salicylates and ethyl-salicylate

A toxicological and dermatological review of ethyl salicylate when used as a fragrance ingredient is presented.

Topics: Animals; Consumer Product Safety; Dose-Response Relationship, Drug; Humans; Irritants; Perfume; Risk Assessment; Salicylates; Skin; Skin Absorption; Skin Irritancy Tests; Skin Tests; Toxicity Tests

Methyl salicylate (MeSA) is a plant metabolite that induces plant defence resistance and an odorous volatile compound presenting green nuances. This volatile compound was shown to be present in wine samples, sometimes at concentrations above its olfactory detection threshold. MeSA is localized in grapes, particularly in the skins and stems, and is extracted during red wine vinification. It was detected at the highest concentrations in wines of several grape varieties, made from grapes affected by cryptogamic diseases, namely downy mildew caused by Plasmopara viticola, and black rot caused by Guignardia bidwellii. It has also been detected in wines from vines affected by Esca, a Grapevine Trunk Disease. MeSA can also be considered to be a chemical marker in grapes and wine indicative of the level of development of several vine cryptogamic diseases.

Topics: Ascomycota; Chromatography, High Pressure Liquid; Fruit; Gas Chromatography-Mass Spectrometry; Humans; Plant Diseases; Salicylates; Solid Phase Extraction; Taste; Vitis; Wine

In this work, we developed a number of generalised skin diffusion based pharmacokinetic models to relate published in vivo urinary excretion data to matching experimentally generated in vitro human skin permeation test (IVPT) data for a series of topically applied salicylate esters. A simplified linear in vivo model was found to inadequately describe the time course of urinary excretion over the entire sampling period. We represented the skin barrier as both a one layer (stratum corneum) and a two-layer (stratum corneum with viable epidermis) diffusion model and convoluted their Laplace solutions with that for a single exponential disposition phase to describe the urinary excretion profiles in the Laplace domain. We also derived asymptotic approximations for the model and estimated the conditions under which they could be used. We then sought to develop in vitro - in vivo relationships (IVIVR) for topically applied methyl, ethyl and glycol salicylates using our experimental IVPT data and the literature urinary excretion data. Good linear IVIVRs for ethyl and glycol salicylates were obtained, but the IVIVR for methyl salicylate was poor, perhaps because of topical stimulation of local skin blood flow by methyl salicylate. The ratio of the hydrated to dehydrated skin permeation for all salicylate esters was the same in both the IVPT and in vivo studies. A diffusion based one compartment pharmacokinetic model was also developed to describe the urinary excretion of solutes after removal of topical products and to compare the methyl salicylate skin permeation for five different body sites. The work presented here is consistent with the development of skin IVIVRs, but suggests that different skin conditions, application sites and local skin effects may affect model predictions.

Topics: Administration, Cutaneous; Diffusion; Female; Humans; Models, Biological; Permeability; Salicylates; Skin; Skin Absorption

Treatment of cardiovascular diseases suffers from the lack of transplantable small-diameter blood vessel (SDBV) grafts that can prohibit/eliminate thrombosis. Although expanded poly(tetrafluoroethylene) (ePTFE) has the potential to be used for SDBV grafts, recurrence of thrombus remains the biggest challenge. In this study, a reactive oxygen species (ROS)-responsive antithrombogenic drug synthesis and a bulk coating process were employed to fabricate functional ePTFE grafts capable of prohibiting/eliminating blood clots. The synthesized drug that would release antiplatelet ethyl salicylate (ESA), in responding to ROS, was dissolved in a polycaprolactone (PCL) solution, followed by a bulk coating of the as-fabricated ePTFE grafts with the PCL/drug solution. Nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) were employed to investigate and confirm the synthesis and presence of the ROS-responsive drug in the ePTFE grafts. The ESA release functions were demonstrated via the drug-release profile and dynamic anticoagulation tests. The biocompatibility of the ROS-responsive ePTFE grafts was demonstrated via lactate dehydrogenase (LDH) cytotoxicity assays, live and dead cell assays, cell morphology, and cell-graft interactions. The ROS-responsive, antithrombogenic ePTFE grafts provide a feasible way for maintaining long-term patency, potentially solving a critical challenge in SDBV applications.

Topics: Animals; Fibrinolytic Agents; Fluorocarbons; Humans; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Microscopy, Atomic Force; Polyesters; Polymers; Polytetrafluoroethylene; Reactive Oxygen Species; Salicylates; Spectroscopy, Fourier Transform Infrared; Thrombosis

This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data.. Simulated diffusion model and experimental IVPT data were generated for ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in ethyl salicylate solubility.. Both simulated and experimental IVPT - time profiles were markedly affected by receptor phase solubility and receptor sampling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect.. Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.

Topics: Diffusion; Humans; Hydrodynamics; Permeability; Salicylates; Skin; Skin Absorption; Solubility

Capsaicinoids, salicylic acid, methyl and ethyl salicylate, glycol monosalicylate, camphor and l-menthol are widely used in topical formulations to relieve local pain. For each separate compound or simple mixtures, quantitative analysis methods are reported. However, for a mixture containing all above mentioned active compounds, no assay methods were found. Due to the differing physicochemical characteristics, two methods were developed and optimized simultaneously. The non-volatile capsaicinoids, salicylic acid and glycol monosalicylate were analyzed with liquid chromatography following liquid-liquid extraction, whereas the volatile compounds were analyzed with static headspace-gas chromatography. For the latter method, liquid paraffin was selected as compatible dilution solvent. The optimized methods were validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentrations. For both methods, peaks were well separated without interference of other compounds. Linear relationships were demonstrated with R² values higher than 0.996 for all compounds. Accuracy was assessed by performing replicate recovery experiments with spiked blank samples. Mean recovery values were all between 98% and 102%. Precision was checked at three levels: system repeatability, method precision and intermediate precision. Both methods were found to be acceptably precise at all three levels. Finally, the method was successfully applied to the analysis of some real samples (cutaneous sticks).

Topics: Analgesics, Non-Narcotic; Camphor; Capsaicin; Chromatography, Gas; Chromatography, Liquid; Liquid-Liquid Extraction; Menthol; Ointments; Pharmaceutical Preparations; Salicylates; Salicylic Acid; Sensitivity and Specificity

The design and development of a novel extractive electrospray ionisation (EESI) device for on-line reaction monitoring is described. The EESI apparatus uses a secondary, grounded nebuliser to produce an analyte aerosol and a Venturi pump is then used to transfer a sample of the aerosol to an electrospray source where it is ionised. The EESI apparatus was then tested with a variety of small, organic molecules to assess sensitivity, linearity and dynamic range. The performance of the technique will depend on the mass spectrometer used for the experiments; in the configurations used here it has a usable dynamic range of around 3.5 orders of magnitude with a linear range of around 2.5 orders of magnitude and is capable of analysing species present down to low µg/mL with signal-to-noise ratio greater than 2.5. The use of EESI for reaction monitoring was validated using a series of mock reaction mixtures and then used to monitor the base hydrolysis of ethyl salicylate to salicylic acid.

Topics: Aerosols; Organic Chemicals; Pharmaceutical Preparations; Salicylates; Salicylic Acid; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Nicotine and flavorant compound levels were measured in 10 "mint"-related sub-brands and 8 "wintergreen" sub-brands of smokeless tobacco (SLT). Also analyzed were "mint"-related and "wintergreen" confectionery products. Of the "mint" SLT, "Timberwolf Packs Mint Pouches" contained the highest menthol level (5.3 mg/g); the average for the five most-highly mentholated SLT products was 4.3 mg/g. The average for the most five most-highly mentholated confectionery products was 3.5 mg/g. For hard candy, a reported average of maximum use levels is 2.1 mg/g (Burdock, 2009). Of the "wintergreen" SLT, "Hawken Wintergreen" was found to contain the highest methyl salicylate (MS) level (29.7 mg/g). The average of the five highest SLT MS levels was 23.8 mg/g, i.e., 5x higher than the level found in the confectionery product with the highest MS level (LifeSavers Wint O Green Sugar Free, 4.6 mg/g). For hard candy, a reported average of maximum use levels is 2.0 mg/g (Burdock, 2009). Assuming 23.8 mg/g MS in SLT, SLT use at 15 g/day, 100% bodily absorption of the MS, and 60 kg body weight, the average daily intake would be 6.0 mg/kg-day, i.e., 12x the acceptable daily intake (ADI) of 0.5 mg/kg-day established for this compound by a joint FAO/WHO committee.

Topics: Candy; Flavoring Agents; Mentha; Menthol; Nicotine; Oils, Volatile; Plant Extracts; Salicylates; Tobacco, Smokeless

The complexation of methyl salicylate (MS) and ethyl salicylate (ES), non-steroidal analgesic, anti-inflammatory and antirrheumatic drugs with beta-cyclodextrin (betaCD) has been studied from thermodynamic and structural points of view. The complexation with betaCD has been investigated using reversed-phase liquid chromatography. Retention behavior has been analyzed on a reverse-phase column Luna 18(2) 5 microm. The mobile-phase was methanol:water in different ratios (55:45 to 70:30) in which betaCD (1-9 mM) was incorporated as a mobile-phase additive. The decrease in retention times with increasing concentrations of betaCD enables the determination of the apparent stability constant of the complexes. Values at 30 degrees C with 55% methanol were K(MS:betaCD): 15.84 M(-1) and K(ES:betaCD): 12.73 M(-1) for MS and ES, respectively. The apparent stability constants decrease as the polarity of the solvent decreases. The low solubility of MS and ES in aqueous solution has been improved by complexation with betaCD (1-9 mM). The stability constants of the complexes obtained from the phase-solubility diagrams using a UV-vis spectrophotometric method were K(MS:betaCD): 229 M(-1) and K(ES:betaCD): 166 M(-1). In addition, semi-empirical quantum mechanics calculations using AM1 and PM3 methods in vacuum were performed. The energetically favorable inclusion structures were identified and the most favorable orientation for the inclusion process was found to be the head-down orientation for both complexes. Enthalpy for encapsulation processes was found to be favorable (DeltaH degrees <0), while entropy (DeltaS degrees <0) and Gibbs free energy were unfavorable (DeltaG degrees >0). By means of HPLC and UV-vis measurements and quantum mechanics calculations, it was found that MS and ES form a 1:1 inclusion complex with betaCD. The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.

Topics: Antirheumatic Agents; beta-Cyclodextrins; Chromatography, High Pressure Liquid; Kinetics; Models, Molecular; Quantum Theory; Salicylates; Solubility; Spectrophotometry, Ultraviolet; Temperature; Thermodynamics

Atherton-Todd reaction has been extensively applied to the synthesis of phosphates and phosphoroamidates. Under Atherton-Todd reaction conditions, dialkyl phosphites were probably transformed into diakyl phosphorochloridates. We have tried to use Atherton-Todd reaction to synthesize phosphate of salicylic-acid. But when the -COOH of salicylic acid was under unprotected, the yield was quite low. It was found that the -COOH possibly participated in the reaction. The competitive reaction between the -COOH and -OH of salicylic acid probably existed. In order to understand the detail mechanism, ethyl-salicylate was selected to be phosphorylated In the end, ethyl-salicylate successfully phosphorylated by modification of the classical Atherton-Todd procedure through dropping the DEPH and tetrachloromethane into the mixed solution of ethyl-salicylate, triethylamine and dioxane with good yields. The structures were elucidated by NMR and ESI/MS/MS data.

Topics: Models, Molecular; Phosphorylation; Polyamines; Salicylates; Spectrophotometry, Infrared; Wasp Venoms

The aim of this study was to investigate the percutaneous penetration and dermal metabolism of a new potential anti-acne prodrug--TU-2100 [bis(o-carboxyphenyl ethyl ester)nonanedioate] in guinea pigs. The fluxes of this agent through excised skin after applications of TU-2100 gels at 3 and 10% concentrations were similar. However, after 24 h from the time of drug application, the total amounts of permeated TU-2100 into the skin compartment and through the skin into the receiver were 271.7 (+/-30.7 S.E.) microg/cm(2) from the 3% gel and 779.4.0 (+/-98.5 S.E.) microg/cm(2) from the 10% gel, demonstrating a relatively high skin accumulation. Higher degradation of TU-2100 to ethylsalicylate occurred after application of drug at 10% concentration than after the application of 3% gel. In contrast, the fraction of permeated drug metabolized was twofold higher after the 3% gel application than after the 10% gel (F(m)=20 vs. 10.5 mole %). Since F(m) is reversibly related to the total permeating drug, the obtained values actually reflect the significant difference in TU-2100 permeation from the 3% (271.7 microg) and the 10% (779.4 microg) gels. An in vivo--in vitro comparison revealed similar drug accumulations in the skin after application of both 3 and 10% gels, however, skin metabolism was found to be significantly higher in vivo than in vitro.

Topics: Administration, Cutaneous; Animals; Dermatologic Agents; Drug Evaluation, Preclinical; Gels; Guinea Pigs; Irritants; Male; Prodrugs; Salicylates; Skin; Skin Absorption

A gas chromatographic-mass spectrometric (GC-MS) assay was developed for the quantitative analysis of methyl salicylate (MeS), ethyl salicylate (ES) and salicylic acid (SA) from biological fluids. The method was validated from 100-microl rat liver homogenate preparations (5 mg/ml protein) in 70 mM KH2PO4 (pH 7.4) buffer and from 100 microl rat plasma. The samples were extracted with chloroform, derivatized with BSTFA and quantitated by GC-MS in the SIM mode. The standard curves ranged from 31 ng/ml to 800 or 1250 ng/ml. Relative standard deviations and bias were less than 11% in plasma and homogenate for all compounds except SA which evidenced greater variability. The assay was used in preliminary experiments to characterize the pharmacokinetics of MeS in rats.

Topics: Animals; Body Fluids; Gas Chromatography-Mass Spectrometry; Liver; Male; Rats; Rats, Sprague-Dawley; Salicylates; Salicylic Acid; Sensitivity and Specificity

A novel method is proposed for the evaluation of the activity of an antifungal agent administered as a gas. This system is composed of a batch-flow type reaction vessel, a gas flow system, and a microscopic observation system. The agar plate was prepared on the ceiling of the reaction vessel, and the mycelium of a fungus (Aspergillus niger or Rhizoctonia solani) was inoculated onto it. After preincubation at 25 degrees C for 24 h, the reaction vessel was connected to the gas flow system. An appropriate hypha was selected, and its elongation rate was measured. Then a sample holder containing an antifungal compound was inserted into the reaction vessel from the side hole to saturate the atmosphere inside with its vapor. The retardation or inhibition of the hypha elongation was observed on a television monitor and recorded on a video tape recorder. The antifungal compound was then removed, and the reaction vessel was flushed with air. If the hypha lived, it began to elongate again. By this method, antifungal activity of seven odor compounds could be evaluated quantitatively within several hours.

Topics: Acrolein; Acyclic Monoterpenes; Antifungal Agents; Aspergillus niger; Benzaldehydes; Cyclohexanols; Cyclohexenes; Eucalyptol; Limonene; Menthol; Microbial Sensitivity Tests; Monoterpenes; Rhizoctonia; Salicylates; Terpenes; Volatilization

A topically applied rubifacient delivered by aerosol (Deep-Heat) was studied. After spray application to the forearms of volunteers, without massage, the erythema produced was measured by thermography and correlated with the concentration of 2 salicylate components of the mixture found in local and systemic venous blood. Maximum erythema occurred at about 30 minutes, while blood salicylate levels were maximal between 20 and 30 minutes after application. Methyl salicylate was absorbed before ethyl salicylate. Over the time period of the erythematous response oxygen levels in local venous blood were raised. Finally, platelets collected from venous blood draining from the sprayed site, when induced to clump by the addition of arachidonic acid in an aggregometer, showed increased resistance to clumping when compared with control cells. The mechanism of these observed phenomena and the mode of action of the constituents of Deep-Heat are discussed.

Topics: Administration, Topical; Adult; Aerosols; Female; Forearm; Humans; Irritants; Male; Niacin; Oxygen; Platelet Aggregation; Salicylates; Skin Temperature; Thermography

Topics: Coagulase; Hot Temperature; Humans; Salicylates; Sodium; Staphylococcus