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1.
AIDS ; 38(8): 1248-1256, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38518076

RESUMEN

OBJECTIVE: We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations. DESIGN: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020). METHODS: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa. RESULTS: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( ß â€Š= 0.77, 95% CI = 0.70-0.84, P  < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ  = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ  = 0.83, 95% CI 0.76-0.90). CONCLUSION: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Humanos , Profilaxis Pre-Exposición/métodos , Masculino , Países Bajos , Infecciones por VIH/prevención & control , Estudios Prospectivos , Adulto , Fármacos Anti-VIH/administración & dosificación , Organofosfatos/administración & dosificación , Adenina/análogos & derivados , Adenina/administración & dosificación , Adenina/farmacocinética , Homosexualidad Masculina , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Autoinforme , Tenofovir/administración & dosificación , Pruebas con Sangre Seca
2.
Chem Res Toxicol ; 34(12): 2500-2511, 2021 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-34847329

RESUMEN

Triphenyl phosphate (TPhP) is a broad-spectrum organophosphate compound widely used as an additive in several products to prevent ignition. However, its utilization produces a hazardous impact on various organisms. So far, very few studies have investigated the acute toxicity of TPhP at environmentally relevant concentrations in nontarget aquatic species. This study aimed to assess whether the short-term exposure of TPhP (4, 20, and 100 µg L-1) affects the oxidative stress, antioxidant activity, biomolecule metabolism, DNA stability, chromosomal integrity, apoptosis, and pathological changes in various organs of Labeo rohita fingerlings. The results illustrated that the reactive oxygen species (ROS) production and lipid peroxidation (LPO) rates were significantly higher in tissues (brain, liver, and kidney) of TPhP-treated groups. Interestingly, superoxide dismutase (SOD) and catalase (CAT) activities were remarkably decreased in tissues following TPhP exposure. The levels of protein, glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in various tissues were also found to be significantly altered in TPhP-exposed fish fingerlings. These significant alterations in the antioxidant system and biochemical profile induced genotoxic responses such as DNA and chromosomal damage in the fish fingerlings. Furthermore, the incidence of the observed genotoxic responses was also found to be dose-dependent. Likewise, the apoptotic responses were also significantly altered following TPhP acute exposure in L. rohita fingerlings. The subsequent effects on oxidative stress, antioxidant inhibition, dysregulated biomolecule metabolism, and genotoxicity might be the possible reason for the observed pathological changes in various tissues of L. rohita. Taken together, the present findings showed that the toxicity of TPhP is principally associated with exposure concentrations. Therefore, this study illustrates the toxicity risks of TPhP to vertebrate organisms at real-world concentrations.


Asunto(s)
Encéfalo/efectos de los fármacos , Riñón/efectos de los fármacos , Organofosfatos/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Carpas , Daño del ADN , Relación Dosis-Respuesta a Droga , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Estructura Molecular , Organofosfatos/administración & dosificación , Organofosfatos/química , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
3.
Commun Biol ; 4(1): 1161, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34620990

RESUMEN

Recent data show that parasites manipulate the physiology of mosquitoes and human hosts to increase the probability of transmission. Here, we investigate phagostimulant activity of Plasmodium-metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), in the primary vectors of multiple human diseases, Anopheles coluzzii, An. arabiensis, An. gambiae s.s., Aedes aegypti, and Culex pipiens/Culex torrentium complex species. The addition of 10 µM HMBPP to blood meals significantly increased feeding in all the species investigated. Moreover, HMBPP also exhibited a phagostimulant property in plant-based-artificial-feeding-solution made of beetroot juice adjusted to neutral pH similar to that of blood. The addition of AlbuMAXTM as a lipid/protein source significantly improved the feeding rate of An. gambiae s.l. females providing optimised plant-based-artificial-feeding-solution for delivery toxins to control vector populations. Among natural and synthetic toxins tested, only fipronil sulfone did not reduce feeding. Overall, the toxic-plant-based-artificial-feeding-solution showed potential as an effector in environmentally friendly vector-control strategies.


Asunto(s)
Aedes/fisiología , Anopheles/fisiología , Culex/fisiología , Mosquitos Vectores/fisiología , Organofosfatos/administración & dosificación , Plasmodium falciparum/química , Aedes/efectos de los fármacos , Animales , Anopheles/efectos de los fármacos , Sangre , Culex/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Interacciones Microbiota-Huesped , Mosquitos Vectores/efectos de los fármacos , Organofosfatos/metabolismo
4.
Neurotoxicology ; 87: 149-155, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34582899

RESUMEN

Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children's cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior.


Asunto(s)
Inteligencia/efectos de los fármacos , Organofosfatos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Adulto , Niño , Femenino , Humanos , Pruebas de Inteligencia , Masculino , Organofosfatos/administración & dosificación , Embarazo
5.
Mol Cancer Ther ; 20(8): 1454-1461, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34108261

RESUMEN

Everolimus monotherapy use for metastatic renal cell carcinoma (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients. To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent, were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus + BNC105P. Median PFS (mPFS) was 4.9 (95% CI, 2.8-6.2) months. A four-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus ± BNC105P [AUC, 86.9% (95% CI, 79.2-94.7)]. This was validated in 130 patients from CheckMate 025 treated with everolimus [AUC, 60.2% (95% CI, 49.7-70.7)]. Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus + BNC105P was associated with significantly longer mPFS compared with everolimus alone (10.4 vs. 6.9 months; HR, 0.49; 95% CI, 0.24-1.002; P = 0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a vascular disrupting agent.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Transcriptoma , Anciano , Anciano de 80 o más Años , Benzofuranos/administración & dosificación , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Ensayos Clínicos Fase III como Asunto , Everolimus/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Organofosfatos/administración & dosificación , Pronóstico , Tasa de Supervivencia , Estudios de Validación como Asunto
6.
AAPS PharmSciTech ; 22(2): 62, 2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33528714

RESUMEN

Nowadays, the incidence of acute bacterial skin and skin structure infection (ABSSSI) is increasing. The increased bioavailability and reduced drug resistance of antibiotics are crucial to obtain a more effective treatment response in these infections. These favorable properties could be achieved by different drug delivery systems such as liposomes. In this study, nanosized, radiolabeled tedizolid phosphate liposomal formulations were prepared and evaluated with their in vitro cellular binding capacity and biocompatible profile for topical treatment of ABSSSI. Liposomes were characterized by evaluation of their visual inspection, particle size (about 190-270 nm), zeta potential value (around 0), and encapsulation efficiency (nearly 10%). The release rate of tedizolid phosphate from liposomes was also studied using dialysis membranes and evaluated kinetically. The stability of formulations was observed at three different temperatures and humidity conditions for 28 days. Afterward, liposomes were labeled with 99mTc, and the optimal amount of reducing agent (stannous chloride) was determined as 500 µg in this direct labeling procedure. All liposome formulations were successfully radiolabeled with high efficiency and exhibited high radiochemical purity (> 80%) during 6 h in different media. Furthermore, the cellular bindings of liposomal formulations were evaluated in human skin fibroblast cells by measuring the radioactivity. Higher radioactivity values were obtained in CCD-1070Sk cells incubated by liposome formulations compared to sodium pertechnetate. This finding suggested that liposomal formulation increased the cellular binding of radioactivity. By the result of our study, nanosized, tedizolid phosphate encapsulated liposome formulation was found to be a favorable carrier system in the treatment of ABSSSI.


Asunto(s)
Antibacterianos/administración & dosificación , Organofosfatos/administración & dosificación , Organofosfatos/farmacocinética , Oxazoles/administración & dosificación , Oxazoles/farmacocinética , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Tecnecio/farmacocinética , Administración Tópica , Animales , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Liposomas/administración & dosificación , Liposomas/farmacocinética , Organofosfatos/química , Oxazoles/química
7.
Expert Rev Anti Infect Ther ; 19(8): 961-966, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33331202

RESUMEN

Introduction: For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side effects, past intolerance, and administration inability contribute to the need for novel drug classes in this population.Areas Covered: Herein, we review the pharmacology, clinical efficacy, and safety profile of fostemsavir, a first in its class attachment inhibitor recently FDA approved for use.Expert Opinion: Fostemsavir is a well-tolerated oral medication with relatively few drug-drug interactions. Clinical trial data demonstrates virologic and notable immunologic response in conjunction with optimal background therapy in HTE persons living with HIV. Fostemsavir exhibits no cross-resistance with other ARV classes and thus is an important advancement for patients harboring drug-resistant HIV. Further study will be needed to determine outstanding clinical questions such as the role of drug resistance testing and fostemsavir use outside of the HTE population.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Organofosfatos/administración & dosificación , Piperazinas/administración & dosificación , Administración Oral , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Organofosfatos/efectos adversos , Organofosfatos/farmacología , Piperazinas/efectos adversos , Piperazinas/farmacología
8.
Neurotoxicol Teratol ; 83: 106945, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33333156

RESUMEN

Organophosphorus flame retardants (OPFRs) have been extensively used as chemical additives in polymer based consumer products. Among them, Isopropylphenyl phosphate (IPPP) and tripropyl phosphate (TPP) are predominant, which have potential to cause neuro-toxic effects on non-target organisms. As behavior (swimming activity) response is the first adjustment due to neurotoxic stress on the fitness of fish. In this study, the quantified swimming activity of zebrafish (Danio rerio) under IPPP and TPP exposure in an online monitoring system was investigated to assess the neurotoxin effects under long-term exposure periods, no swimming anomalies were observed in the control group. Whereas, in the OPFR exposures ((treatment I: 5 µg/L and treatment II: 25 µg/L), a series of anomalies were identified. Hyperactivity was shown in IPPP treatment I group (5 µg/L), whereas zebrafish swimming activity was declined throughout the study period in IPPP treatment II (25 µg/L), and TPP groups (5 µg/L and 25 µg/L) when compared to the control group. Circadian rhythm was not affected in the present study. The results of the present study indicated that the fitness of test individuals was a valid biomarker for eco-toxicity assessment under unescapable conditions. Hypoactivity of zebrafish signified the neurotoxic effects of IPPP and TPP. A concentration based improvement in swimming activity was observed under recovery conditions, which suggested that recovery capacity along with toxicity responses could be a comprehensive non-invasive technique to assess the eco-toxicity of waterborne chemicals.


Asunto(s)
Conducta Animal/efectos de los fármacos , Organofosfatos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiología , Animales , Conducta Animal/fisiología , Retardadores de Llama/administración & dosificación , Retardadores de Llama/toxicidad , Neurotoxinas/toxicidad , Organofosfatos/administración & dosificación , Esfuerzo Físico/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Natación/fisiología , Factores de Tiempo , Contaminantes Químicos del Agua/administración & dosificación
9.
Lancet HIV ; 7(11): e740-e751, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33128903

RESUMEN

BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.


Asunto(s)
Inhibidores de Fusión de VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Organofosfatos/administración & dosificación , Piperazinas/administración & dosificación , Adulto , Fármacos Anti-VIH/administración & dosificación , Recuento de Linfocito CD4 , Farmacorresistencia Viral Múltiple , Femenino , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Profármacos/administración & dosificación , Seguridad , Resultado del Tratamiento , Carga Viral/efectos de los fármacos
10.
Nat Commun ; 11(1): 4885, 2020 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-32985503

RESUMEN

Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/administración & dosificación , Neuronas Dopaminérgicas/efectos de los fármacos , Organofosfatos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Sustancias Protectoras/administración & dosificación , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Humanos , Masculino , Ratones , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Agregado de Proteínas/efectos de los fármacos , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
12.
Pharmazie ; 75(5): 172-176, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32393422

RESUMEN

This is a report on the chemical stability and physical compatibility of intravenous tedizolid phosphate 0.8 mg/mL-sodium rifampicin 2.4 mg/mL and tedizolid phosphate 0.8 mg/mL-meropenem 4 mg/mL combinations in polypropylene 0.9% sodium chloride infusion bags stored at different storage conditions. Triplicate solutions of both admixtures were prepared in 0.9% sodium chloride polypropylene infusion bags and stored under light protection at room temperature (25±2 °C), refrigeration (2-8 °C) or freezing (-15 - -25 °C) conditions. The study was performed using a validated and stability-indicating liquid chromatography (LC) method. For both admixtures and for all storage conditions, at least 90% of the initial drug concentration of tedizolid phosphate remained unchanged throughout the entire study period. Stability of sodium rifampicin at 25±2 °C was determined to be seven hours and six days when it was stored at 2-8 °C. Under the same storage conditions, meropenem was stable for 12 h or 6 days, respectively. Under freezing conditions, sodium rifampicin was stable throughout all 28 days, while stability of meropenem was only 8 days. Solutions of 0.8 mg/mL tedizolid phosphate admixtured with 2.4 mg/mL rifampicin or 4 mg/mL meropenem, in polypropylene 0.9% sodium chloride infusion bags, are stable for at least 7 or 12 hours, respectively, when stored at 25±2 °C. When stored at 2-8 °C, stability was increased to 6 days for both admixtures.


Asunto(s)
Antibacterianos/química , Meropenem/química , Organofosfatos/química , Oxazoles/química , Rifampin/química , Antibacterianos/administración & dosificación , Cromatografía Liquida , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Congelación , Infusiones Intravenosas , Meropenem/administración & dosificación , Organofosfatos/administración & dosificación , Oxazoles/administración & dosificación , Polipropilenos/química , Refrigeración , Rifampin/administración & dosificación , Cloruro de Sodio/química , Temperatura , Factores de Tiempo
13.
Neuropharmacology ; 174: 108150, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32442543

RESUMEN

More frequent and widespread nerve agent attacks highlight the need for efficacious pre- and post-exposure organophosphate (OP) counter-measures to protect military and civilian populations. Because of critical targeting of acetylcholinesterase (AChE) in the CNS by OPs, a pre-treatment candidate for preventing/reducing poisoning will be a broadly acting molecule that scavenges OPs in blood before they reach their physiological targets. Prophylactic human butyrylcholinesterase (HuBChE), the leading pretreatment candidate, has been shown to protect against multiple LD50's of nerve agents in rodents, macaques, and minipigs. This review describes the development of a HuBChE bioscavenger pretreatment from early proof-of-concept studies to pre-clinical studies with the native injectable enzyme and the development of aerosolized forms of recombinant enzyme, which can be delivered by inhalation nebulizer devices, to effect protection against inhaled OP nerve agents and insecticides. Early animal studies utilized parenteral exposure. However, lungs are the portal of entry for most volatile OP vapors and represent the major means of OP intoxication. In this regard, pretreat-ment with 7.5 mg/kg of HuBChE by IM injection protected minipigs against lethal sarin vapor and prevented AChE inhibition in the blood. This is similar to the five-day protection in macaques by an aerosolized rHuBChE using a nebulizer against aerosolized paraoxon (estimated to be an 8 mg/kg estimated human dose). Importantly, lethal inhaled doses of OP may be smaller relative to the same dose delivered by injection, thus reducing the protective HuBChE dose, while a combination of HuBChE and post-exposure oxime may prolong protection.


Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/administración & dosificación , Exposición por Inhalación , Organofosfatos/administración & dosificación , Animales , Inhibidores de la Colinesterasa/toxicidad , Humanos , Exposición por Inhalación/efectos adversos , Macaca , Organofosfatos/toxicidad , Especificidad de la Especie , Porcinos , Porcinos Enanos
14.
J Vet Med Sci ; 82(5): 598-606, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32213749

RESUMEN

Four commonly used organophosphates (fenitrothion, dichlorvos, chlorpyrifos, and trichlorfon) were orally administered to male Sprague-Dawley rats for five days in order to explore their effects on the activities of liver cytochrome P450 (CYP). In addition, Michaelis-Menten kinetics of the metabolic reactions catalyzed by liver CYPs were analyzed following the addition of these compounds to the assay system to examine their potential inhibitory effects on liver CYPs activities. These reactions included ethoxyresorufin O-deethylation, midazolam 4-hydroxylation, tolbutamide hydroxylation, and bufuralol 1'-hydroxylation for CYP1A, 3A, 2C, and 2D activities, respectively. Total CYP content was also examined after oral administration of each organophosphate. Results revealed that oral giving of fenitrothion inhibited significantly CYP1A and 3A activities while elevated activity of CYP2C. Fenitrothion is a potent inhibitor for CYP1A and 2C with Ki values of 0.42 and 36.1 µM, respectively but had a weak inhibitory effect on CYP2D and 3A with Ki values of 290 and 226 µM, respectively. Chlorpyrifos is a potent inhibitor of CYP1A with Ki 0.24 µM and moderately inhibited CYP2C or 3A with Ki values of 84.8 and 77.7 µM, respectively. On the other hand, dichlorvos and trichlorfon caused extremely low or negligible inhibition of different CYP activities. From these results, it is concluded that both fenitrothion and chlorpyrifos may increase the toxicity of chemicals in environmental living organisms through their potent inhibitory effects on these CYP activities, but dichlorvos and trichlorfon may not.


Asunto(s)
Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Hígado/enzimología , Organofosfatos/farmacología , Administración Oral , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Masculino , Organofosfatos/administración & dosificación , Farmacocinética , Ratas Sprague-Dawley
15.
Mol Ther ; 28(4): 1167-1176, 2020 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-32087148

RESUMEN

Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of the autophagy-lysosomal pathway (ALP) often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, prion protein (PrP), Tau, and amyloid ß progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a "molecular tweezer" that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of the ALP was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting the ALP and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs.


Asunto(s)
Autofagia/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Mucopolisacaridosis III/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Organofosfatos/administración & dosificación , Amiloide/antagonistas & inhibidores , Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Hidrocarburos Aromáticos con Puentes/farmacología , Cuerpo Celular/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/metabolismo , Enfermedades Neurodegenerativas/etiología , Organofosfatos/farmacología , Resultado del Tratamiento
16.
Clin Transl Sci ; 13(4): 769-776, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32027457

RESUMEN

Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure-response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (Cmax ) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503).


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Síndrome de QT Prolongado/diagnóstico , Organofosfatos/efectos adversos , Piperazinas/efectos adversos , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Farmacorresistencia Viral Múltiple , Quimioterapia Combinada , Electrocardiografía/efectos de los fármacos , Femenino , VIH-1/efectos de los fármacos , Humanos , Síndrome de QT Prolongado/inducido químicamente , Masculino , Persona de Mediana Edad , Organofosfatos/administración & dosificación , Piperazinas/administración & dosificación , Profármacos/administración & dosificación , Profármacos/efectos adversos , Adulto Joven
17.
J Acquir Immune Defic Syndr ; 83(2): 173-180, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31929405

RESUMEN

BACKGROUND: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration. METHODS: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression. RESULTS: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively. CONCLUSIONS: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.


Asunto(s)
Adenina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Organofosfatos/uso terapéutico , Polifosfatos/uso terapéutico , Resultado del Embarazo , Adenina/administración & dosificación , Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Estudios de Casos y Controles , Cromatografía Liquida , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Femenino , Humanos , Modelos Logísticos , Lopinavir/uso terapéutico , Cumplimiento de la Medicación , Organofosfatos/administración & dosificación , Polifosfatos/administración & dosificación , Embarazo , Complicaciones del Embarazo , Estudios Retrospectivos , Ritonavir/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico
18.
J Appl Toxicol ; 40(5): 600-618, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31884710

RESUMEN

Tris(2-ethylhexyl) phosphate (TEHP, CAS no. 78-42-2) is a plasticizer and a flame retardant, while di(2-ethylhexyl) phosphoric acid (DEHPA, CAS no. 298-07-7) is an oil additive and extraction solvent. Publicly-available information on repeated exposure to these two related organophosphate compounds is fragmentary. Hence, adult male and female Fischer rats were exposed to TEHP (300, 1000 and 3000 mg/kg body weight [BW]/day) or DEHPA (20, 60 and 180 mg/kg BW/day) by gavage for 28 consecutive days, to assess and compare their toxicities. Although significantly impaired BW gains and evidence of TEHP enzymatic hydrolysis to DEHPA were observed only in males, exposures to the highest TEHP and DEHPA doses often resulted in similar alterations of hematology, serum clinical chemistry and liver enzymatic activities in both males and females. The squamous epithelial hyperplasia and hyperkeratosis observed in the non-glandular forestomach of rats exposed to the middle and high DEHPA doses were most likely caused by the slightly corrosive nature of this chemical. Although tubular degeneration and spermatid retention were observed only in the testes of males exposed to the highest TEHP dose, numerous periodic acid-Schiff stained crystalline inclusions were observed in testis interstitial cells at all TEHP dose levels. No-observed-adverse-effect levels for TEHP and DEHPA are proposed, but the lower serum pituitary hormone levels resulting from TEHP and DEHPA exposures and the perturbations of testicular histology observed in TEHP-treated males deserve further investigation. Improved characterization of the toxicity of flame retardants will contribute to better informed substitution choices for legacy flame retardants phased-out over health concerns.


Asunto(s)
Retardadores de Llama/toxicidad , Organofosfatos/toxicidad , Plastificantes/toxicidad , Solventes/toxicidad , Administración Oral , Animales , Biomarcadores/sangre , Biomarcadores/orina , Femenino , Retardadores de Llama/administración & dosificación , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos , Organofosfatos/administración & dosificación , Plastificantes/administración & dosificación , Ratas Endogámicas F344 , Medición de Riesgo , Solventes/administración & dosificación , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , Factores de Tiempo , Pruebas de Toxicidad
19.
Toxicology ; 425: 152250, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31326399

RESUMEN

Evidence suggests that low concentration perinatal exposure to environmental contaminants, such as organophosphate (OP) is associated with later life insulin resistance and type 2 diabetes. The aim of this work was to investigate whether chronic maternal OP exposure exacerbates metabolic dysfunctions in early-overfed rats. During pregnancy and lactational periods, dams received OP by gavage. To induce neonatal overnutrition at postnatal day 3, pups were standardized to 9 or 3 per nest. At 90-days-old, glucose-insulin homeostasis and insulin release from pancreatic islets were analyzed. While both OP exposure and overfeeding alone did induce diabetogenic phenotypes in adulthood, there was no exacerbation in rats that experienced both. Unexpectedly, the group that experienced both had improved adiposity, metabolic parameters, attenuated insulin release from isolated islets in the presence of glucose and low function of muscarinic acetylcholine receptor M3, as well as an attenuation of beta cell mass hyperplasia. High levels of butyrylcholinesterase and low levels of insulin in milk may contribute to the OP-induced developmental programming. Our study showed that maternal OP exposure may program insulin release as well as endocrine pancreas structure, thus affecting metabolism in adulthood. Our data suggest that while perinatal OP exposure alone increases the risk for later life T2D, it actually reverses many of the programmed metabolic dysfunction that is induced by postnatal overfeeding. These surprising results may suggest that low-dose administration of acetylcholinesterase inhibitors could be of utility in preventing detrimental developmental programming that is caused by early-life overnutrition.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Exposición Materna , Enfermedades Metabólicas/tratamiento farmacológico , Organofosfatos/farmacología , Hipernutrición/tratamiento farmacológico , Animales , Animales Recién Nacidos , Glucemia/análisis , Composición Corporal/efectos de los fármacos , Inhibidores de la Colinesterasa/administración & dosificación , Ingestión de Energía/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Enfermedades Metabólicas/etiología , Organofosfatos/administración & dosificación , Hipernutrición/complicaciones , Embarazo , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Ratas , Ratas Wistar
20.
Sci Rep ; 9(1): 10530, 2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31324839

RESUMEN

Biomarkers are frequently used in ecotoxicology as they allow to study toxicant effects happening at low concentrations of exposure. However, most sublethal studies only evaluate cellular biomarkers which lack evident ecological relevance. We used a multibiomarker approach to estimate the toxic effects of ethoprophos, an organophosphate insecticide commonly used in banana plantations, on the tropical fish Astyanax aeneus (Characidae). We measured biomarkers at sub-individual (cellular) and individual (metabolism, behavior) levels and examined relationships among these responses. A sublethal exposure to ethoprophos caused a significant (54%) reduction of brain Cholinesterase (ChE) activity, reflecting the pesticide's high neurotoxicity. However, other biomarkers like oxidative stress, biotransformation reactions, and resting metabolic rate were not affected. Exposure to ethoprophos modified antipredator behaviors such as escape response and detection avoidance (light/dark preference): exposed fish escaped slower from a simulated attack and preferred brighter areas in a novel tank. The relationship between ChE activity and reaction time suggests that pesticide-induced ChE inhibition reduces escape ability in fish. Our results provide evidence that impacts of organophosphate pesticides on fish ecological fitness can occur even with short exposures at very low concentrations.


Asunto(s)
Characidae/fisiología , Reacción de Fuga/efectos de los fármacos , Insecticidas/toxicidad , Organofosfatos/toxicidad , Compuestos Organotiofosforados/toxicidad , Residuos de Plaguicidas/toxicidad , Conducta Predatoria , Contaminantes Químicos del Agua/toxicidad , Animales , Reacción de Prevención/efectos de los fármacos , Metabolismo Basal/efectos de los fármacos , Biomarcadores , Encéfalo/enzimología , Colinesterasas/análisis , Relación Dosis-Respuesta a Droga , Estuarios , Insecticidas/administración & dosificación , Luz , Proteínas Musculares/análisis , Músculo Esquelético/enzimología , Proteínas del Tejido Nervioso/análisis , Organofosfatos/administración & dosificación , Organotiofosfatos , Compuestos Organotiofosforados/administración & dosificación , Residuos de Plaguicidas/química , Contaminantes Químicos del Agua/química
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