Casuística das intoxicações por inibidores das colinesterases pelo Centro de Informação e Assistência Toxicológica do Paraná (CIATox/PR) entre 2015 e 2019 / Casuistics of poisonings by cholinesterases inhibitors by the Information and Toxicological Assistance Center of Paraná (CIATox/PR) between 2015 and 2019

Esta pesquisa buscou analisar os casos de intoxicações por organofosforados e carbamatos, presentes em agrotóxicos e pesticidas, registrados na base de dados do Centro de Informação e Assistência Toxicológica do Paraná (CIATox/PR). Trata-se de estudo retrospectivo em que foram avaliadas variáveis sociodemográficas e clínicas relacionadas à intoxicação, à forma de exposição, à causa e ao desfecho. Para a análise estatística foram utilizados testes de Kolmogorov-Smirnov, Shapiro-Wilk, Qui-Quadrado e Teste Exato de Fisher, considerando p<0,05. A amostra foi composta por 426 casos, sendo 218 (51,2%) mulheres. O principal agente foi raticida clandestino em 278 (65,2%) pacientes. A principal circunstância das intoxicações foi tentativa de suicídio com 293 (68,8%) casos. Houve predominância de exposição via oral (89,9%) e zona urbana em 349 (81,9%) casos, a maioria considerados leves (52,6%) e assistidos em serviços médicos (66,4%). Cerca de 327 (76,8%) indivíduos apresentavam manifestações clínicas. O tempo decorrido entre a exposição e o contato com o CIATox/PR foi maior nos casos considerados graves (p= 0,041). A atropina foi utilizada em 94 (49%) pacientes intoxicados por carbamatos, em 31 (33,3%) por organofosforados e em 84 (59,6%) por outros inibidores da colinesterase não especificados. Duas mulheres e um adolescente apresentaram desfecho fatal, tendo em comum a ingesta intencional de "chumbinho". A casuística predominante nesta série histórica foi paciente do sexo feminino, faixa etária adulta, residente na região metropolitana, exposta a agrotóxico por via oral, sintomática, classificada como gravidade leve, sem necessidade de atropina, contudo ocorreram três casos com desfecho para o óbito.

This research aimed to analyze the cases of poisoning by organophosphates and carbamates, present in agrochemicals and pesticides, registered in the database of the Information and Toxicological Assistance Center of Paraná (CIATox/PR). This is a retrospective study in which sociodemographic and clinical variables related to intoxication, form of exposure, cause and outcome were evaluated. For the statistical analysis, the Kolmogorov-Smirnov, Shapiro-Wilk, Chi-Square and Fisher's Exact Test were used, considering p<0.05. The sample consisted of 426 cases, 218 (51.2%) of which were women. The main agent was clandestine rodenticide in 278 (65.2%) patients. The main circumstance of intoxication was a suicide attempt with 293 (68.8%) cases. There was a predominance of oral exposure (89.9%) and urban areas in 349 (81.9%) cases, most considered mild (52.6%) and assisted in medical services (66.4%). About 327 (76.8%) individuals had clinical manifestations. The time elapsed between exposure and contact with CIATox/PR was longer in cases considered severe (p=0.041). Atropine was used in 94 (49%) patients intoxicated by carbamates, in 31 (33.3%) by organophosphates and in 84 (59.6%) by other unspecified cholinesterase inhibitors. Two women and one teenager had a fatal outcome, having in common the intentional ingestion of "chumbinho". The predominant casuistry in this historical series was a female patient, adult age, living in the metropolitan region, exposed to pesticides orally, symptomatic, classified as mild severity, without the need for atropine, however, there were three cases with an outcome of death.

Uso de ayudas diagnósticas en el paciente intoxicado en el servicio de urgencias / Use of diagnostic aids in the poisoned patient in the emergency department / Uso de ajudas diagnósticas em paciente intoxicado no atendimento de emergência

Objetivo: La incidencia de intoxicaciones en el servicio de urgencias viene en aumento en Colombia. En el abordaje inicial se solicitan paraclínicos de rutina, en ocasiones sin una correlación entre el xenobiótico, la fisiopatología y el riesgo clínico. El objetivo de esta investigación es describir el uso de las ayudas diagnósticas en el paciente intoxicado en el servicio de urgencias de un hospital de alta complejidad. Metodología: Estudio descriptivo transversal con disponibilidad de datos para el periodo 2014-2016. Se recopiló información de los registros de las historias clínica de los pacientes que acudieron al servicio de urgencias con diagnósticos relacionados con intoxicaciones. Resultados: El 55.4% de la población fue de sexo femenino, el 54.5% eran menores de 25 años y la mayoría pertenencia al área urbana (77.7%). La intencionalidad en el 68.9% fue suicida. Se reportó el toxídrome en el 17.6% de los casos, donde el sedante fue el más común (9.2%). Las sustancias más usadas fueron los psicofármacos (22.8%), siendo los antidepresivos tricíclicos más comunes con un 10.9%; seguidos de los plaguicidas (19.1%), donde los organofosforados fueron los más comunes (8.8%). Las ayudas diagnósticas más solicitadas fueron el hemograma en un 94.3% de los casos, seguido de la creatinina en un 90.2%. El electrocardiograma se realizó en el 49.7% de los casos y los tóxicos en orina en el 7.8%. Conclusión: Se evidencia un uso rutinario de ayudas diagnósticas en el servicio de urgencias; se requieren estudios adicionales que evalúen la pertinencia de ayudas diagnósticas en este escenario.

Objective: The incidence of poisoning in the emergency department is increasing in Colombia. In the initial approach, paraclinical routines are requested, sometimes without a correlation between xenobiotic, pathophysiology and clinical risk. The objective of this research is to describe the use of diagnostic aids in poisoned patients in the emergency department of a high-complexity hospital. Methodology: Descriptive cross-sectional study with retrospective data availability for the 2014-2016 period. Information was collected from the medical records of patients who came to the emergency department with diagnoses related to poisoning. Results: 55.4 % of the population was female, 54.5 % were under the age of 25, the majority belonging to the urban area (77%). The intentionality in 68.9% of them was suicidal. Toxidrome was reported in 17.6% of cases, the sedative being the most common (9.2%). Psychotropic drugs were the most commonly used substances (22.8%), the tricyclic anti-depressant being the most used with 10.9%, followed by pesticides with 19.1%, among which organophosphates were the most common (8.8%). The most requested diagnostic aids were the hemogram in 94.3% of the cases, followed by creatinine in 90.2%. The electrocardiogram was performed in 49.7% of the cases and the toxic in urine in 7.8%. Conclusions: A routine use of diagnostic aids is evidenced in the emergency department. Therefore, additional studies are required to evaluate the relevance of diagnostic aids in this setting.

Objetivo: A incidência de intoxicações no setor de emergência está aumentando na Colômbia. Na abordagem inicial, são solicitadas paraclínicas de rotina, às vezes sem correlação entre o xenobiótico, a fisiopatologia e o risco clínico. O objetivo desta pesquisa é descrever a utilização de meios auxiliares de diagnóstico em pacientes intoxicados no pronto-socorro de um hospital de alta complexidade. Metodologia: Estudo transversal descritivo com disponibilidade de dados para o período 2014-2016. As informações foram coletadas nos prontuários dos pacientes que compareceram ao pronto-socorro com diagnóstico de intoxicação. Resultados: 55,4% da população era do sexo feminino, 54,5% tinham menos de 25 anos e a maioria pertencia à zona urbana (77,7%). A intencionalidade em 68,9% foi suicida. Toxidromia foi relatada em 17,6% dos casos, sendo o sedativo o mais comum (9,2%). As substâncias mais utilizadas foram os psicotrópicos (22,8%), sendo os antidepressivos tricíclicos mais comuns com 10,9%; seguido por agrotóxicos (19,1%), onde os organo-fosforados foram os mais comuns (8,8%). Os meios diagnósticos mais solicitados foram o hemograma em 94,3% dos casos, seguido da creatinina em 90,2%. O eletrocardiograma foi realizado em 49,7% dos casos e a urina tóxica em 7,8%. Conclusão: Evidencia-se o uso rotineiro de meios auxiliares de diagnóstico no pronto-socorro; Estudos adicionais são necessários para avaliar a relevância dos auxiliares de diagnóstico neste cenário.

Influence of agricultural extension activities on tick control among cattle on family dairy farms in the southeast Brazil

The aim of the present study was to evaluate the resistance of tick populations on 16 family farms that were members of the agricultural producers' cooperative of the São Pedro region of the state of São Paulo (COOPAMSP). Bioassays were conducted on nine commercial products in 2018 and 2019. Their active agents were as follows: deltamethrin, amitraz, cypermethrin + chlorpyrifos + citronella, cypermethrin + chlorpyrifos + fenthion, cypermethrin + chlorpyrifos + piperonyl butoxide, dichlorvos + chlorpyrifos, cypermethrin, chlorfenvinphos + dichlorvos, and ivermectin. On some farms, a larval packet test (LPT) was also performed. Overall, four acaricides presented mean efficacy greater than 89%, among which two were associations of pyrethroids + organophosphates and two were associations of organophosphates + organophosphates. Deltamethrin, cypermethrin and ivermectin presented mean efficacy lower than 50%. In the bioassays using the LPT, all five farms showed resistance to diazinon, while only one farm presented resistance to cypermethrin. The results were handed over to each farmer with appropriate guidance for treatments. This study demonstrated that the important points to be implemented related directly to use control strategies, based on direct assistance for farmers and diagnosis of tick population sensitivities.

Desgaste del esmalte por diferentes tratamientos químicos y mecánicos / Wear of the enamel by different chemical and mechanical treatments / Desgaste do esmalte por diferentes tratamentos químicos e mecânicos

Introducción: La microabrasión se describe como un procedimiento realizado sobre el esmalte dental en el cual mediante la utilización de un agente ácido y un agente abrasivo se logra corregir alteraciones cromáticas superficiales. Algunos estudios demuestran como los parámetros de tiempo, número de aplicaciones y la presión ejercida, influyen en la can-tidad de esmalte eliminado. Objetivo: Establecer el espesor de esmalte dental eliminado según la capacidad abrasiva de 9 tratamientos químico mecánicos, mediante estereomicroscopia. Materiales y métodos: Con el aval del comité de ética de la Facultad de Odontología de la Universidad Nacional de Colombia, se recolectaron 90 terceros molares bajo consentimiento informado y se mantuvieron almacenados bajo los parámetros de la norma ISO 11405. Sobre bloques de acrílico se fijaron las mitades linguales de las coronas dentales, creando sobre ellas superficies planas mediante serie de lijas con irrigación y tomando impresiones con silicona de adición. Se distribuyeron de forma aleatoria en 9 grupos (n 10). Cada grupo recibió un tratamiento por un periodo de 30 segundos: G1: Opalustre® (Ultradent), G2: Piedra pómez y ácido fosfórico al 37% (Ultra-Etch®, Ultradent), G3: Piedra pómez, glicerina y ácido fosfórico al 37% (Ultra-Etch®, Ultradent), G4: Fresas de halo amarillo (Komet), G5: Fresas de halo blanco (Komet), G6: Discos Sof-Lex® (3M), color amarillo, G7: Discos Sof-Lex® (3M), color amarillo y amarillo claro, G8: Arenado, y G9: Puntas ultrasónicas Perfect Margin (Acteon). El espesor de desgaste creado fue medido utilizando un estéreo microscopio con un aumento de 10X. Los datos reco-lectados se analizaron a través de las pruebas de Kruskal-Wallis (p≤0.05) para comparar todos los grupos y la prueba U de Mann-Whitney (p≤0.05) para comparaciones individuales. Resultados: Independientemente del tratamiento realizado todos los grupos presentaron un desgaste del esmalte. El mayor desgaste se registró para el grupo tratado con fresa de halo amarillo (122,66 ± 22,64µm) y el menor desgaste para el grupo de arenado (11,5 ± 2,36µm). Se presentó diferencia estadísticamente significativa entre todos los grupos. Conclusiones: Bajo las limitaciones del presente estudio se puede concluir: La mayor microabrasión en esmalte se produjo con fresas de grano extrafino (halo amarillo) y el menor desgaste se produjo con arenado.

Introduction: Microabrasion is described as a procedure performed on tooth enamel in which the use of an acidic agent and an abrasive agent can correct surface chromatic alterations. Some studies show how the parameters of time, number of applications and the pressure exerted influence the amount of enamel removed.Objective: To establish the thickness of tooth enamel removed according to the abrasive capacity of 9 mechanical chemical treatments, using stereomicroscopy. Materials and methods: With the endorsement of the ethics committee of the School of Dentistry of the National University of Colombia, 90 third molars were collected under informed consent and kept stored under the parameters of ISO 11405. Acrylic blocks were fixed the lingual halves of the dental crowns, creating on them flat surfaces by means of series of sandpaper with irrigation and taking impressions with silicone of addition.They were distributed randomly in 9 groups (n 10). Each group was treated for a period of 30 seconds: G1: Opalustre® (Ultradent), G2: Pumice and 37% phosphoric acid (Ultra-Etch®, Ultradent), G3: Pumice, glycerin and phosphoric acid 37 % (Ultra-Etch®, Ultradent), G4: Yellow halo straw-berries (Komet), G5: White halo strawberries (Komet), G6: Sof-Lex® discs (3M), yellow color, G7: Sof-Lex discs ® (3M), yellow and light yellow, G8: Sandblasted, and G9: Perfect Margin ultrasonic tips (Acteon). The wear thickness created was measured using a stereo microscope with an increase of 10X. The collected data were analyzed through the Kruskal-Wallis tests (p≤0.05) to compare all groups and the Mann-Whitney U test (p≤0.05) for individual comparisons. Results: Regard-less of the treatment performed, all groups presented enamel wear. The highest wear was recorded for the group treated with yellow halo strawberry (122.66 ± 22.64µm) and the lowest wear for the sandblasting group (11.5 ± 2.36µm). There was a statistically significant difference between all groups. Conclusions: Under the limitations of the present study, it can be concluded: The greatest microabrasion in enamel was produced with strawberries of extra-fine grain (yellow halo) and the least wear occurred with sandblasting.

Introdução: A microabrasão do esmalte dental é descrita como um procedimento realizado no esmalte dentário, no qual o uso de um agente ácido e um abrasivo pode corrigir alterações cromáticas na superfície. Alguns estudos mos-tram como os parâmetros de tempo, número de aplicações e pressão exercida influenciam na quantidade do esmalte removido. Objetivo: Estabelecer a espessura do esmalte dentário removido de acordo com a capacidade abrasiva de 9 tratamentos químicos ou mecânicos, utilizando estereomicroscopia. Materiais e métodos: Com o aval do comitê de ética da Faculdade de Odontologia da Universidade Nacional da Colômbia, 90 terceiros molares hígidos foram coletados sob consentimento informado e mantidos armazenados sob os parâmetros da norma ISO 11405. Em blocos de acrílico foram fixadas as metades linguais das coroas dentárias, criando sobre elas superfícies planas por meio de séries de lixa mais irrigação e toma de impressões com silicone de adição. Eles foram distribuídos aleatoriamente em 9 grupos (n= 10). Cada grupo foi tratado por um período de 30 segundos: G1: Opalustre® (Ultradent), G2: Pedra-pomes e ácido fosfórico a 37% (Ultra-Etch®, Ultradent), G3: Pedra-pomes, glicerina e ácido fosfórico 37 % (Ultra-Etch®, Ultradent), G4: brocas diaman-tadas halo amarelo (Komet), G5: brocas diamantadas halo branco (Komet), G6: discos Sof-Lex® (3M), cor amarelo, G7: discos Sof-Lex ® (3M), amarelo e amarelo claro, G8: jateamento e G9: pontas ultra-sônicas Perfect Margin® (Acteon). A espessura de desgaste criada foi medida usando um microscópio estéreo com um aumento de 10X. Os dados coletados foram analisados pelos testes de Kruskal-Wallis (p≤0,05) para comparar todos os grupos e pelo teste U de Mann-Whit-ney (p≤0,05) para comparações individuais. Resultados: Independentemente do tratamento realizado, todos os grupos apresentaram desgaste do esmalte. O maior desgaste foi registrado para o grupo tratado com broca diamantada com halo amarelo (122,66 ± 22,64 µm) e o menor desgaste para o grupo de jateamento (11,5 ± 2,36 µm). Houve diferença estatisticamente significante entre todos os grupos. Conclusões: Sob as limitações do presente estudo, pode-se concluir que a maior microabrasão no esmalte foi produzida com brocas de grão extra-fino (halo amarelo) e o menor desgaste ocorreu com o jateamento.

Intra-individual variations of organophosphate pesticide metabolite concentrations in repeatedly collected urine samples from pregnant women in Japan

BACKGROUND@#Low-dose exposure to organophosphate (OP) insecticides during pregnancy may adversely affect neurodevelopment in children. To evaluate the OP exposure levels, single urine sampling is commonly adopted to measure the levels of dialkylphosphates (DAPs), common OP metabolites. However, the inter-day variations of urinary DAP concentrations within subjects are supposed to be large due to the short biological half-lives of the metabolites, and it is thus considered difficult to accurately assess OP exposure during pregnancy with single sampling. This study aimed to assess intra-individual variations of DAP concentrations and the reproducibility of the exposure dose categorization of OPs according to DAP concentration ranges in pregnant women in Japan.@*METHODS@#Urine samples were collected from 62 non-smoking pregnant women (12-22 weeks of gestation) living in Aichi Prefecture, Japan. First morning void (FMV) and spot urine samples taken between lunch and dinner on the same day were collected on five different days during 2 weeks. The concentrations of DAP and creatinine in urine samples were measured using an ultra performance liquid chromatography with tandem mass spectrometry. Creatinine-adjusted and unadjusted concentrations were used for the intraclass correlation coefficient (ICC) calculations and surrogate category analyses.@*RESULTS@#For all DAP metabolites, the creatinine-adjusted single ICCs exceeded 0.4, indicating moderate reliability. Overall, ICCs of spot urine samples taken in the afternoon were better than those taken as FMV. Surrogate category analyses showed that participants were categorized accurately into four exposure dose groups according to the quartile points.@*CONCLUSION@#This study indicated that a single urine sample taken in the afternoon may be useful in assessing OP exposure as long as the exposure is categorized into quartiles when conducting epidemiological studies in early to mid-pregnant women in Japan.

Acetylcholinesterase activity in the brain of wild birds in Korea—2014 to 2016

Acetylcholinesterase (AChE) activity level can be used as a diagnostic marker for anticholinesterase pesticide poisoning. In this study, we aimed to establish a baseline level of normal brain AChE activity in wild birds. AChE activity was measured in the brains of 87dead wild birds (26 species). The level of AChE activity ranged from 6.40 to 15.9 µmol/min/g of brain tissue in normal wild birds. However, the brain tissue AChE activity level in wild birds exposed to organophosphate (OP) pesticide was 48.0%–96.3% of that in the normal birds. These results may serve as reference values to facilitate routine diagnosis and monitoring of OP-poisoned wild birds.

A novel chlorpyrifos hydrolase CPD from Paracoccus sp. TRP: molecular cloning, characterization and catalytic mechanism

Background: Biodegradation is a reliable approach for efficiently eliminating persistent pollutants such as chlorpyrifos. Despite many bacteria or fungi isolated from contaminated environment and capable of degrading chlorpyrifos, limited enzymes responsible for its degradation have been identified, let alone the catalytic mechanism of the enzymes. Results: In present study, the gene cpd encoding a chlorpyrifos hydrolase was cloned by analysis of genomic sequence of Paracoccus sp. TRP. Phylogenetic analysis and BLAST indicated that CPD was a novel member of organophosphate hydrolases. The purified CPD enzyme, with conserved catalytic triad (Ser155-Asp251-His281) and motif Gly-Asp-Ser-Ala-Gly, was significantly inhibited by PMSF, a serine modifier. Molecular docking between CPD and chlorpyrifos showed that Ser155 was adjacent to chlorpyrifos, which indicated that Ser155 may be the active amino acid involved in chlorpyrifos degradation. This speculation was confirmed by site-directed mutagenesis of Ser155Ala accounting for the decreased activity of CPD towards chlorpyrifos. According to the key role of Ser155 in chlorpyrifos degradation and molecular docking conformation, the nucleophilic catalytic mechanism for chlorpyrifos degradation by CPD was proposed. Conclusion: The novel enzyme CPD was capable of hydrolyze chlorpyrifos and Ser155 played key role during degradation of chlorpyrifos.

Different Clinical Courses for Poisoning with WHO Hazard Class Ia Organophosphates EPN, Phosphamidon, and Terbufos in Humans

PURPOSE: Extremely hazardous pesticides are classified as World Health Organization (WHO) hazard class Ia. However, data describing the clinical course of WHO class Ia OP (organophosphate) poisonings in humans are very scarce. Here, we compare the clinical features of patients who ingested hazard class Ia OPs. METHODS: This retrospective observational case study included 75 patients with a history of ingesting ethyl p-nitrophenol thio-benzene phosphonate (EPN), phosphamidon, or terbufos. The patients were divided according to the chemical formulation of the ingested OP. Data regarding mortality and the development of complications were collected and compared among groups. RESULTS: There were no differences in the baseline characteristics and severity scores at presentation between the three groups. No fatalities were observed in the terbufos group. The fatality rates in the EPN and phosphamidon groups were 11.8% and 28.6%, respectively. Patients poisoned with EPN developed respiratory failure later than those poisoned with phosphamidon and also tended to require longer mechanical ventilatory support than phosphamidon patients. The main cause of death was pneumonia in the EPN group and hypotensive shock in the phosphamidon group. Death occurred later in the EPN group than in the phosphamidon group. CONCLUSION: Even though all three drugs are classified as WHO class Ia OPs (extremely hazardous pesticides), their clinical courses and the related causes of death in humans varied. Their treatment protocols and predicted outcomes should therefore also be different based on the chemical formulation of the OP.

Relative Risk and Clinical Severity Assessment in Patients with Non-Oral Route Organophosphate Poisoning Compared with Oral Route Poisoning

PURPOSE: Organophosphates, commonly used in agricultural pesticides, pose high risks and incidences of poisoning. In the present study, we investigated the relative risk and clinical severity, including laboratory results, of non-oral route poisoning (NORP) patients, compared to oral route poisoning (ORP) patients. MATERIALS AND METHODS: A single institutional toxicology database registry was utilized to gain information on clinical laboratory results on organophosphate poisoning patients who visited the emergency department (ED) between January 2000 and October 2016. Clinical outcomes, such as mortality and complication rates, were compared using 1:2 propensity score matching in the total cohort. RESULTS: Among a total of 273 patients in our study, 34 experienced NORP. After 1:2 propensity score matching, rates of respiratory complications and mortality were higher in the ORP group than in the NORP group. However, there was no difference in hospitalization time and time spent in the intensive care unit between the two groups. Compared with ORP patients after matching, the relative risk of mortality in NORP patients was 0.34, and the risk of respiratory distress was 0.47. The mean level of pseudocholinesterase was significantly higher in the NORP group than in the ORP group, while recovery rates were similar between the two groups. CONCLUSION: Although the majority of NORP patients were admitted to the ED with unintentional poisoning and the relative risk of NORP was lower than that for ORP, we concluded that NORP is as critical as ORP. Considerable medical observation and intensive therapeutic approaches are also needed for NORP patients.

Case Control Study of Impulsivity, Aggression, Pesticide Exposure and Suicide Attempts Using Pesticides among Farmers / 生物医学与环境科学（英文）

A case-control study was conducted to investigate associations between organophosphate pesticide (OP) exposure, aggression, impulsivity, and attempted suicide. Questionnaires were used to collect information; impulsivity and aggression were measured by the Barratt Impulsivity Scale (BIS) and the Aggression Inventory (AI). A greater number of OP symptoms was associated with an increased odds of a suicide attempt after adjusting for marital status and income (OR = 1.45; CI 1.14-1.86). Attempted suicide was significantly associated with high impulsivity scores (means: 72.4 vs. 60.6, P < 0.0001) and high aggression scores (means: 38.5 vs. 26.1, P < 0.0001). Suicide attempters had a higher number of OP exposure symptoms than controls and scored higher on scales of impulsivity and aggression.

Sudden death caused by trichlorfon poisoning in Korean native cattle / 대한수의학회지

Two 12-month-old cattle with anthelmintics containing trichlorfon the day before death presented to the Animal and Plant Quarantine Agency for diagnosis. In necropsy, they revealed enlargement of the spleens, redness of mucosa and serosa in stomachs and intestines, and friable kidneys. Histopathologically, hemorrhages in the spleens, omasums, abomasums, and intestines as well as renal tubular necrosis were observed. Trichlorfon was detected at above the lethal dose in the ruminal contents. Based on these findings, we diagnosed this case as death caused by trichlorfon poisoning.

Efficacy of commercial synthetic pyrethroids and organophosphates associations used to control Rhipicephalus (Boophilus) microplus in Southern Brazil / Eficácia de associações comerciais entre piretroides sintéticos e organofosforados utilizados no controle de Rhipicephalus (Boophilus) microplus na Região Sul do Brasil

Abstract This study evaluated the acaricidal efficiency of synthetic pyrethroids (SP) associated with organophosphates (OP) against Rhipicephalus (Boophilus) microplus populations in the state of Rio Grande do Sul, Southern Brazil. Ticks were collected in 54 cattle farms and tested using in vitro adult immersion test against four commercially available acaricide mixtures of SP and OP. Only one of four acaricides, comprising a mixture of cypermethrin, chlorpyrifos, and fenthion, had a mean efficiency higher than 95%, and was effective in 94.44% (51/54) of the cattle farms tested. The acaricide with a mixture of cypermethrin, chlorpyrifos, and citronelall had the lowest mean efficiency (62.11%), and was effective in 29.62% (16/54) of cattle farms tested. Furthermore, R. (B.) microplus in Southern Brazil exhibited differing degrees of resistance to SP and OP mixtures. The results suggest that the presence of fenthion contributes to the higher efficiency of the formulation with this active principle. This is possibly due to its recent commercial availability, as tick populations have been lower challenged with this product. Monitoring the resistance of ticks to carrapaticides is essential to maximize the efficiency of these products in the control of R. (B.) microplus.

Resumo Este estudo avaliou a eficiência acaricida de piretroides sintéticos (SP) associados a organofosforados (OP) sobre populações de Rhipicephalus (Boophilus) microplus no estado do Rio Grande do Sul, Brasil. Carrapatos foram coletados em 54 fazendas de bovinos, testados in vitro pelo teste de imersão de teleóginas, contra quatro associações acaricidas comercialmente disponíveis de SP e OP. Apenas um dos quatro acaricidas, constituído por associação de cipermetrina, clorpirifós e fenthion, teve eficiência média superior a 95%, sendo eficaz em 94,44% (51/54) das fazendas testadas. O acaricida com associação de cipermetrina, clorpirifós e citronelal teve menor eficiência média (62,11%), sendo efetivo em 29,62% (16/54) das fazendas testadas. Além disso, o R. (B.) microplus no sul do Brasil, apresentou diferentes graus de resistência às associações de SP e OP. Os resultados sugerem que a presença do fenthion contribui para a maior eficiência da formulação com esse princípio ativo. Possivelmente, isso ocorre em função da sua recente introdução no mercado, já que as populações de carrapatos foram pouco desafiadas com este produto. Monitorar a resistência dos carrapatos aos carrapaticidas é fundamental para maximizar a eficiência desses produtos no controle de R. (B.) microplus.

In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid and tedizolid

Abstract Introduction Treatment of multidrug-resistant Gram-positive infections caused by Staphylococcus aureus remains as a clinical challenge due to emergence of new resistance mechanisms. Tedizolid is a next-generation oxazolidinone, recently approved for skin and soft tissues infections. We conducted a study to determine in vitro susceptibility to vancomycin, daptomycin, linezolid and tedizolid in MRSA clinical isolates from adult patients with skin and soft tissue infections. Material and methods Methicillin-resistant S. aureus isolates were collected in three tertiary-care hospitals of Medellin, Colombia, from February 2008 to June 2010 as part of a previous study. Clinical characteristics were assessed by medical records and MIC values were determined by Epsilometer test. Genotypic analysis included spa typing, MLST, and SCCmec typing. Results A total of 150 MRSA isolates were evaluated and tedizolid MIC values obtained showed higher in vitro activity than other antimicrobials, with MIC values ranging from 0.13 µg/mL to 0.75 µg/mL and lower values of MIC50 and MIC90 (0.38 µg/mL and 0.5 µg/mL). In contrast, vancomycin and linezolid had higher MIC values, which ranged from 0.5 µg/mL to 2.0 µg/mL and from 0.38 µg/mL to 4.0 µg/mL, respectively. Tedizolid MICs were 2- to 5-fold lower than those of linezolid. Clinical characteristics showed high previous antimicrobial use and hospitalization history. The majority of the strains belong to the CC8 harboring the SCCmec IVc and were associated with the spa t1610 (29.33%, n = 44). Conclusion In vitro effectiveness of tedizolid was superior for isolates from skin and soft tissue infections in comparison with the other antibiotics evaluated. The above added to its less toxicity, good bioavailability, daily dose and unnecessity of dosage adjustment, make tedizolid in a promising alternative for the treatment of infections caused by MRSA.

Quanto custa o atraso na concessão de patentes de medicamentos para a saúde no Brasil? / How much does the backlog on drug patents cost for health in Brazil? / ¿Cuánto cuesta el atraso en las patentes de medicamentos para la salud en Brasil?

Resumo: O backlog na análise de pedidos de patentes é um problema que persiste desde a promulgação da Lei nº 9.279/1996, quando o Brasil passou a conceder patentes para medicamentos novamente. Os órgãos responsáveis pela concessão dessas patentes, Instituto Nacional da Propriedade Industrial (INPI) e Agência Nacional de Vigilância Sanitária (Anvisa), alegam motivos técnico-administrativos para justificar o atraso. No entanto, os impactos econômicos para a saúde devido à ineficiência do sistema de patentes brasileiro ainda foram pouco investigados. Assim sendo, este trabalho propõe uma metodologia para estimar o quanto as compras públicas de medicamentos são oneradas em função da morosidade na análise dos pedidos de patentes no país. Os resultados mostram que mais de R$ 14 milhões são gastos desnecessariamente anualmente pelo Governo Federal com apenas um medicamento antirretroviral por causa da extensão da vigência das patentes. Conclui-se que medidas governamentais de controle dessa situação são prementes no âmbito dos Três Poderes. Dentre elas, destacam-se a contratação de servidores para o INPI, análise dos projetos de lei que tramitam na Câmara dos Deputados e Senado Federal para a alteração da Lei da Propriedade Industrial, e julgamento das Ações Diretas de Inconstitucionalidade para a supressão do dispositivo legal que possibilita a extensão da vigência das patentes.

Abstract: The backlog in processing patent applications in Brazil has persisted since the enactment of Law 9,279/1996, when the country resumed granting patents on drugs. The agencies responsible for granting such patents, namely the Brazilian National Patent and Trademark Office (INPI) and the Brazilian National Health Surveillance Agency (Anvisa) cite technical and administrative reasons for the backlog. However, little research has focused on the economic impacts for health due to the inefficiency of the Brazilian patent system. The current study thus proposes a methodology to estimate the extent to which government procurement of medicines is burdened by the backlog in drug patent applications. According to the results, a total of more than BRL 14 million (USD 4.5 million) is spent unnecessarily per year by the Federal Government on just one antiretroviral drug due to the extension of the respective patent's life. Measures to resolve this situation are urgently needed in the three branches of government. These include hiring more staff for the INPI, analysis of bills of law under review in the two houses of the Brazilian Congress to amend the Industrial Property Law, and ruling on direct class action claims of unconstitutionality to suppress the legal mechanisms that allow extending the life of patents.

Resumen: El atraso en el procesamiento de solicitudes de patentes en Brasil ha persistido desde la promulgación de la Ley 9.279/1996, cuando el país reanudó la concesión de patentes sobre drogas. Los organismos encargados de otorgar las patentes, a saber, la Oficina Nacional de Patentes y Marcas (INPI) y la Agencia Nacional de Vigilancia Sanitaria (Anvisa), alegan motivos técnico-administrativos para justificar el retraso. Sin embargo, poca investigación se ha centrado en los impactos económicos para la salud debido a la ineficiencia del sistema brasileño de patentes. El presente estudio propone una metodología para estimar el grado en que la contratación pública de medicamentos está cargada con el atraso en las solicitudes de patente de medicamentos. De acuerdo con los resultados, el gobierno federal gasta innecesariamente un total de más de BRL 14 millones (USD 4.5 millones) por un solo medicamento antirretroviral debido a la extensión de la vida de la respectiva patente. Las medidas para resolver esta situación son urgentemente necesarias en las tres ramas del gobierno. Estos incluyen la contratación de más personal para la INPI, el análisis de los proyectos de ley en revisión en las dos cámaras del Congreso brasileño para enmendar la Ley de Propiedad Industrial, y la decisión sobre demandas de acción colectiva directa de inconstitucionalidad para suprimir los mecanismos legales que permiten extender la vida de las patentes.

Tyrosine phosphorylation of Kv1. 5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension

Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.

Organophospahte Pesticide Mixture Exposure: The Relationship With The Motor Coordination Of Children From Paddy Farming Area In Tanjung Karang, Malaysia

@#Paddy cultivation is one of the widely planted crop in Malaysia. The growth of agricultural activity leads to the use of Organophosphate pesticide to protect the crop. This study is to determine the relationship between the levels of blood cholinesterase with the performance of motor coordination of children living in paddy farming area in Tanjung Karang, Selangor. This cross sectional study was conducted among 683 children from four schools in an agricultural area. Majority of the children have at a family member worked as farmer and was involved with pesticides. A set of questionnaire on the was given to the children to be filled by their parents. To measure their exposure to pesticide, blood cholinesterase levels were measured. Blood samples were taken through finger prick technique and were then analysed using LOVIBOND 412870 AF287. The children were administered with motor-coordination performance test using WHO Neurobehavioral Core Test Battery and McCarthy Learning Ability Scale. Young group children (6-85 years) showed a mean score of 56.66 in motor-coordination test while older group children (10-11)= years) scored a mean of 45.37. There was a significant relationship between blood cholinesterase level and motor coordination performance among the young-group children (r=0.215, p<0.001) and the older-group children (r=0.106, p=0.049). Based on the Linear Regression test results, total household income of family, and mode of transport used were found to have significant relationship with blood cholinesterase level of children in both groups. In addition, blood cholinesterase level and mothers’ occupation were found to have significant relationship with the motor-coordination performance of all children.

Methidathion Poisoning / 대한구급학회지

Although methidathion is an organophosphate insecticide, it is different from the other organophosphates in terms of toxicity. Because of its relatively high fat solubility, the apparent volume of methidathion distribution throughout the body is very high, indicating that hemoperfusion is not effective in removing this organophosphate from the body. Redistribution of methidathion from fat to blood can also occur when plasma levels diminish. Additionally, acetylcholinesterase aging, which is the loss of an alkyl side chain that prevents reactivation by oximes, is very rapid so that the effective reactivation by oximes is thwarted. Thus, methidathion's effect on acetylcholinesterase inhibition is long lasting, particularly with a high dose. In addition to its parasympatholytic effect and ability to induce muscle paralysis, methidathion poisoning is associated with a profound and long-lasting circulatory collapse due to sympathetic ganglion blockade. This report presents the case of a 55-year-old man who accidentally ingested a high dose of methidathion. He later developed enteroinvasive aspergillosis infection-induced multiple bowel perforations on two separate occasions while on mechanical ventilator support, resulting in a fatal outcome. The renin-angiotensin axis activated by sympathetic ganglion blockade may have reduced the patient's splanchnic blood flow, contributing to translocation of endotoxin. Also, the effect of excessive acetylcholine on non-neuronal acetylcholine receptors may have contributed to the development of fatal enteroinvasive aspergillosis in this patient.

Methidathion Poisoning / 대한중환자의학회지

Although methidathion is an organophosphate insecticide, it is different from the other organophosphates in terms of toxicity. Because of its relatively high fat solubility, the apparent volume of methidathion distribution throughout the body is very high, indicating that hemoperfusion is not effective in removing this organophosphate from the body. Redistribution of methidathion from fat to blood can also occur when plasma levels diminish. Additionally, acetylcholinesterase aging, which is the loss of an alkyl side chain that prevents reactivation by oximes, is very rapid so that the effective reactivation by oximes is thwarted. Thus, methidathion's effect on acetylcholinesterase inhibition is long lasting, particularly with a high dose. In addition to its parasympatholytic effect and ability to induce muscle paralysis, methidathion poisoning is associated with a profound and long-lasting circulatory collapse due to sympathetic ganglion blockade. This report presents the case of a 55-year-old man who accidentally ingested a high dose of methidathion. He later developed enteroinvasive aspergillosis infection-induced multiple bowel perforations on two separate occasions while on mechanical ventilator support, resulting in a fatal outcome. The renin-angiotensin axis activated by sympathetic ganglion blockade may have reduced the patient's splanchnic blood flow, contributing to translocation of endotoxin. Also, the effect of excessive acetylcholine on non-neuronal acetylcholine receptors may have contributed to the development of fatal enteroinvasive aspergillosis in this patient.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Acute Kidney Injury after Intravenous Injection of an Organophosphate Compound

Poisoning may result from self-injection. Previous reports have described acute cholinergic crisis, intermediate syndrome, and delayed toxicity resulting from parenteral organophosphate administration. These complications have been managed with antidotal and conservative treatment. Acute kidney injury was not listed among the complications. We report a case of acute kidney injury after intravenous injection with an unknown liquid. After chemical composition analysis, organophosphate dichlorvos has been identified as the injected liquid substance. A 50-year-old man injected this into his left arm. He visited the emergency department with a mental change accompanied by seizure. During admission, there were no typical cholinergic symptoms or intermediate syndrome; however, there was a development of acute oliguric kidney injury. The patient was treated successfully with a combination of hemodialysis, hemoperfusion, and conservative management. The manifested seizure, altered mental state, and acute kidney injury could have been caused by several types of poisoning. Based on patient history, which was obtained during the early treatment period, there was no information of what the injected material may have been, and there were no signs of a typical organophosphate toxidrome. However, the patient was successfully treated with rapid initiation of renal replacement treatment, without the use of antidotes. Poisoning by unknown causative substances poses a diagnostic challenge to emergency physicians. In many cases, treatment may be delayed while the physician tries to identify the toxin. However, the basic toxicology principle of focusing on the patient treatment rather than the poisonous substance should not be forgotten.