Eficacia del cloruro de etilo en aerosol como anestésico local previo a la punción arterial: ensayo clínico aleatorizado controlado con placebo / Ethyl chloride aerosol spray for local anesthesia before arterial puncture: randomized placebo-controlled trial

Objetivos. Evaluar la eficacia del cloruro de etilo en aerosol aplicado sobre la piel frente a placebo para disminuir el dolor provocado por una punción arterial durante la realización de una gasometría en el servicio de urgencias (SU). Método. Ensayo clínico aleatorizado, simple ciego y controlado con placebo realizado en el SU del Hospital de Basurto (Bilbao, España). Se incluyeron 126 pacientes a los que se les había solicitado una gasometría arterial, asignándoles al azar al grupo de tratamiento tópico experimental con cloruro de etilo en aerosol (n = 66) o al grupo control con mezcla hidroalcohólica en aerosol (n = 60), ambos administrados inmediatamente antes de la punción arterial. La variable de resultado principal fue la intensidad del dolor autopercibido por el paciente medida por la escala NRS-11. Resultados. El dolor percibido por el paciente tuvo una mediana (rango intercuartílico) de 2 (1-5) en el grupo tratado con cloruro de etilo y de 2 (1-4,5) en el grupo placebo (p = 0,72). Conclusiones. La aplicación de cloruro de etilo tópico no reduce el dolor por punción arterial (AU)

Objective. To compare the efficacy of an ethyl chloride aerosol spray to a placebo spray applied in the emergency department to the skin to reduce pain from arterial puncture for blood gas analysis. Material and methods. Single-blind, randomized placebo-controlled trial in an emergency department of Hospital de Basurto in Bilbao, Spain. We included 126 patients for whom arterial blood gas analysis had been ordered. They were randomly assigned to receive application of the experimental ethyl chloride spray (n=66) or a placebo aerosol spray of a solution of alcohol in water (n=60). The assigned spray was applied just before arterial puncture. The main outcome variable was pain intensity reported on an 11-point numeric rating scale. Results. The median (interquartile range) pain level was 2 (1-5) in the experimental arm and 2 (1-4.5) in the placebo arm (P=.72). Conclusion. Topical application of an ethyl chloride spray did not reduce pain caused by arterial puncture (AU)

Physical and physicochemical factors effecting transport of chlorohydrocarbon gases from lung alveolar air to blood as measured by the causation of narcosis.

This systematic investigation examines gas transport in the lung for two sets of chlorohydrocarbons (CHCs): the chloromethanes (C1) and chloroethanes (C2). The C1 series includes chloromethane, methylene chloride, chloroform, and carbon tetrachloride, and the C2 series includes chloroethane, 1,2-dichloroethane, 1, 1, 2-trichloroethane, and 1, 1, 2, 2-tetrachloroethane. Most CHC gases cause narcosis. The comprehensive narcosis work of Lehmann and colleagues on CHCs was used as a basis for the narcosis endpoint in the present examination. The sites for narcosis are located in the brain (midline cortex and posterior parietal area), the spine, and at many peripheral nerve sites. Central nervous system (CNS) exposure executes a multisite, neural transmission set of inhibitions that promotes rapid loss of consciousness, sensory feeling, and current and stored memory while providing temporary amnesia. Absorption into the system requires dissolution into many lipid membranes and binding to lipoproteins. Lipophilicity is a CHC property shared with many anesthetics according to the Meyer-Overton Rule. Many structurally different lipid chemicals produce the narcosis response when the lipid concentration exceeds -67 mM. This suggests narcotic or anesthetic dissolution into CNS membranes until the lipid organization is disrupted or perturbed. This perturbation includes loading of Na(+)- and K(+)-channel transmembrane lipoprotein complexes and disrupting their respective channel functional organizations. The channel functions become attenuated or abrogated until the CHC exposure ceases and CHC loading reverses. This investigation demonstrates how the CHC physical and chemical properties influence the absorption of these CHCs via the lung and the alveolar system on route to the blood. Narcosis in test animals was used here as an objective biological endpoint to study the effects of the physical factors Bp, Vp, Kd (oil: gas) partition, Henry's constant (HK), and water solubility (S%) on gas transport. Narcosis is immediate after gas exposure and requires no chemical activation only absorption into the blood and circulation to CNS narcotic sites. The three physical factors Bp, K(d) (oil: air), and S% vary directly with unitary narcosis (UN) whereas Vp and HK vary inversely with UN in linear log-log relationships for the C2 series but not for the C1 series. Physicochemical properties of C1 series gases indicate why they depart from what is usually assumed to be an Ideal Gas. An essential discriminating process in the distal lung is the limiting alveolar film layer (AFL) and the membrane layer of the alveolar acini. The AFL step influences gas uptake by physically limiting the absorption process. Interaction with and dissolution into aqueous solvent of the AFL is required for transport and narcotic activity. Narcotics or anesthetics must engage the aqueous AFL with sufficient strength to allow transport and absorption for downstream CNS binding. CHCs that do not engage well with the AFL are not narcotic. Lipophilicity and amphipathicity are also essential solvency properties driving narcotics' transport through the alveolar layer, delivery to the blood fats and lipoproteins, and into critical CNS lipids, lipoproteins, and receptor sites that actuate narcosis. AFL disruption is thought to be strongly related to a number of serious pulmonary diseases such acute respiratory distress syndrome, infant respiratory distress syndrome, emphysema, chronic obstructive pulmonary disease, asthma, chronic bronchitis, pneumonia, pulmonary infections, and idiopathic pulmonary fibrosis. The physical factors (Bp, Vp, Kd [oil: gas] partition, Henry's constant, and water solubility [S%]) combine to affect a specific transport through the AFL if lung C > C(0) (threshold concentration for narcosis). The degree of blood CHC absorption depends on dose, lipophilicity, and lung residence time. AFL passage can be manipulated by physical factors of increased pressure (kPa) or increased gas exposure (moles). Molecular lipophilicity facilitates narcosis but lipophilicity alone does not explain narcosis. Vapor pressure is also required for narcosis. Narcotic activity apparently requires stereospecific processing in the AFL and/or down-stream inhibition at stereospecific lipoproteins at CNS inhibitory sites. It is proposed that CHCs likely cannot proceed through the AFL without perturbation or disruption of the integrity of the AFL at the alveoli. CHC physicochemical properties are not expected to allow their transport through the AFL as physiological CO(2) and O(2) naturally do in respiration. This work considers CHC inspiration and systemic absorption into the blood with special emphasis on the CHC potential perturbation effects on the lipid, protein liquid layer supra to the alveolar membrane (AFL). A heuristic gas transport model for the CHCs is presented as guidance for this examination. The gas transport model can be used to study absorption for other gas delivery endpoints of environmental concern such as carcinogens.

Physiologically based pharmacokinetic modeling of chloroethane disposition in mice, rats, and women.

Chloroethane was observed in a chronic cancer bioassay to be a mouse-specific uterine carcinogen at a single high inhaled concentration (15,000 ppm). Although high incidence occurred in the female mouse (86%), no uterine tumor increases were observed in female rats. Chloroethane is a weak alkylating agent and has low acute toxicity. No genotoxicity potential has been observed below 40,000 ppm. Chloroethane is eliminated from the body by pulmonary exhalation and metabolically by oxidation via cytochrome P-450 (likely producing acetaldehyde) and conjugation with glutathione (GSH). The mode of action for the mouse-specific uterine tumors is not definitively known and could involve parent chemical and/or metabolite(s). A physiologically based pharmacokinetic (PBPK) model for chloroethane disposition in the rat was developed previously, but no such models have been described for mice or humans. For the work reported here, the existing PBPK model for chloroethane in rats was expanded and refined, and PBPK models for chloroethane disposition in mice and humans were developed to allow species comparisons of internal dosimetry and for possible insights into the carcinogenic mode of action. The amounts metabolized via glutathione-S-transferase (GST) versus cytochrome P-450, and the total amount of chloroethane absorbed, were most consistent with the observations made concerning uterine tumors, with amounts metabolized via GST providing the larger quantitative difference between the two rodent species. Choice of the most relevant dose metric for risk assessments involving uterine tumors in mice will require pharmacodynamic considerations in the mode of action in addition to the pharmacokinetic differences reported here.

Quantitative structure-pharmacokinetic relationship modelling.

This article presents the current methods in quantitative structure-pharmacokinetic relationship (QSPkR) modelling along with examples using chemicals of toxicological significance. The common method involves: (i) collecting pharmacokinetic data or determining pharmacokinetic parameters (e.g. elimination half-life, volume of distribution) by fitting to experimental data; and (ii) associating them with the structural features of chemicals using a Free-Wilson model. Such QSPkRs have been developed for a few series of chemicals but their usefulness is limited to the exposure scenario and conditions under which the experimental data were originally collected. The alternative approach involves the development of quantitative structure-property relationship (QSPR) models for parameters, blood:air partition coefficient, tissue:blood partition coefficient, maximal velocity for metabolism and Michaelis affinity constant, of physiologically-based pharmacokinetic (PBPK) models which are useful for conducting species, route, dose and scenario extrapolations of the tissue dose of chemicals. Mechanistic QSPRs are available for predicting tissue:blood and blood:air partition coefficients from molecular structure information of chemicals, whereas such approaches are not currently available for hepatic metabolism parameters. However, at the present time, the pharmacokinetics of inhaled volatile organic chemicals can be simulated adequately by considering the physiological limits of the hepatic extraction ratio (0-1) and molecular structure-based estimates of partition coefficients in the PBPK model. This current state-of-the-art of structure-based modelling of pharmacokinetics will advance with the development of QSPRs for other chemical-specific parameters of PBPK models. Integrated QSPR-PBPK modelling should facilitate the identification of chemicals of a family that possess desired properties of bioaccumulation and blood concentration profile in both test animals and humans.

[Combined effects caused by chronic exposure to vinyl chloride and dichloroethane]. / Kombinirovannoe deistvie vinilkhlorida i dikhlorétana pri dlinel'nov postuplenii v ornanizm.

The authors studied solitary and combined effects of vinyl chloride and dichloroethane in chronic (4 months) inhalation experiment using concentrations of 50 and 500 mg/m3. The experiment revealed general toxic effects including disorders of central nervous system and liver. Those disorders are caused by reductive-oxidative reactions disturbances and dystrophic processes. The authors determined safe combinations of vinyl chloride and dichloroethane concentrations for associated action.

Species differences in the biotransformation of ethyl chloride. I. Cytochrome P450-dependent metabolism.

Groups of male and female F-344 rats and B6C3F1 mice were exposed to 15,000 ppm ethyl chloride (monochloroethane, ECL) or to air for 5 days (6 h/day). In this report, features of the P450-dependent ECL metabolism in the animals are described. A concurrent report describes the in vitro and in vivo features of the GSH-dependent ECL metabolism (Fedtke et al. 1994). ECL is oxidatively dechlorinated in an NADPH- and O2-dependent reaction, resulting in the formation of acetaldehyde (AC). The oxidative ECL metabolism rates in microsomal incubations were measured. The results indicated induction of the oxidative ECL metabolism by ECL itself in mice and female rats. The hydroxylation of p-nitrophenol, which was used as an indicator of P450IIE1 activity, was also induced in microsomal incubations from ECL-exposed mice and female rats, but, corresponding to the ECL metabolism, not in male rats. In contrast, catalytic activities related to P450IA and IIB subfamilies were not induced by ECL treatment. Additional experiments with the P450IIE1-specific inhibitor 3-amino-1,2,4-triazole and induction experiments with acetone, phenobarbital and methylcholanthrene confirmed that the isoenzyme mainly involved in the dechlorination reaction is cytochrome P450IIE1. AC was not detected in serum of ECL exposed animals and only slightly enhanced amounts were detected in urine samples from ECL exposed mice, reflecting the high capacities of the AC metabolizing pathways in vivo. The data are discussed with regard to the results of a 2-year bioassay with F-344 rats and B6C3F1 mice exposed to 15,000 ppm ECL (NTP 1989a).(ABSTRACT TRUNCATED AT 250 WORDS)