RESUMEN
The most recent global health crisis caused by the SARS-CoV-2 outbreak and the alarming use of chemical warfare agents highlight the necessity to produce efficient protective clothing and masks against biohazard and chemical threats. However, the development of a multifunctional protective textile is still behind to supply adequate protection for the public. To tackle this challenge, we designed multifunctional and regenerable N-chlorine based biocidal and detoxifying textiles using a robust zirconium metal-organic framework (MOF), UiO-66-NH2, as a chlorine carrier which can be easily coated on textile fibers. A chlorine bleaching converted the amine groups located on the MOF linker to active N-chlorine structures. The fibrous composite exhibited rapid biocidal activity against both Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus) with up to a 7 log reduction within 5 min for each strain as well as a 5 log reduction of SARS-CoV-2 within 15 min. Moreover, the active chlorine loaded MOF/fiber composite selectively and rapidly degraded sulfur mustard and its chemical simulant 2-chloroethyl ethyl sulfide (CEES) with half-lives less than 3 minutes. The versatile MOF-based fibrous composite designed here has the potential to serve as protective cloth against both biological and chemical threats.
Asunto(s)
Antibacterianos/farmacología , Antivirales/farmacología , Sustancias para la Guerra Química/química , Cloro/farmacología , Estructuras Metalorgánicas/farmacología , Ropa de Protección , Animales , Antibacterianos/síntesis química , Antivirales/síntesis química , Línea Celular , Cloro/química , Escherichia coli/efectos de los fármacos , Halogenación , Humanos , Estructuras Metalorgánicas/síntesis química , Pruebas de Sensibilidad Microbiana , Gas Mostaza/análogos & derivados , Gas Mostaza/química , Oxidación-Reducción , SARS-CoV-2/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Textiles , Circonio/químicaRESUMEN
Organophosphorus nerve agents (OPNAs) are highly toxic compounds inhibiting cholinergic enzymes in the central and autonomic nervous systems and neuromuscular junctions, causing severe intoxications in humans. Medical countermeasures and efficient decontamination solutions are needed to counteract the toxicity of a wide spectrum of harmful OPNAs including G, V and Novichok agents. Here, we describe the use of engineered OPNA-degrading enzymes for the degradation of various toxic agents including insecticides, a series of OPNA surrogates, as well as real chemical warfare agents (cyclosarin, sarin, soman, tabun, VX, A230, A232, A234). We demonstrate that only two enzymes can degrade most of these molecules at high concentrations (25 mM) in less than 5 min. Using surface assays adapted from NATO AEP-65 guidelines, we further show that enzyme-based solutions can decontaminate 97.6% and 99.4% of 10 gâm-2 of soman- and VX-contaminated surfaces, respectively. Finally, we demonstrate that these enzymes can degrade ethyl-paraoxon down to sub-inhibitory concentrations of acetylcholinesterase, confirming their efficacy from high to micromolar doses.
Asunto(s)
Descontaminación/métodos , Enzimas/química , Insecticidas/química , Agentes Nerviosos/química , Compuestos Organofosforados/químicaRESUMEN
In recent years, Zr-based metal-organic frameworks (MOFs) have been developed that facilitate catalytic degradation of toxic organophosphate agents, such as chemical warfare agents (CWAs). Because of strict regulations, experiments using live agents are not possible for most laboratories and, as a result, simulants are used in the majority of cases. Reports that employ real CWAs are scarce and do not cover the whole spectrum of agents. We here present a comparative study in which UiO-66-NH2, NU-1000, MOF-808, and PCN-777 are evaluated for their effectiveness in the degradation of paraoxon and the chemical warfare agents tabun, VX, and soman, in N-ethylmorpholine buffer (pH 10) as well as in pure water. All MOFs showed excellent ability to degrade the agents under basic conditions. It was further disclosed that tabun is degraded by different mechanisms depending on the conditions. The presence of an amine, either as part of the MOF structure (UiO-66-NH2) or in the agent itself (VX, tabun), is the most important factor governing degradation rates in water. The results show that MOFs have great potential in future protective applications. Although the use of simulants provides valuable information for initial screening and selection of new MOFs, the use of live agents revealed additional mechanisms that should aid the future development of even better catalysts.
RESUMEN
The development of materials that enable the efficient removal of toxic compounds is important for the improvement of current protective materials or decontamination technologies. Current materials rely either on agent removal by adsorption or by effecting (catalytic) degradation. Ideally, both of these mechanisms are combined in a single material in order to target a more broad spectrum of toxic agents and to improve the performance of the materials. Recent attempts to combine materials with either adsorptive or catalytic properties into a composite material are promising, although the overall performance often suffers from competition for the agent between the adsorptive and catalytic domains in the composites. In this work, we propose that metal-organic frameworks (MOFs) could feature both adsorptive properties as well as catalytic properties in a single structural domain, thereby avoiding a reduction in the overall performance originating from competitive agent interactions. We showcase this concept using the MOF Ni3(BTP)2, which exhibits strong affinity and high capacity for the storage of a nerve agent simulant and a pesticide. Moreover, it is demonstrated that the adsorbed agents are efficiently degraded and that the nontoxic degradation products are rapidly expelled from the MOF pores. Its ability to catalyze the hydrolytic degradation of both organophosphate and organophosphorothioate compounds highlights another unique feature of this material. The presented concept illustrates the feasibility for developing materials that target a broader spectrum of agents via adsorption, catalysis, or both and by their broader reactivity toward different types of agents.
RESUMEN
The A-series is the most recent generation of chemical warfare nerve agents (CWA) which act directly on the inhibition of the human acetylcholinesterase (HssAChE) enzyme. These compounds lack accurate experimental data on their physicochemical properties, and there is no evidence that traditional antidotes effectively reactivate HssAChE inhibited by them. In the search for potential antidotes, we employed virtual screening, molecular docking, and molecular dynamics (MD) simulations for the theoretical assessment of the performance of a library of Mannich phenols as potential reactivators of HssAChE inhibited by the Novichok agents A-230, A-232, and A-234, in comparison with the commercial oximes pralidoxime (2-PAM), asoxime (HI-6), trimedoxime (TMB-4), and obidoxime. Following the near-attack conformation (NAC) approach, our results suggest that the compounds assessed would face difficulties in triggering the proposed nucleophilic in-line displacement mechanism. Despite this, it was observed that certain Mannich phenols presented similar or superior results to those obtained by reference oximes against A-232 and A-234 model, suggesting that these compounds can adopt more favourable conformations. Additional binding energy calculations confirmed the stability of the model/ligands complexes and the reactivating potential observed in the molecular docking and MD studies. Our findings indicate that the Mannich phenols could be alternative antidotes and that their efficacy should be evaluated experimentally against the A-series CWA.
Asunto(s)
Sustancias para la Guerra Química , Reactivadores de la Colinesterasa , Agentes Nerviosos , Humanos , Antídotos/farmacología , Reactivadores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Oximas/farmacología , Oximas/química , Trimedoxima/química , Trimedoxima/farmacología , Sustancias para la Guerra Química/farmacología , Compuestos de Piridinio/farmacologíaRESUMEN
Virucidal activity of immobilized quaternary ammonium compounds (IQACs) coated onto glass and plastic surfaces was tested against enveloped influenza A (H1N1) virus and nonenveloped poliovirus Sabin1. The IQACs tested were virucidal against the influenza virus within 2 min, but no virucidal effect against poliovirus was found in 6 h.
Asunto(s)
Antivirales/farmacología , Desinfectantes/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Poliovirus/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Vidrio/química , Humanos , Pruebas de Sensibilidad Microbiana , Plásticos/químicaRESUMEN
Novichoks are a novel class of nerve agents (also referred to as the A-series) that were employed in several poisonings over the last few years. This calls for the development of novel countermeasures that can be applied in protective concepts (e.g., protective clothing) or in decontamination methods. The Zr metal-organic framework MOF-808 has recently emerged as a promising catalyst in the hydrolysis of the V- and G-series of nerve agents as well as their simulants. In this paper, we report a detailed study of the degradation of three Novichok agents by MOF-808 in buffers with varying pH. MOF-808 is revealed to be a highly efficient and regenerable catalyst for Novichok agent hydrolysis under basic conditions. In contrast to the V- and G-series of agents, degradation of Novichoks is demonstrated to proceed in two consecutive hydrolysis steps. Initial extremely rapid P-F bond breaking is followed by MOF-catalyzed removal of the amidine group from the intermediate product. The intermediate thus acted as a competitive substrate that was rate-determining for the whole two-step degradation route. Under acidic conditions, the amidine group in Novichok A-230 is more rapidly hydrolyzed than the P-F bond, giving rise to another moderately toxic intermediate. This intermediate could in turn be efficiently hydrolyzed by MOF-808 under basic conditions. These experimental observations were corroborated by density functional theory calculations to shed light on molecular mechanisms.
RESUMEN
Metal-organic frameworks (MOFs) are a class of porous organic-inorganic solids extensively explored for numerous applications owing to their catalytic activity and high surface area. In this work MOF thin films deposited in a one-step, molecular layer deposition (MLD), an all-gas-phase process, on glass wool fibers are characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and their capabilities towards toxic industrial chemical (TIC) capture and chemical warfare agents (CWA) degradation are investigated. It is shown that despite low volume of the active material used, MOFs thin films are capable of removal of harmful gaseous chemicals from air stream and CWA from neutral aqueous environment. The results confirm that the MLD-deposited MOF thin films, amorphous and crystalline, are suitable materials for use in air filtration, decontamination, and physical protection against CWA and TIC.
RESUMEN
The RSDL® (Reactive Skin Decontamination Lotion) Kit contains a lotion-impregnated sponge extensively studied for the removal or neutralization of chemical warfare agents from skin. Pilot investigation of efficacy with industrial threat compounds noted that synthetic opioid fentanyl citrate was removed by the RSDL Kit but not chemically inactivated by the lotion. This implies that after use the RSDL Kit will contain intact fentanyl, which may pose a dermal health hazard if the fentanyl is then transferred to skin after use without proper handling. This in vitro investigation studied the contaminated RSDL Kit using three different concentrations of fentanyl with a skin contact time of 15 min under direct interaction from passive contact, light touch, and leaning with one hand. It was demonstrated that the expected transfer of fentanyl from contaminated RSDL depends on 1) the concentration of fentanyl and 2) the area of the exposed surface. From a toxicological perspective, the contact risk of fentanyl under the conditions tested can be considered low but not absent. The present study determined that a contaminated RSDL Kit, used for removal of fentanyl, should be handled with proper care. Use of protective gloves in operational use and washing skin afterwards is advised to prevent undesired contamination.
Asunto(s)
Analgésicos Opioides/efectos adversos , Analgésicos Opioides/análisis , Contaminación de Medicamentos , Fentanilo/efectos adversos , Fentanilo/análisis , Crema para la Piel/efectos adversos , Crema para la Piel/análisis , Animales , Sustancias para la Guerra Química/química , Técnicas In Vitro , Proyectos Piloto , Medición de Riesgo , Absorción Cutánea , PorcinosRESUMEN
Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich phenols can reactivate the inhibited enzyme very effectively, and may therefore represent an attractive complementary class of reactivators. In this paper we further probe the effect of structural variation on the in vitro efficacy of Mannich phenol based reactivators. Thus, we present the synthesis of 14 compounds that are close variants of the previously reported 4-amino-2-(1-pyrrolidinylmethyl)-phenol, a very effective non-oxime reactivator, and 3 dimeric Mannich phenols. All compounds were assessed for their ability to reactivate human acetylcholinesterase inhibited by the nerve agents VX, tabun, sarin, cyclosarin and paraoxon in vitro. It was confirmed that the potency of the compounds is highly sensitive to small structural changes, leading to diminished reactivation potency in many cases. However, the presence of 4-substituted alkylamine substituents (as exemplified with the 4-benzylamine-variant) was tolerated. More surprisingly, the dimeric compounds demonstrated non-typical behavior and displayed some reactivation potency as well. Both findings may open up new avenues for designing more effective non-oxime reactivators.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Agentes Nerviosos/química , Agentes Nerviosos/farmacología , Oximas/química , Oximas/farmacología , Sustancias para la Guerra Química/química , Sustancias para la Guerra Química/farmacología , Reactivadores de la Colinesterasa/metabolismo , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Humanos , Relación Estructura-ActividadRESUMEN
PURPOSE: This study investigated the decontamination effectiveness of selected toxic industrial chemicals using RSDL® (Reactive Skin Decontamination Lotion Kit; Emergent BioSolutions Inc.; https://www.rsdl.com/). MATERIALS AND METHODS: Quantitative analytical methods were developed for dermal toxic compounds of varying physicochemical properties: sulfuric acid, hydrofluoric acid, ammonia, methylamine, hydrazine, phenylhydrazine, 1,2-dibromoethane, capsaicin, and fentanyl. These methods were subsequently used to evaluate the decontamination effectiveness on painted metal substrates at an initial chemical contamination level of 10g/m2 (0.1g/m2 for fentanyl). RESULTS: The decontamination effectiveness ranged from 97.79% to 99.99%. DISCUSSION AND CONCLUSION: This study indicates that the RSDL kit may be amenable for use as an effective decontaminant for material substrates beyond the classical chemical warfare agents and the analytical methods may be used for future decontamination assessment studies using contaminated skin or other materials.
Asunto(s)
Sustancias para la Guerra Química/toxicidad , Descontaminación/métodos , Fentanilo/toxicidad , Administración Cutánea , Humanos , PielRESUMEN
Poisoning by organophosphorus compounds (OP) is characterized by inhibition of the key enzyme acetylcholinesterase (AChE) and potentially fatal outcomes in humans. Insufficient efficacy of the standard therapy with atropine and AChE reactivators (oximes) against certain OP initiated synthesis of novel non-oxime reactivators basing on the common structure 4-amino-2-((diethylamino)methyl)phenol (ADOC). Recently, we reported of a pyrrolidine-bearing ADOC analogue (3 l) with a remarkable ability to reactivate OP-inhibited AChE. This in vitro study was undertaken to determine reactivity, affinity and overall reactivation constants of 3 l, the reference compound ADOC and two structural analogues with human AChE inhibited by paraoxon, sarin, cyclosarin and VX. The data showed a 10 to 34-fold reactivating potency of 3 l compared to ADOC mainly due to improved affinity. Additionally, various interactions between non-oximes, human or guinea pig (GP) AChE and structurally different OP were investigated: OP-inhibited guinea pig AChE was less amenable to reactivation by ADOC and 3 l than human AChE. Compound 3 l was considered as potential pretreatment to prevent AChE from irreversible inhibition by OP: In the presence of 10 µM 3 l inhibition of native human AChE was attenuated resulting in protective indices (PI) ranging from about 2.7 to 6.0. A combination of 3 l and the bispyridinium oxime HI-6 was tested to reactivate OP-inhibited AChE: The superior reactivator of the respective OP-AChE combination dominated the reactivation process and a synergistic effect could not be observed. In conclusion, novel non-oxime reactivators like 3 l may be considered as promising templates for the design of more potent therapeutics against poisoning by highly toxic OP.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Compuestos Organofosforados/toxicidad , Fenoles/farmacología , Animales , Reactivadores de la Colinesterasa/química , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/enzimología , Cobayas , Humanos , Técnicas In Vitro , Cinética , Fenoles/química , Relación Estructura-ActividadRESUMEN
Organophosphorous (OP) compounds (such as nerve agents) inhibit the enzyme acetylcholinesterase (AChE) by covalent phosphylation of a key serine residue in the active site of the enzyme resulting in severe symptoms and ultimately death. OP intoxications are currently treated by administration of certain oxime compounds. The presently fielded oximes reactivate OP-inhibited AChE by liberating the phosphylated serine. Recent research towards new reactivators was predominantly devoted to design, synthesis and evaluation of new oxime-based compounds dedicated to overcoming some of the major limitations such as their intrinsic toxicity, their permanent charge which thwarts penetration of brain tissues and their inability to effectively reactivate all types of nerve agent inhibited AChEs. However, in over six decades of research only limited success has been achieved, indicating that there is a need for alternative classes of compounds that could reactivate OP-inhibited AChE. Recently, a number of non-oxime compounds was discovered in which the 4-amino-2-((diethylamino)methyl)phenol (ADOC) motif proved to be able to reactivate OP-inhibited AChE to some extent. In this paper several structural derivatives of ADOC were synthesized and screened for their ability to reactivate human AChE (hAChE) inhibited by the nerve agents VX, sarin, tabun, cyclosarin and paraoxon. We here disclose that one of those compounds showed a remarkable ability to reactivate OP-inhibited hAChE in vitro and that it is the most potent non-oxime reported to date.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas , Agentes Nerviosos/farmacología , Compuestos Organofosforados/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Agentes Nerviosos/síntesis química , Agentes Nerviosos/química , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/química , Relación Estructura-ActividadRESUMEN
The three-dimensional (3D) microporous titanium aminoterephthalate MIL-125-NH2 (MIL: Material of Institut Lavoisier) was successfully isolated as monodispersed nanoparticles, which are compatible with intravenous administration, by using a simple, safe and low-cost synthetic approach (100 °C/32 h under atmospheric pressure) so that for the first time it could be considered for encapsulation and the release of drugs. The nerve agent antidote 2-[(hydroxyimino)methyl]-1-methyl-pyridinium chloride (2-PAM or pralidoxime) was effectively encapsulated into the pores of MIL-125-NH2 as a result of the interactions between 2-PAM and the pore walls being mediated by π-stacking and hydrogen bonds, as deduced from infrared spectroscopy and Monte Carlo simulation studies. Finally, colloidal solutions of MIL-125-NH2 nanoparticles exhibited remarkable stability in different organic media, aqueous solutions at different pH and under relevant physiological conditions over time (24 h). 2-PAM was rapidly released from the pores of MIL-125-NH2 in vitro.
RESUMEN
Recently, a new class of reactivators of chemical warfare agent inhibited acetylcholinesterase (AChE) with promising in vitro potential was developed by the covalent linkage of an oxime nucleophile and a peripheral site ligand. However, the complexity of these molecular structures thwarts their accessibility. We report the compatibility of various oxime-based compounds with the use of the Ugi multicomponent reaction in which four readily accessible building blocks are mixed together to form a product that links a reactivating unit and a potential peripheral site ligand. A small library of imidazole and imidazolium reactivators was successfully synthesized using this method. Some of these compounds showed a promising ability to reactivate AChE inhibited by various types of CWA in vitro. Molecular modeling was used to understand differences in reactivation potential between these compounds. Four compounds were evaluated in vivo using sarin-exposed rats. One of the reactivators showed improved in vivo efficacy compared to the current antidote pralidoxime (2-PAM).
Asunto(s)
Acetilcolinesterasa/metabolismo , Reactivadores de la Colinesterasa/síntesis química , Reactivadores de la Colinesterasa/farmacología , Animales , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/efectos adversos , Reactivadores de la Colinesterasa/administración & dosificación , Reactivadores de la Colinesterasa/farmacocinética , Humanos , Imidazoles/administración & dosificación , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/farmacología , Cinética , Masculino , Modelos Moleculares , Simulación del Acoplamiento Molecular , Agentes Nerviosos/efectos adversos , Oximas/administración & dosificación , Oximas/síntesis química , Oximas/farmacocinética , Oximas/farmacología , Compuestos de Pralidoxima/farmacología , Ratas Wistar , Sarín/efectos adversosRESUMEN
In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.
Asunto(s)
Acetilcolinesterasa/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oximas/química , Sarín/química , Acetilcolinesterasa/metabolismo , Sitios de Unión , Humanos , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Oximas/farmacología , Unión Proteica , Sarín/farmacologíaRESUMEN
Since the discovery of peptide nucleic acids (PNAs) as DNA mimics in the early 1990s, a tremendous effort has been directed to their application as antisense and antigene probes. With the aim of further enhancing their properties, PNAs have been conjugated to a variety of effector molecules. Among these, small peptide fragments, often derived from functional proteins, are able to convey their specific properties to the conjugate.
Asunto(s)
Ácidos Nucleicos de Péptidos/síntesis química , Péptidos/síntesis química , Ligandos , Ácidos Nucleicos de Péptidos/química , Péptidos/químicaRESUMEN
Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase.
Asunto(s)
Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Alquilación , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Cristalografía por Rayos X , Humanos , Cinética , Ligandos , Modelos Moleculares , Fosforilación , Compuestos de Pralidoxima/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Serina/química , Soman/toxicidadRESUMEN
Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was therefore hypothesized that an extra contribution in affinity may be achieved by covalently connecting a peripheral site ligand (PSL) to a non-ionic reactivator, which may result in a higher reactivation potency of the total construct. This validity of this approach, which proved successful for charged pyridinium oximes in earlier work, is now further exemplified with the covalent linkage of a neutral PSL via a spacer to a non-ionic and otherwise almost non-reactivating α-ketoaldoxime. It is demonstrated that the linkage of the PSL resulted in a remarkable increase in reactivation potency of the hybrid compounds. Although the molecules reported here are still inefficient reactivators compared to the current pyridinium oximes, the presented approach holds promise for the future design and synthesis of non-ionic oxime reactivators with improved BBB penetration and may be suited as well for non-oxime reactivators thus further widening the scope in the ongoing search for broad-spectrum reactivators.
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Acetilcolinesterasa/química , Sustancias para la Guerra Química/farmacología , Inhibidores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/farmacología , Oximas/farmacología , Sitios de Unión , Reactivadores de la Colinesterasa/síntesis química , Reactivadores de la Colinesterasa/química , Humanos , Ligandos , Estructura Molecular , Oximas/síntesis química , Oximas/química , Unión Proteica , Espectrometría de Masa por Ionización de Electrospray , Especificidad por Sustrato , Espectrometría de Masas en TándemRESUMEN
The present study investigated whether airway responses of sensitized rats to trimellitic anhydride (TMA) were concentration dependent and whether these were related to irritation by TMA. Groups of BN and Wistar rats were sensitized by two dermal applications of TMA (50% w/v, followed by 25% w/v in vehicle). Controls received vehicle (acetone-olive oil 4:1, v/v). All animals were challenged 3 wk after the first sensitization by inhalation of one of a range of concentrations of TMA (0.2-61 mg/m3 for BN rats, 15-250 mg/m3 for Wistar rats). Breathing pattern, breathing frequency, and tidal volume were measured before, during, and after challenge to assess allergic and irritative airway responses. One day after challenge, nonspecific airway responsiveness to a range of concentrations of methacholine was measured. At necropsy on the same day, blood was withdrawn for measuring total serum immunoglobulin E (IgE) and organs were weighed. Larynx, trachea and lungs were examined histopathologically. In BN rats, TMA sensitization elevated total IgE levels; subsequent inhalation challenge with 2 mg/m3 of TMA and higher caused laryngeal inflammation with squamous epithelial metaplasia, and pulmonary hemorrhages. Concentration-related decreases in breathing frequency and alterations in breathing pattern, which differed from the irritation-induced pattern, were also observed at these levels. Inhalation challenge with TMA concentrations of 12 mg/m3 and higher increased lung weight. Increased nonspecific airway responsiveness was observed at the 2 next higher tested concentrations of 46 and 61 mg/m3. In unsensitized BN rats, only laryngeal squamous metaplasia was observed, albeit at higher challenge concentrations of TMA, and decreased breathing frequency, a typical breathing pattern characteristic of irritation. Identically sensitized Wistar rats showed airway inflammation and pulmonary hemorrhages upon challenge with TMA, but no functional changes, even at distinctly irritating concentrations of TMA up to 250 mg/m3. In conclusion, TMA challenge of sensitized BN rats caused challenge concentration-related allergic airway inflammation, asthmalike changes in breathing pattern, and increased nonspecific airway responsiveness. The lowest no-observed-effect level (NOEL) based on the most sensitive endpoint investigated was 0.2 mg/m3, a value that is well below the irritation concentration. The presence of a NOEL in the sensitized BN rat suggests that assessment of safe human exposure levels is feasible.