Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects. METHODS: In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects. RESULTS: Following a single oral dose of AMG 986, the geometric mean maximum observed concentration (Cmax) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC0-120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81-0.96) and 0.72 (90% CI 0.57-0.91) for AUC0-120h and Cmax, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity. CONCLUSION: There was a modest 12% decrease in AUC0-120h and a 28% decrease in Cmax with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects. METHODS: This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg. RESULTS: Following oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity. CONCLUSION: AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.

A Phase 1, Open-Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects.

This phase 1, open-label study evaluated the effect of food and administration of the cytochrome P450 3A4 and P-glycoprotein inhibitor itraconazole (ITZ) on the pharmacokinetics of AMG 986. In cohort 1, 12 healthy subjects received a single oral dose of AMG 986 200 mg ± food on days 1 and 10. In cohort 2, 15 healthy subjects received oral ITZ 200 mg once daily on days 8 to 15 and a single oral dose of AMG 986 10 mg on days 1 and 11. The geometric least squares mean ratios of fed/fasted for AMG 986 maximum observed concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 0.76 (90%CI, 0.61-0.95) and 1.07 (90%CI, 0.94-1.22), respectively. The geometric least squares mean ratios of AMG 986 10 mg plus ITZ 200 mg/AMG 986 10 mg alone for AMG 986 Cmax and AUCinf were 1.36 (90%CI, 1.25-1.48) and 5.13 (90%CI, 4.71-5.59), respectively. Overall, 3 subjects experienced mild treatment-related adverse events; there were no serious or fatal adverse events. In conclusion, food had no apparent effect on the exposure of AMG 986 200 mg; therefore, food restrictions are not required. Potent cytochrome P450 3A4 and/or P-glycoprotein inhibitors may warrant AMG 986 dose reduction and should be coadministered with caution in patients with heart failure treated with AMG 986.

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986.

INTRODUCTION: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure (HF). The safety and pharmacokinetics (PK) of AMG 986 in participants with renal impairment (RI) remains unknown. METHODS: This phase 1 study compared the safety and PK of AMG 986 200 mg in six participants with severe RI (estimated glomerular filtration rate [eGFR] 15-29 mL/min/1.73 m2) versus six participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). RESULTS: Following a single oral dose of AMG 986 200 mg on day 1, the maximum observed concentration increased 1.41-fold (90% confidence interval [CI] 0.88-2.27) and the area under the curve from time zero to infinity increased 1.23-fold (90% CI 0.73-2.06) in participants with severe RI versus normal renal function. AMG 986 had an acceptable safety profile; all adverse events were mild in severity. CONCLUSIONS: The results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments. TRIAL REGISTRATION NUMBER: NCT03318809 (registered: October 24, 2017).

Clinical and epidemiological characteristics of cases of acute Chagas disease in the Peruvian Amazon basin, 2009-2016. / Características clínicas y epidemiológicas de casos de enfermedad de Chagas aguda en la cuenca amazónica peruana, 2009-2016.

Acute Chagas disease (ACD) cases are reported sporadically in Peru. In this report we describe the clinical and epidemiological characteristics of eight new ACD cases detected by the surveillance system in the Amazon basin, between 2009 and 2016. The average age was 12,7 ±13.7 years, range between 1 to 44 years and 4/8 cases were men. One case was associated with acute diarrheal disease, another with Leptospirosis, and two with urinary tract infection. The global case fatality-rate was 12.5% ​​(1/8). Late detection is a frequent characteristic related with low diagnostic suspicion in patients with a history of fever. The TcI and TcIV lineage was identified as the etiological agent of Chagas disease. Eight new cases of ACDs are reported, of which seven were children.

Los casos de la enfermedad de Chagas aguda (ECA) se reportan en forma esporádica en el Perú. En este artículo se describe las características clínicas y epidemiológicas de ocho nuevos casos de ECA detectados por el sistema de vigilancia en la cuenca amazónica, entre 2009 y 2016. La media de la edad fue 12,7 ± 13,7 años, rango de 1 a 44 años y 4/8 casos fueron varones. Un caso se asoció a enfermedad diarreica aguda, otro a leptospirosis y dos a infección del tracto urinario. La tasa de letalidad global fue 12,5% (1/8). La detección tardía es una característica frecuente relacionada a una escasa sospecha diagnóstica en pacientes con historial de fiebre. Se identificó el linaje TcI y TcIV del agente etiológico de la enfermedad de Chagas. Se reporta ocho nuevos casos de ECA, de los cuales siete fueron menores de edad.

Características clínicas y epidemiológicas de casos de enfermedad de Chagas aguda en la cuenca amazónica peruana, 2009-2016 / Clinical and epidemiological characteristics of cases of acute Chagas disease in the Peruvian Amazon basin, 2009-2016

RESUMEN Los casos de la enfermedad de Chagas aguda (ECA) se reportan en forma esporádica en el Perú. En este artículo se describe las características clínicas y epidemiológicas de ocho nuevos casos de ECA detectados por el sistema de vigilancia en la cuenca amazónica, entre 2009 y 2016. La media de la edad fue 12,7 ± 13,7 años, rango de 1 a 44 años y 4/8 casos fueron varones. Un caso se asoció a enfermedad diarreica aguda, otro a leptospirosis y dos a infección del tracto urinario. La tasa de letalidad global fue 12,5% (1/8). La detección tardía es una característica frecuente relacionada a una escasa sospecha diagnóstica en pacientes con historial de fiebre. Se identificó el linaje TcI y TcIV del agente etiológico de la enfermedad de Chagas. Se reporta ocho nuevos casos de ECA, de los cuales siete fueron menores de edad.

ABSTRACT Acute Chagas disease (ACD) cases are reported sporadically in Peru. In this report we describe the clinical and epidemiological characteristics of eight new ACD cases detected by the surveillance system in the Amazon basin, between 2009 and 2016. The average age was 12,7 ±13.7 years, range between 1 to 44 years and 4/8 cases were men. One case was associated with acute diarrheal disease, another with Leptospirosis, and two with urinary tract infection. The global case fatality-rate was 12.5% ​​(1/8). Late detection is a frequent characteristic related with low diagnostic suspicion in patients with a history of fever. The TcI and TcIV lineage was identified as the etiological agent of Chagas disease. Eight new cases of ACDs are reported, of which seven were children.

Características clínicas y epidemiológicas de casos de enfermedad de Chagas aguda en la cuenca amazónica peruana, 2009-2016 / Clinical and epidemiological characteristics of cases of acute Chagas disease in the Peruvian Amazon basin, 2009-2016

RESUMEN Los casos de la enfermedad de Chagas aguda (ECA) se reportan en forma esporádica en el Perú. En este artículo se describe las características clínicas y epidemiológicas de ocho nuevos casos de ECA detectados por el sistema de vigilancia en la cuenca amazónica, entre 2009 y 2016. La media de la edad fue 12,7 ± 13,7 años, rango de 1 a 44 años y 4/8 casos fueron varones. Un caso se asoció a enfermedad diarreica aguda, otro a leptospirosis y dos a infección del tracto urinario. La tasa de letalidad global fue 12,5% (1/8). La detección tardía es una característica frecuente relacionada a una escasa sospecha diagnóstica en pacientes con historial de fiebre. Se identificó el linaje TcI y TcIV del agente etiológico de la enfermedad de Chagas. Se reporta ocho nuevos casos de ECA, de los cuales siete fueron menores de edad.

ABSTRACT Acute Chagas disease (ACD) cases are reported sporadically in Peru. In this report we describe the clinical and epidemiological characteristics of eight new ACD cases detected by the surveillance system in the Amazon basin, between 2009 and 2016. The average age was 12,7 ±13.7 years, range between 1 to 44 years and 4/8 cases were men. One case was associated with acute diarrheal disease, another with Leptospirosis, and two with urinary tract infection. The global case fatality-rate was 12.5% ​​(1/8). Late detection is a frequent characteristic related with low diagnostic suspicion in patients with a history of fever. The TcI and TcIV lineage was identified as the etiological agent of Chagas disease. Eight new cases of ACDs are reported, of which seven were children.

Calidad higiénico-sanitaria en plantas de faena de la provincia de Tucumán: Detección, aislamiento y caracterización de Escherichia coli productor de toxina Shiga / Hygienic-sanitary quality in abattoirs from Tucuman province, Argentina: Detection, isolation and characterization of Shiga toxin-producing Escherichia coli

Los bovinos son el principal reservorio de Escherichia coli productor de toxina Shiga (STEC); las estrategias para evitar su transmisión se concentran en la planta de faena. El objetivo de este trabajo fue evaluar la calidad higiénico-sanitaria y la frecuencia de detección de STEC en medias reses bovinas de frigoríficos de tránsito provincial. Se procesaron 274 esponjados de media res; en 9 (3,3%) el recuento de E. coli genérico fue marginal, en 4 (1,4%) se aisló E. coli O157, de los cuales 2 fueron caracterizados como stx2c(vh-a)/eae/ehxA, y los otros 2 como no toxigénicos. A partir de una (0,4%) muestra se aisló E. coli no-O157 ONT:H49, stx2a/ehxA/saa. En este trabajo la calidad del producto analizado indica que en la provincia de Tucumán se cumplen las buenas prácticas de manufactura en la faena de bovinos.

Cattle are the main reservoir of Shiga toxin-producing Escherichia coli (STEC), and the strategies to prevent the transmission of these microorganisms are concentrated in the slaughtering plant. The aim of this study was to evaluate the hygienic-sanitary quality and the frequency of detection of STEC in beef carcasses in abattoirs from Tucuman province. Two hundred and seventy four beef carcass sponges were processed; the count of generic E. coli was marginal in 9 (3,3%) of them. Escherichia coli O157 was isolated in 4 (1,4%) samples; 2 of which were characterized as stx2c(vh-a)/eae/ehxA whereas the other 2 were non-toxigenic strains. Non-O157 E. coli ONT:H49, stx2a/ehxA/saa was isolated from 1 sample (0,4%). In this work the quality of the analyzed product indicates that the good practices of manufacture are fulfilled in slaughtering facilities in Tucumán province.

[Hygienic-sanitary quality in abattoirs from Tucuman province, Argentina. Detection, isolation and characterization of Shiga toxin-producing Escherichia coli]. / Calidad higiénico-sanitaria en plantas de faena de la provincia de Tucumán. Detección, aislamiento y caracterización de Escherichia coli productor de toxina Shiga.

Cattle are the main reservoir of Shiga toxin-producing Escherichia coli (STEC), and the strategies to prevent the transmission of these microorganisms are concentrated in the slaughtering plant. The aim of this study was to evaluate the hygienic-sanitary quality and the frequency of detection of STEC in beef carcasses in abattoirs from Tucuman province. Two hundred and seventy four beef carcass sponges were processed; the count of generic E. coli was marginal in 9 (3,3%) of them. Escherichia coli O157 was isolated in 4 (1,4%) samples; 2 of which were characterized as stx2c(vh-a)/eae/ehxA whereas the other 2 were non-toxigenic strains. Non-O157 E. coli ONT:H49, stx2a/ehxA/saa was isolated from 1 sample (0,4%). In this work the quality of the analyzed product indicates that the good practices of manufacture are fulfilled in slaughtering facilities in Tucumán province.

Identification of fungal clinical isolates by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry

Introducción. En los últimos años, la identificación bacteriana mediante espectrometría de masas (EM) MALDI-TOF ha adquirido progresivamente importancia, dada su rapidez y fiabilidad. La identificación micológica convencional tiene algunos inconvenientes, como son su lentitud, su baja fiabilidad en algunos casos, y el hecho de que para algunos procedimientos es imprescindible la intervención de personas con amplia experiencia. Sin embargo, la población de riesgo para infecciones fúngicas, y por tanto su importancia clínica, han aumentado en los últimos años. Material y métodos. Se identificaron 153 aislamientos de hongos filamentosos y de levaduras mediante métodos convencionales y mediante EM MALDI-TOF. Cuando se dieron discrepancias entre ambos, éstas fueron dilucidadas mediante secuenciación del segmento ITS-2. Resultados. La correlación entre los métodos convencionales y la EM MALDI-TOF para la identificación de levaduras fue muy alta (99,2% a nivel de especie y 100% al de género). La única discrepancia que debió ser comprobada mediante secuenciación, corroboró el resultado obtenido con la EM. La correlación fue más heterogénea en el caso de los hongos filamentosos. 68,7% de los aislamientos mostraron correlación al menos al nivel de género, y 40,6% al nivel de especie. En conjunto, la correlación entre identificación convencional y MALDI-TOF para la identificación de hongos fue del 87% al nivel de especie, y del 93,5% a nivel de género. Conclusiones. La identificación de hongos mediante EM MALDI-TOF es fiable, y presenta ventajas potenciales con respecto a los métodos convencionales (AU)

Background. Recently, bacterial identification by MALDI-TOF MS has acquired a high relevance in terms of speed and reliability. Conventional mycological identification has some disadvantages: it is frequently slow, reliability is sometimes low, and an extensive experience is required. The risk population for fungal infections, and therefore their clinical significance has progressively increased in recent years. Methods. 153 yeast and mould clinical isolates were analyzed by MALDI-TOF MS and conventional identification. When both methods were discrepant to the genus or species level, ITS-2 sequencing was performed. Results. The correlation in yeasts identification between conventional identification methods and MALDI-TOF MS was extremely high (99.2% to the species level and 100% to the genus level). The only discrepancy was checked by ITS-2 sequencing and confirmed the MALDI-TOF identification. The correlation in moulds identification was more heterogeneous. 68.7% of the isolates showed correlation at least to the genus level and 40.6% to the species level. Therefore, the correlation between conventional identification and MALDI-TOF MS in fungal identification was, in whole, 87% to the species level, and 93.5% to the genus level. Conclusions. Identification of fungi by MALDI-TOF MS is reliable and shows potential advantages over conventional identification methods (AU)

New focus of active transmission of Chagas disease in indigenous populations in the Peruvian Amazon basin.

INTRODUCTION: Several cases of acute Chagas disease (ACD) have been reported in the Peruvian Amazon basin. METHODS: The objective was to describe and investigate 6 ACD cases in children from indigenous Amazon communities in the province of Datem del Marañón in Loreto department (2006-2010). RESULTS: The mean age was 3.6 years. All patients had fever, 4/6 hepatomegaly, 2/6 splenomegaly, and 5/6 had trypomastigotes of Trypanosoma cruzi on thick smears. The fatality rate was 33.3%. Rhodnius pictipes and Rhodnius robustus adults were found inside the homes and in the peri-domiciles. CONCLUSIONS: All cases reported were isolated cases. We report a new focus of ACD in indigenous populations.

New focus of active transmission of Chagas disease in indigenous populations in the Peruvian Amazon basin

Introduction Several cases of acute Chagas disease (ACD) have been reported in the Peruvian Amazon basin. Methods The objective was to describe and investigate 6 ACD cases in children from indigenous Amazon communities in the province of Datem del Marañón in Loreto department (2006-2010). Results The mean age was 3.6 years. All patients had fever, 4/6 hepatomegaly, 2/6 splenomegaly, and 5/6 had trypomastigotes of Trypanosoma cruzi on thick smears. The fatality rate was 33.3%. Rhodnius pictipes and Rhodnius robustus adults were found inside the homes and in the peri-domiciles. Conclusions All cases reported were isolated cases. We report a new focus of ACD in indigenous populations. .

Factores asociados al dolor en mujeres con fibromialgia / Associated factors to pain in women with fibromyalgia

Objetivo. Ponderar las variables psicopatológicas asociadas al dolor en la fibromialgia (FM). Material y Métodos. A 100 pacientes mujeres con FM se les aplicó las pruebas de escala visual análoga para evaluar la intensidad del dolor, el cuestionario de calidad de vida, el cuestionario de ansiedad rasgo y la escala de satisfacción de la vida y se indagó sobre experiencias adversas de crianza. Resultados. Se encontró que las pacientes con FM tienen mayores niveles de dolor, ansiedad, depresión y afectos negativos y menores de calidad de vida, satisfacción por la vida y afectos positivos. Las pruebas asociadas funcionalmente a estructuras cerebrales se correlacionaron análogamente entre ellas. En el análisis factorial como de correspondencia, las variables de valencia negativa: dolor, ansiedad estado-rasgo, depresión, afectos negativos y maltrato psicológico fueron de signo contrario a las de valencia positiva: función social y salud mental. Conclusión. Las pacientes con FM padecen de un dolor crónico severo donde el maltrato psicológico fue el fondo sobre el cual se proyectó la enfermedad.

Objective. To evaluate the psychopathological variables associated with pain in patients with fibromyalgia (FM). Material and Methods. A hundred female patients were submitted to the visual analog scale test to assess pain intensity, the quality of life questionnaire, the trait anxiety questionnaire and scale of life satisfaction and adverse parenting experiences were also investigated. Results. The FM patients had higher levels of pain, anxiety, depression and negative affect and lower quality of life, life satisfaction andpositive affect. The functional tests associated to brain structures correlated between them. Factor and correspondence analysis showed that negative valence variables: pain, state-trait anxiety, depression, negative affect and psycho-logical abuse were of opposite sign to the positive valence: social function and mental health. Conclusion. FM patients suffer from severe chronic pain where the psychological abuse was the background on which it projected the disease.

Technical reproducibility of genotyping SNP arrays used in genome-wide association studies.

During the last several years, high-density genotyping SNP arrays have facilitated genome-wide association studies (GWAS) that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. Moreover, discordance observed in results between independent GWAS indicates the potential for Type I and II errors. High reliability of genotyping technology is needed to have confidence in using SNP data and interpreting GWAS results. Therefore, reproducibility of two widely genotyping technology platforms from Affymetrix and Illumina was assessed by analyzing four technical replicates from each of the six individuals in five laboratories. Genotype concordance of 99.40% to 99.87% within a laboratory for the sample platform, 98.59% to 99.86% across laboratories for the same platform, and 98.80% across genotyping platforms was observed. Moreover, arrays with low quality data were detected when comparing genotyping data from technical replicates, but they could not be detected according to venders' quality control (QC) suggestions. Our results demonstrated the technical reliability of currently available genotyping platforms but also indicated the importance of incorporating some technical replicates for genotyping QC in order to improve the reliability of GWAS results. The impact of discordant genotypes on association analysis results was simulated and could explain, at least in part, the irreproducibility of some GWAS findings when the effect size (i.e. the odds ratio) and the minor allele frequencies are low.

Gel transmisor de ultrasonidos: una causa infrecuente de urticaria a frigore / Ultrasound gel: An unusual cause of cold urticaria

No disponible