CD patients was significantly and inversely associated with frequency of ADR reports: inexperienced health team members tended to report more.

RESUMEN El presente estudio evaluó y comparó el seguimiento y la notificación de reacciones adversas medicamentosas (RAM) en pacientes con enfermedad de Chagas tratados con benznidazol por dos equipos de salud con diferentes niveles de experiencia, mediante el uso de los expedientes médicos de 204 pacientes que participaron en el primer año de un programa de salud pública ampliado para la detección de casos de enfermedad de Chagas y su tratamiento, realizado en los 46 centros de atención primaria de salud del distrito de La Plata (Buenos Aires) en el 2014. Ambos equipos tenían experiencia en la atención de pacientes con enfermedad de Chagas, estaban capacitados en la administración de benznidazol e incluían médicos experimentados, pero uno de los equipos nunca había usado benznidazol, mientras que el otro tenía tres años de experiencia por su participación en el proyecto piloto del programa. Los pacientes con pruebas serológicas positivas para la enfermedad de Chagas recibieron 5 mg/kg/día de benznidazol durante 60 días. La mediana de edad de los pacientes era de 35 años y 84,3% eran mujeres. Hubo una diferencia estadísticamente significativa entre el número de reacciones adversas medicamentosas notificadas por el equipo de salud experimentado y el equipo sin experiencia (18 y 44, respectivamente; P<0.001). Tanto la experiencia de los equipos de salud en la administración de benznidazol a los pacientes con enfermedad de Chagas como la duración del tratamiento se asociaron significativamente con la notificación de reacciones adversas medicamentosas (razones de posibilidades ajustadas, 0,340; intervalo de confianza de 95% [IC]: 0,177-0,652; y 0,967, IC: 0,942-0,993, respectivamente). La notificación de reacciones adversas medicamentosas aumentó a mayor edad de los pacientes; la frecuencia máxima (42,9%) se observó en las personas mayores de 50 años. Todas las interrupciones del tratamiento (nueve) fueron en pacientes atendidos por el equipo de salud sin experiencia. El nivel de experiencia en la administración de benznidazol a los pacientes con enfermedad de Chagas mostró una asociación significativa e inversa con la frecuencia de notificación de reacciones adversas medicamentosas: los miembros del equipo de salud sin experiencia tendieron a notificar más reacciones.

RESUMO Neste estudo foram analisados e comparados dados notificados de reação adversa medicamentosa e de acompanhamento de pacientes com doença de Chagas tratados com benznidazol (BZN) por dois grupos de profissionais da saúde com níveis de experiência distintos. Os dados foram obtidos dos prontuários médicos de 204 pacientes que participaram do primeiro ano de um programa expandido de saúde pública para detecção de casos e tratamento da doença de Chagas implantado nas 46 unidades básicas de saúde do distrito de La Plata em Buenos Aires, Argentina, em 2014. Ambos os grupos eram formados por médicos mais graduados e profissionais com experiência na conduta de pacientes com doença de Chagas e capacitados em administrar BZN, porém um dos grupos era inexperiente em administrar BZN enquanto o outro contava com experiência de três anos por ter participado do projeto-piloto do programa. Os pacientes com sorologia positiva para doença de Chagas foram tratados com 5 mg/kg/dia de BZN por 60 dias. A mediana de idade foi 35 anos e 84,3% dos pacientes eram do sexo feminino. Verificou-se uma diferença estatisticamente significativa no número de reações adversas medicamentosas notificadas pelo grupo experiente em relação ao grupo inexperiente (18 vs. 44, respectivamente; P < 0.001). Ter experiência em administrar BZN aos pacientes com doença de Chagas e a duração do tratamento foram fatores significativamente associados à notificação de reação adversa medicamentosa (razão de chances ajustada [aOR] 0,340, intervalo de confiança de 95% [IC 95%] 0,177-0,652 e aOR 0,967, IC 95% 0,942-0,993, respectivamente). A notificação de reação adversa medicamentosa aumentou de acordo com a idade do paciente, ocorrendo com maior frequência (42,9%) nos pacientes acima de 50 anos. Os 9 casos de interrupção do tratamento ocorreram em pacientes acompanhados pelo grupo inexperiente. O nível da experiência em administrar BZN aos pacientes com doença de Chagas teve uma associação significativa e inversa com a frequência de notificação de reação adversa medicamentosa: os integrantes do grupo inexperiente tenderam a notificar mais.

Albendazole and ivermectin for the control of soil-transmitted helminths in an area with high prevalence of Strongyloides stercoralis and hookworm in northwestern Argentina: A community-based pragmatic study.

BACKGROUND: Recommendations for soil-transmitted helminth (STH) control give a key role to deworming of school and pre-school age children with albendazole or mebendazole; which might be insufficient to achieve adequate control, particularly against Strongyloides stercoralis. The impact of preventive chemotherapy (PC) against STH morbidity is still incompletely understood. The aim of this study was to assess the effectiveness of a community-based program with albendazole and ivermectin in a high transmission setting for S. stercoralis and hookworm. METHODOLOGY: Community-based pragmatic trial conducted in Tartagal, Argentina; from 2012 to 2015. Six communities (5070 people) were enrolled for community-based PC with albendazole and ivermectin. Two communities (2721 people) were re-treated for second and third rounds. STH prevalence, anemia and malnutrition were explored through consecutive surveys. Anthropometric assessment of children, stool analysis, complete blood count and NIE-ELISA serology for S. stercoralis were performed. PRINCIPAL FINDINGS: STH infection was associated with anemia and stunting in the baseline survey that included all communities and showed a STH prevalence of 47.6% (almost exclusively hookworm and S. stercoralis). Among communities with multiple interventions, STH prevalence decreased from 62% to 23% (p<0.001) after the first PC; anemia also diminished from 52% to 12% (p<0.001). After two interventions S. stercoralis seroprevalence declined, from 51% to 14% (p<0.001) and stunting prevalence decreased, from 19% to 12% (p = 0.009). CONCLUSIONS: Hookworm' infections are associated with anemia in the general population and nutritional impairment in children. S. stercoralis is also associated with anemia. Community-based deworming with albendazole and ivermectin is effective for the reduction of STH prevalence and morbidity in communities with high prevalence of hookworm and S. stercoralis.

Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease.

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmax were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Ka and kel were 1.16 h-1 (95% CrI, 0.59, 1.76 h-1) and 0.052 h-1 (95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.

NGcGM3 ganglioside: a privileged target for cancer vaccines.

Active specific immunotherapy is a promising field in cancer research. N-glycolyl (NGc) gangliosides, and particularly NGcGM3, have received attention as a privileged target for cancer therapy. Many clinical trials have been performed with the anti-NGc-containing gangliosides anti-idiotype monoclonal antibody racotumomab (formerly known as 1E10) and the conjugated NGcGM3/VSSP vaccine for immunotherapy of melanoma, breast, and lung cancer. The present paper examines the role of NGc-gangliosides in tumor biology as well as the available preclinical and clinical data on these vaccine products. A brief discussion on the relevance of prioritization of cancer antigens in vaccine development is also included.