RESUMEN
By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated into a single physiologically based pharmacokinetic (PBPK) model that enables more confident extrapolation to humans. Because available data suggested there might be differences in PQ kinetics between primates and non-primates, a radiolabelled study was conducted to characterize pharmacokinetics and excretion in Cynomolgus monkeys. Following single intravenous doses of 0.01 or 0.1 mg paraquat dichloride/kg bw, plasma PQ concentration-time profiles were dose-proportional. Excretion up to 48 h (predominantly urinary) was 82.9%, with ca. 10% remaining unexcreted. In vitro blood binding was similar across Cynomolgus monkeys, humans and rat. Our PBPK model for the rat, mouse and dog, employing a single set of PQ-specific parameters, was scaled to Cynomolgus monkeys and well represented the measured plasma concentration-time profiles over 14 days. Addition of a cartilage compartment to the model better captured the percent remaining in the monkeys at 48 h, whilst having negligible effect on model predictions for the other species. The PBPK model performed well for all four species, demonstrating there is little difference in PQ kinetics between non-primates and primates enabling a more confident extrapolation to humans. Scaling of the PBPK model to humans, with addition of a human-specific dermal submodel based on in vitro human dermal absorption data, provides a valuable tool that could be employed in defining internal dosimetry to complement human health risk assessments.
Asunto(s)
Herbicidas/farmacocinética , Modelos Biológicos , Paraquat/farmacocinética , Animales , Simulación por Computador , Herbicidas/administración & dosificación , Herbicidas/sangre , Herbicidas/toxicidad , Humanos , Infusiones Intravenosas , Eliminación Intestinal , Macaca fascicularis , Paraquat/administración & dosificación , Paraquat/sangre , Paraquat/toxicidad , Ratas , Eliminación Renal , Medición de Riesgo , Absorción Cutánea , Especificidad de la Especie , Distribución Tisular , ToxicocinéticaRESUMEN
Paraquat dichloride (PQ) is a non-selective herbicide which has been the subject of numerous toxicology studies over more than 50 years. This paper describes the development of a physiologically-based pharmacokinetic (PBPK) model of PQ kinetics for the rat, mouse and dog, firstly to aid the interpretation of studies in which no kinetic measurements were made, and secondly to enable the future extension of the model to humans. Existing pharmacokinetic data were used to develop a model for the rat and mouse. Simulations with this preliminary model were then used to identify key data gaps and to design a new blood binding study to reduce uncertainty in critical aspects of the model. The new data provided evidence to support the model structure, and its predictive performance was then assessed against dog and rat datasets not used in model development. The PQ-specific model parameters are the same for all three species, with only the physiological parameters varying between species. This consistency across species provides a strong basis for extrapolation to other species, as demonstrated here for the dog. The model enables a wide range of PQ data to be linked together to provide a broad understanding of PQ pharmacokinetics in rodents and the dog, showing that the key aspects of PQ kinetics in these species are understood and adequately encapsulated within the model.
Asunto(s)
Herbicidas/farmacocinética , Modelos Biológicos , Paraquat/farmacocinética , Animales , Simulación por Computador , Perros , Herbicidas/sangre , Herbicidas/toxicidad , Eliminación Intestinal , Ratones , Paraquat/sangre , Paraquat/toxicidad , Unión Proteica , Ratas , Eliminación Renal , Medición de Riesgo , Especificidad de la Especie , Distribución Tisular , ToxicocinéticaRESUMEN
The MTT assay was the first widely accepted method to assess cytotoxicity and cell viability. However, there is controversy on whether this indicator is a useful tool. In this work we intend to expand the interpretability of the MTT study by its combination with widely used cellular biology techniques. We propose complementary approaches to the colorimetric assay, based on the use of measurements in three different settings: confocal microscopy, multi-well plate assay and flow cytometry. Using confocal microscopy, we confirmed that MTT uptake and reduction by cells is a time-dependent process, and that formazan accumulates in round-shaped organelles. Quantitative measurements with a multi-well fluorimeter combined with nuclear staining result in a useful method, yielding a ratio between formazan production and cell number that informs about the average cell metabolic state. We also found that flow cytometry is a suitable technique to measure MTT reduction in large cell populations. When assaying the effect of an oxidizing agent such as paraquat (PQ), this approach allows for the distinction of subpopulations of cells with different reducing power. Finally, we prove that it is feasible to monitor MTT reduction in an in vivo model, the Drosophila larvae, without affecting its survival rate. Formazan accumulates exclusively in the larval fat body, confirming its lipid solubility. The methods explored in this work expand the MTT potential as a useful tool to provide information of the physiological state of cells and organisms.
Asunto(s)
Formazáns , Larva/efectos de los fármacos , Paraquat/farmacología , Sales de Tetrazolio , Animales , Bioensayo , Recuento de Células , Drosophila/efectos de los fármacos , Cuerpo Adiposo/efectos de los fármacos , Citometría de Flujo , Formazáns/química , Células HeLa , Humanos , Lípidos/farmacocinética , Microscopía Confocal , Oxidación-Reducción , Paraquat/farmacocinética , Solubilidad , Sales de Tetrazolio/química , Factores de TiempoRESUMEN
Paraquat (N, N'-dimethyl-4,4'-bipyridium dichloride) is a potent and widely used herbicide in agricultural countries, including Thailand. The presence of this chemical in the body can lead to toxic effects in the liver, kidney, and lung. Pulmonary toxicity has been identified as the main cause of acute toxicity in animals and humans. Chronic exposure to paraquat is associated with Parkinson's disease in humans. Paraquat is transported into the lungs by neutral amino acid transporter. Therefore, a physiologically based pharmacokinetic (PBPK) model of paraquat was developed with a description of the protein transporter mechanism. To develop a PBPK model of paraquat, a pharmacokinetic study of paraquat in rats was selected from the ThaiLIS and Pubmed database. The selected study contained tissue-specific concentration-time course information such as paraquat concentration levels in liver, kidney and lung. Physiologic parameters were acquired from the literature or determined using a Markov-Chain Monte Carlo (MCMC) technique. The developed PBPK model consisted of 5 organ compartments (i.e. kidney, liver, slowly perfused organs, richly perfuse organs and lung), featuring an incorporation of neutral amino acid transporter in the lung. Our model simulations could explain the data from the literature and adequately describe pharmacokinetics of paraquat in the rats. This developed PBPK model may be able help in understanding of paraquat-induced Parkinson's disease as well as in risk assessment of paraquat.
Asunto(s)
Paraquat/farmacocinética , Animales , Herbicidas , Cadenas de Markov , Modelos Biológicos , Método de Montecarlo , Ratas , Distribución TisularRESUMEN
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative condition that has genetic susceptibility, aging, and exposure to certain chemicals as risk factors. In recent decades, epidemiological and experimental studies have investigated the role of pesticides in the development of PD, in particular that of the herbicide paraquat. Here, we, therefore, aim to systematically review the association between paraquat exposure and PD. METHODS: Observational studies (cohort, case-control, and cross-sectional) eligible for this systematic review will enroll any participant who was occupationally and/or environmentally exposed to paraquat. Experimental studies, including in vivo and in vitro assays designed to assess neurotoxicological endpoints or mechanisms of paraquat neurotoxicity, will also be eligible. Outcomes of interest include the following: PD diagnosis; neurobehavioral, biochemical, and/or morphological alterations; and cellular, biochemical, and/or molecular pathways to oxidative stress. Using terms to include all forms of paraquat combined with PD, the following electronic databases will be searched: PubMed, EMBASE, LILACS, Toxnet, and Web of Science, without restrictions as to language, year, or status of publication. A team of reviewers will independently select potential titles and abstracts, extract data, assess risk of bias, and determine the overall quality of evidence for each outcome using the Office of Health Assessment and Translation (OHAT) approach for systematic reviews and evidence integration. Dichotomous data will be summarized as odds ratios, and continuous data will be given as mean differences, both with their respective 95% confidence intervals. DISCUSSION: This is the first time that the OHAT systematic review protocol will be applied to investigate a possible causal association between exposure to paraquat and PD. Results from this study could serve as basis for regulatory agencies to define paraquat levels of concern, supporting its risk assessment process. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016050861.
Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Paraquat/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Plaguicidas/toxicidad , Proyectos de Investigación , Literatura de Revisión como Asunto , Animales , Relación Dosis-Respuesta a Droga , Humanos , Vías Nerviosas/efectos de los fármacos , Estudios Observacionales como Asunto , Paraquat/farmacocinética , Enfermedad de Parkinson Secundaria/fisiopatología , Plaguicidas/farmacocinética , Factores de Riesgo , Revisiones Sistemáticas como AsuntoRESUMEN
Laboratory studies involving repeated exposure to paraquat (PQ) in different animal models can induce many of the pathological features of Parkinson's disease (PD), such as the loss of dopaminergic neurons in the nigrostriatal dopamine system. Epidemiological studies identify an increased risk of developing PD in human populations living in areas where PQ exposure is likely to occur and among workers lacking appropriate protective equipment. The mechanisms involved in developing PD may not be due to any single cause, but rather a multifactorial situation may exist where PQ exposure may cause PD in some circumstances. Multifactorial theory is adopted into this review that includes a number of sub-cellular mechanisms to explain the pathogenesis of PD. The theory is placed into an environmental context of chronic low-dose exposure to PQ that consequently acts as an oxidative stress inducer. Oxidative stress and the metabolic processes of PQ-inducing excitotoxicity, α-synuclein aggregate formation, autophagy, alteration of dopamine catabolism, and inactivation of tyrosine hydroxylase are positioned as causes for the loss of dopaminergic cells. The environmental context and biochemistry of PQ in soils, water, and organisms is also reviewed to identify potential routes that can lead to chronic rates of low-dose exposure that would replicate the type of response that is observed in animal models, epidemiological studies, and other types of laboratory investigations involving PQ exposure. The purpose of this review is to synthesize key relations and summarize hypotheses linking PD to PQ exposure by using the multifactorial approach. Recommendations are given to integrate laboratory methods to the environmental context as a means to improve on experimental design. The multifactorial approach is necessary for conducting valid tests of causal relations, for understanding of potential relations between PD and PQ exposure, and may prevent further delay in solving what has proven to be an evasive etiological problem.
Asunto(s)
Neurotoxinas/toxicidad , Paraquat/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Metabolismo Energético/efectos de los fármacos , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Herbicidas/administración & dosificación , Herbicidas/farmacocinética , Herbicidas/toxicidad , Humanos , Modelos Neurológicos , NADPH Oxidasas/metabolismo , Neurotoxinas/administración & dosificación , Neurotoxinas/farmacocinética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Estrés Oxidativo/efectos de los fármacos , Paraquat/administración & dosificación , Paraquat/farmacocinética , Enfermedad de Parkinson Secundaria/metabolismo , Factores de RiesgoRESUMEN
We report a case of a 66-year-old patient with paraquat intoxication resulting in the requirement for hemoperfusion, hemodialysis, and plasma exchange. His initial serum paraquat level was 0.24 µg/mL (0.0-0.1 µg/mL). Activated charcoal (50 g) was administered orally, and high-dose N-acetylcysteine (150 mg/kg) was administered intravenously. In addition, immediate 4 h hemoperfusion was also performed for three consecutive days after admission. Hemodialysis was started on the 4th day after admission because of uremia. On the 9th day after admission, laboratory findings demonstrated hemolytic uremic syndrome (HUS): microangiopathic hemolytic anemia (MAHA), thrombocytopenia, elevated reticulocyte count, and lactate dehydrogenase (LDH). Plasma exchange was performed three times consecutively. Anemia and thrombocytopenia were improved, and LDH was normalized after plasma exchange. Urine output increased to 2240 mL/day on the 18th day after admission, and hemodialysis was discontinued. He is currently being observed at our follow-up clinic without renal impairment or pulmonary dysfunction for 1.5 years since discharge. We should suspect paraquat-associated HUS when thrombocytopenia and anemia are maintained for a long time after paraquat intoxication.
Asunto(s)
Síndrome Hemolítico-Urémico/inducido químicamente , Síndrome Hemolítico-Urémico/terapia , Herbicidas/envenenamiento , Paraquat/envenenamiento , Anciano , Creatinina/sangre , Síndrome Hemolítico-Urémico/fisiopatología , Hemoperfusión , Herbicidas/farmacocinética , Humanos , Masculino , Paraquat/farmacocinética , Intercambio Plasmático , Diálisis Renal , Intento de SuicidioRESUMEN
AIMS: Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. METHODS: A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. RESULTS: The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 µg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. CONCLUSION: The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development.
Asunto(s)
Herbicidas/envenenamiento , Paraquat/farmacocinética , Paraquat/envenenamiento , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos BiológicosRESUMEN
Genetic variation in the multidrug resistance gene ABCB1, which encodes the efflux transporter P-glycoprotein (P-gp), has been associated with Parkinson disease. Our goal was to investigate P-gp transport of paraquat, a Parkinson-associated neurotoxicant. We used in vitro transport models of ATPase activity, xenobiotic-induced cytotoxicity, transepithelial permeability, and rhodamine-123 inhibition. We also measured paraquat pharmacokinetics and brain distribution in Friend leukemia virus B-type (FVB) wild-type and P-gp-deficient (mdr1a(-/-)/mdr1b(-/-)) mice following 10, 25, 50, and 100 mg/kg oral doses. In vitro data showed that: 1) paraquat failed to stimulate ATPase activity; 2) resistance to paraquat-induced cytotoxicity was unchanged in P-gp-expressing cells in the absence or presence of P-gp inhibitors GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] and verapamil-37.0 [95% confidence interval (CI): 33.2-41.4], 46.2 (42.5-50.2), and 34.1 µM (31.2-37.2)-respectively; 3) transepithelial permeability ratios of paraquat were the same in P-gp-expressing and nonexpressing cells (1.55 ± 0.39 and 1.39 ± 0.43, respectively); and 4) paraquat did not inhibit rhodamine-123 transport. Population pharmacokinetic modeling revealed minor differences between FVB wild-type and mdr1a(-/-)/mdr1b(-/-) mice: clearances of 0.47 [95% confidence interval (CI): 0.42-0.52] and 0.78 l/h (0.58-0.98), respectively, and volume of distributions of 1.77 (95% CI: 1.50-2.04) and 3.36 liters (2.39-4.33), respectively; however, the change in clearance was in the opposite direction of what would be expected. It is noteworthy that paraquat brain-to-plasma partitioning ratios and total brain accumulation were the same across doses between FVB wild-type and mdr1a(-/-)/mdr1b(-/-) mice. These studies indicate that paraquat is not a P-gp substrate. Therefore, the association between ABCB1 pharmacogenomics and Parkinson disease is not attributed to alterations in paraquat transport.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Células Epiteliales/efectos de los fármacos , Herbicidas/farmacocinética , Paraquat/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Transporte Biológico/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Colorantes Fluorescentes/metabolismo , Herbicidas/administración & dosificación , Herbicidas/metabolismo , Herbicidas/farmacología , Masculino , Moduladores del Transporte de Membrana/farmacología , Ratones , Ratones Noqueados , Paraquat/administración & dosificación , Paraquat/metabolismo , Paraquat/farmacología , Enfermedad de Parkinson/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Rodamina 123/metabolismo , Sus scrofa , Distribución Tisular , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Paraquat (PQ) is a widely used, highly toxic and non-selective contact herbicide, which has been associated with central neurotoxic effects, namely the development of Parkinson's disease, but whose effects to the blood-brain barrier (BBB) itself have rarely been studied. This work studied the mechanisms of PQ uptake and efflux in a rat's BBB cell model, the RBE4 cells. PQ is believed to enter cells using the basic or neutral amino acid or polyamine transport systems or through the choline-uptake system. In contrast, PQ efflux from cells is reported to be mediated by P-glycoprotein. Therefore, we evaluated PQ-induced cytotoxicity and the effect of some substrates/blockers of these transporters (such as arginine, L-valine, putrescine, hemicholinium-3 and GF120918) on such cytotoxicity. RBE4 cells were shown to be extremely resistant to PQ after 24 h of exposure; even at concentrations as high as 50 mM approximately 45% of the cells remained viable. Prolonging exposure until 48 h elicited significant cytotoxicity only for PQ concentrations above 5 mM. Although hemicholinium-3, a choline-uptake system inhibitor, significantly protected cells against PQ-induced toxicity, none of the effects were observed for arginine, L-valine or putrescine. Meanwhile, inhibiting the efflux pump P-glycoprotein using GF120918 significantly enhanced PQ-induced cytotoxicity. In conclusion, PQ used the choline-uptake system, instead of the transporters for the basic or neutral amino acids or for the polyamines, to enter RBE4 cells. P-glycoprotein extrudes PQ back to the extracellular medium. However, this efflux mechanism only partially explains the observed RBE4 resistance to PQ.
Asunto(s)
Herbicidas/toxicidad , Paraquat/toxicidad , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/efectos de los fármacos , Línea Celular , Colina/metabolismo , Células Endoteliales/efectos de los fármacos , Paraquat/farmacocinética , RatasRESUMEN
BACKGROUND: Paraquat is a highly toxic herbicide, which not only leads to acute organ damage, but also to pulmonary fibrosis. There are only anecdotal reports of rescue lung transplantation, as paraquat is stored and only slowly released from different tissues. Bridging the time to complete depletion of paraquat from the body could render this exceptional therapy strategy possible, but not much is known on the time interval after which transplantation can safely be performed. CASE PRESENTATION: We report on a case of accidental paraquat poisoning in a 23 years old Caucasian man, who developed respiratory failure due to pulmonary fibrosis. The patient was listed for high urgency lung transplantion, and extracorporeal membrane oxygenation was implemented to bridge the time to transplantation. The patient died 32 days after paraquat ingestion, before a suitable donor organ was found. In postmortem tissue specimen, no paraquat was detectable anymore. CONCLUSION: This case report indicates that complete elimination of paraquat after oral ingestion of a lethal dose is achievable. The determined time frame for this complete elimination might be relevant for patients, in which lung transplantation is considered.
Asunto(s)
Oxigenación por Membrana Extracorpórea/métodos , Trasplante de Pulmón , Paraquat , Fibrosis Pulmonar/terapia , Insuficiencia Respiratoria/terapia , Adulto , Resultado Fatal , Humanos , Masculino , Paraquat/farmacocinética , Paraquat/envenenamiento , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/metabolismo , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/metabolismo , Factores de Tiempo , Distribución Tisular , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
The pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25 mg/kg/week. Approximately 0.3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks. PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum. There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc). There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH(+)) neurons. There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays. Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168 h after 1, 2 or 3 doses of PQ. In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 10mg/kg/dose×4 doses, 2 h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing. The number of TH(+) neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum. MPTP-mediated cell death was not attributed to apoptosis. MPTP activated microglia and astrocytes within 4 h of the last dose, reaching a peak within 48 h. The microglial response ended by 96 h in the SNpc, but the astrocytic response continued through 168 h in the striatum. These results bring into question previous published stereological studies that report loss of TH(+) neurons in the SNpc of PQ-treated mice. This study also suggests that even if the reduction in TH(+) neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Herbicidas/farmacocinética , Herbicidas/toxicidad , Paraquat/farmacocinética , Paraquat/toxicidad , Sustancia Negra/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacocinética , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Ganglios Basales/metabolismo , Ganglios Basales/patología , Muerte Celular/efectos de los fármacos , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Semivida , Herbicidas/administración & dosificación , Ácido Homovanílico/metabolismo , Inyecciones Intraperitoneales , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Degeneración Nerviosa , Paraquat/administración & dosificación , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Paraquat (PQ) is a potent toxicant for humans, and poisoning with PQ is associated with high mortality. Patients with severe PQ-induced poisoning may die of multiple organ failure involving the circulatory and respiratory systems. Death resulting from epilepsy-like convulsions, which are infrequently noted reported with PQ poisoning, is observed clinically with this condition. This study presents the clinical data of five patients with severe PQ-induced poisoning who died of epilepsy-like convulsions, and related publications were reviewed in order to investigate the pathogenesis, clinical manifestations, and prognosis of these convulsions. Our results may help prevent this event and improve the success of treatment.
Asunto(s)
Barrera Hematoencefálica , Paraquat/envenenamiento , Convulsiones/patología , Adulto , Resultado Fatal , Femenino , Humanos , Paraquat/farmacocinética , Convulsiones/inducido químicamente , Tomógrafos Computarizados por Rayos X , Adulto JovenRESUMEN
OBJECTIVE: This study was aimed to analyze the scavenging effect of haemoperfusion on plasma paraquat (PQ) and to evaluate the clinical significance of PQ examination in the treatment of patients with acute paraquat poisoning. METHODS: 85 patients with acute paraquat intoxication by oral ingestion were admitted in West China Hospital from Jun, 2010 to Mar, 2011. A standardized therapeutic regimen including emergency haemoperfusion was given on all subjects. A total of 91 whole blood samples were taken before (0 h), underway (1 h after haemoperfusion beginning) and at the end (2 h) of the haemoperfusion therapy. The clearance rate was calculated and related factors were analyzed. RESULTS: As heamoperfusion was going on, the plasma paraquat concentration of the patients kept falling down. After 1 hour of haemoperfusion, the average clearance rate (R(1)) was 37.06±21.81%. After 2 hours of haemoperfusion, the average clearance rate (R(2)) was 45.99±23.13%. The average of R(1)/R(2) ratio was 76.61±22.80%. In the high paraquat concentration group (plasma paraquat concentration (C(0)) >300 ng/mL), both the averages of R(1) and R(2) were significantly higher than those of the low paraquat concentration group (C(0)≤200 ng/mL) (p<0.05), and there was no significant difference of R(1)/R(2) between these two groups (p>0.05). CONCLUSIONS: The dynamic monitoring of plasma PQ concentration was not only critical in the clinical evaluation but also helpful in guiding the treatment of patients with acute PQ intoxication. Haemoperfusion can effectively eliminate paraquat from the plasma in patients with high initial plasma PQ concentration, while in patients with low initial plasma PQ concentration (<200 ng/ml), the clearance effect of harmoperfusion was very limited. Increasing HP time might improve the overall clearance rate of HP on plasma PQ yet decrease the elimination efficiency of HP, while repeated HP treatment was helpful against the rebound phenomena.
Asunto(s)
Hemoperfusión , Herbicidas/sangre , Herbicidas/envenenamiento , Paraquat/sangre , Paraquat/envenenamiento , Adolescente , Adulto , Femenino , Herbicidas/farmacocinética , Humanos , Masculino , Paraquat/farmacocinética , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
Most human health risk assessments are based on animal studies that can be conducted under conditions where exposure to multiple doses of a single chemical can be controlled. Data from epidemiology studies also provide valuable information about human exposure and response to pesticides. Human studies have the potential of evaluating neurobehavioral and other outcomes that may be more difficult to evaluate in animals. The human data together with animal data can contribute to a weight-of-evidence analysis in the characterization of human health risks. Epidemiology data do, however, pose challenges with respect to characterizing human health risks. Similarly, animal data at high doses or routes of exposure not typical for humans also pose challenges to dose-response evaluations needed for risk assessments. This paper summarizes some of the presentations given at a symposium held at the Xi'an, China, International Neurotoxicology Conference held in June 2011. This symposium brought together scientists from government, industry and academia to discuss approaches to evaluating and conducting animal and human neurotoxicity studies for risk assessment purposes, using the pesticides paraquat and chlorpyrifos as case studies.
Asunto(s)
Diseño de Investigaciones Epidemiológicas , Síndromes de Neurotoxicidad/epidemiología , Pruebas de Toxicidad , Animales , Cloropirifos/efectos adversos , Cloropirifos/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Modelos Animales , Paraquat/efectos adversos , Paraquat/farmacocinética , Plaguicidas/efectos adversos , Plaguicidas/farmacocinética , Medición de Riesgo , Factores de Riesgo , Pruebas de Toxicidad/métodosRESUMEN
Paraquat poisoning in Germany is rare. Because plasma levels do not necessarily match the ingested amount of paraquat, repeated measurement of plasma levels is imperative. There is a large potential in the prehospital phase to improve prognosis: further resorption must be terminated by rigorous charcoal administration and early tracheal intubation if necessary. Because paraquat can be resorbed by dermal contact, steps to ensure sufficient protection of emergency medical personnel must be taken.As soon as further resorption has been prevented sufficiently, forced diuresis, renal replacement therapy, and hemoperfusion can be of help, but still remain controversial. To reduce pulmonary fibrosis, inspiratory oxygen concentrations must be adjusted to the minimal amount needed to ensure satisfactory tissue oxygenation. Data supporting the advantageous use of cyclophosphamide combined with methylprednisolone for the treatment of pulmonary fibrosis were recently published. Since the toxic mechanism implies a mismatch of oxidants and anti-oxidants, co-administration of ascorbic acid and N-acetylcysteine are simple treatments with few side effects.
Asunto(s)
Cuidados Críticos/métodos , Herbicidas/envenenamiento , Paraquat/envenenamiento , Intento de Suicidio/prevención & control , Acetilcisteína/administración & dosificación , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/terapia , Lesión Pulmonar Aguda , Adulto , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Terapia Combinada/métodos , Sedación Consciente , Conducta Cooperativa , Relación Dosis-Respuesta a Droga , Servicios Médicos de Urgencia/métodos , Esofagoscopía , Esófago/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Hemofiltración , Herbicidas/farmacocinética , Humanos , Comunicación Interdisciplinaria , Ventilación con Presión Positiva Intermitente , Mucosa Intestinal/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica/fisiología , Terapia por Inhalación de Oxígeno , Paraquat/farmacocinética , Pronóstico , Edema Pulmonar/prevención & controlRESUMEN
Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12-24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF-κB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two-compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment.
Asunto(s)
Herbicidas/envenenamiento , Paraquat/envenenamiento , Compuestos de Aluminio/administración & dosificación , Antídotos/uso terapéutico , Carbón Orgánico/administración & dosificación , Herbicidas/farmacocinética , Humanos , Inmunosupresores/administración & dosificación , Absorción Intestinal/efectos de los fármacos , Compuestos de Magnesio/administración & dosificación , Paraquat/farmacocinética , Intoxicación/terapia , Silicatos/administración & dosificación , Tasa de SupervivenciaRESUMEN
Prenatal in utero conditions are thought to play a role in the development of adult diseases including Parkinson's disease (PD). Paraquat is a common herbicide with chemical structure similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, a neurotoxin known to induce parkinsonism. In order to assess the role of in utero paraquat exposure in PD, uptake in maternal and fetal brains were measured using positron emission tomography (PET)/computed tomography (CT) imaging. Two anesthetized pregnant rhesus macaques in the late second trimester of pregnancy were given bolus iv injections of ¹¹C-paraquat, and whole-body PET/CT imaging was performed. Using maternal ventricular blood pool as the input function, the unidirectional influx rate constants (K(i)s), a measure of the irreversible transport of paraquat from plasma to brain, were calculated for the maternal and fetal brains using Patlak graphical analysis. Results indicate minimal uptake of paraquat by both maternal and fetal brains with average K(i)s of 0.0009 and 0.0016 per minute, respectively. The highest regional cerebral uptake in the maternal brain (0.0009% injected dose) was seen in the pineal gland, a structure known to lack a blood brain barrier. The finding of minimal paraquat uptake in maternal and fetal brains is similar to previous findings in adult male macaques and extends the contention that a single acute paraquat exposure, prenatally or postnatally, is unlikely to play a role in PD.
Asunto(s)
Encéfalo/metabolismo , Feto/efectos de los fármacos , Imagen Multimodal/métodos , Paraquat/farmacocinética , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Femenino , Macaca mulatta , Paraquat/toxicidad , EmbarazoRESUMEN
The p-sulfonatocalix[n]arenes are supposed to show potential application in the clinical treatment of viologen poisoning. In the present study, p-sulfonatocalix[4]arene (C4AS), the most common derivative of p-sulfonatocalix[n]arenes, is used to study the antidotic mechanism for paraquat (PQ) by pharmacokinetics in vivo. A high-performance liquid chromatography (HPLC) method was established to determine the concentration of PQ in rat plasma. The results showed that the peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-t)) were significantly lower after C4AS intervention than in the PQ intoxication group. It was considered that C4AS has great effective detoxication to PQ poisoning, and the results of in vitro intestinal absorption studies showed that C4AS can inhibit the absorption of PQ via oral administration by forming a stable inclusion constant.