Article

The Determination of Salicylates in Gaultheria procumbens for Use as a Natural Aspirin Alternative

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Abstract

A sensitive stable isotope dilution-based method was developed to analyze salicylates in plants. Wintergreen (Gaultheria procumbens L.) was found to contain 10 mg/g FW of total salicylate-the highest levels observed in plants. Levels of free salicylate and methyl salicylate were significantly less in the intact leaves of wintergreen. High levels of total salicylate were also observed in flowers, stems and berries of wintergreen. The salicylate was present predominantly as a derivatized form of methyl salicylate called gaultherin, which may exhibit aspirin-like therapeutic effects without the negative side effects of aspirin. Thus, gaultherin, which is more derivatized than aspirin, may be a safer natural alternative to aspirin.

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... In addition, massage reduces muscle tension, enhancing the effect of reduced pain and discomfort. Moreover, essential oils positively influence regeneration of periarticular tissues [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. To summarize, due to its unique properties, Perskindol gel is an effective and safe alternative to topically applied non-steroidal anti-inflammatory drugs (NSAIDs). ...
... Perskindol gel, due to the topical application of essential oils such as levomenthol, wintergreen oil, or Scots pine oil, has a multidirectional impact on tissues [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. ...
... In addition to direct inhibition of the inflammatory process (salicylates in goltery oil), inhibition of the release of inflammatory mediators and the impact on the synthesis of prostaglandins play an important role in treatment. Furthermore, levomenthol, one of the ingredients of Perskindol, increases the absorption of salicylates, which contributes to the enhancement of the anti-inflammatory effect [19,34,36]. ...
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Introduction: Osteoarthritis (OA) is one of the most common causes of pain in the musculoskeletal system leading to disability. The basic principle of the therapy is the simultaneous use of pharmacological and non-pharmacological treatments. The aim of this study was to evaluate the effectiveness of galvanic and iontophoresis treatments with Perskindol Active Classic Gel (Perskindol) in patients with OA of the knee joints. Moreover, a comparative evaluation of the effectiveness of the application was performed depending on the selection of the active electrode. Material and methods: The study included 100 patients with gonarthrosis, treated at the Rehabilitation Clinic of the Białystok University Hospital. Three groups were randomly selected: in group I (n = 33), anodic galvanic treatment was applied, group II (n = 33) received iontophoresis with Perskindol gel from the negative pole ("-" iontophoresis), and group III (n = 34) received iontophoresis with Perskindol gel from the positive pole ("+" iontophoresis). The VAS, the Laitinen questionnaire, the Lequesne Index, the Lysholm questionnaire, and the SF-36v2 health survey were used for the clinical evaluation of the patients. Results: In the group of patients who underwent iontophoresis with the use of Perskindol gel introduced from the positive pole, a statistically significant improvement was shown in all the assessed parameters in comparison to the patients who underwent anodic galvanic treatment. Conclusions: The most favorable effect of iontophoresis was observed in the case of iontophoresis with Perskindol gel introduced from the positive pole.
... In traditional medicine, various plant organs (leaves, stems, fruits) derived from this taxon and other Gaultheria species have been widely used as anti-inflammatory, analgesic, and antipyretic drugs in the treatment of rheumatoid arthritis, influenza, and pain of various etiology as well as a source of essential oil with similar activity . Active components of the leavesthe most popularly used plant material À are believed to be salicylates, especially methyl salicylate constituting 95% of the essential oil (Nikoli c et al., 2013) and its glycosidic precursor gaultherin {2-[(6-O-b-D-xylopyranosyl-b-D-glucopyranosyl)oxy] benzoic acid methyl ester} (Ribnicki et al., 2003). Numerous in vitro and in vivo studies conducted in the last decade on the Gaultheria species have documented anti-inflammatory activity of the extracts and salicylates isolated from aerial parts of the plants, including their inhibitory influence on release of reactive oxygen species (ROS), NO, and pro-inflammatory cytokines such as tumor necrosis factor (TNF-a) and interleukins IL-1b and IL-6 Xin et al., 2013;Zhang et al., 2015). ...
... These specialized plant metabolites with proven wide-range biological activities, i.e. antioxidant, vaso-, cardio-, and neuroprotective capacities, lipid-lowering action, and vasorelaxant effect, form a foundation for food, cosmetic and pharmaceutical applications of wintergreen leaves not only as anti-inflammatory drugs, but also as preventive agents against various oxidative stress related ailments. However, the quantitative composition of raw leaf materials of American wintergreen remains poorly recognized with data available either for only seven from about thirty non-salicylic constituents of the dried plants (Saleem et al., 2010) or just for total salicylates in the fresh leaves (Ribnicki et al., 2003). The comprehensive quantitative study is thus required to fully characterize the value of the G. procumbens leaf as a phenolic herbal medicine. ...
... As the MQ contents constituted 74-86% of the TFL levels on average, it is not surprising that hydrolytic experiments revealed clear domination (93.3-95.1%) of QU in TFA. Glycosides of methyl salicylate are known as chemotaxonomic markers of the genus Gaultheria and precursors of free methyl salicylate (essential oil), which is formed as a protective agent in an enzymatic hydrolytic process catalyzed by gaulterase upon disruption of the plant cells (Ribnicki et al., 2003). The chief component is gaultherin (monotropitoside), which was found (GT) in the present study as a single representative of glycosidic salicylates of G. procumbens leaves. ...
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Seasonal dynamics in the polyphenolic composition, antioxidant activity, and their relationships during plant development were evaluated for eastern teaberry (Gaultheria procumbens L.) leaves, a traditional herbal medicine of North American natives. With the complementary UHPLC-PDA-ESI-MS³, HPLC-PDA-fingerprint, Folin-Ciocalteau, and n-butanol/HCl assays of methanol-water (75:25, v/v) extracts, the dried leaf samples harvested monthly across the growing season under Polish climate conditions were found rich in structurally diverse polyphenols (149.2–210.7 mg/g DW) including the dominating salicylates (64.6–107.5 mg/g DW), proanthocyanidins (53.0–66.8 mg/g DW), and flavonoids (17.3–25.3 mg/g DW), and the accompanying chlorogenic acid isomers (2.4–4.4 mg/g DW) and simple phenolic acids (0.9–1.1 mg/g DW). Among 28 detected analytes, gaultherin (64.6–107.5 mg/g DW), miquelianin (14.6–21.1 mg/g DW), procyanidin A-type trimer (5.5–9.5 mg/g DW), and (–)-epicatechin (5.8–7.8 mg/g DW) were the most abundant. The phenolic levels and antioxidant activity parameters in the DPPH (EC50, 15.0–18.2 μg DW/mL; 0.95–1.16 mmol Trolox equivalents/g DW) and FRAP (2.3–3.4 mmol Fe ²⁺/g DW; 0.86–1.26 mmol Trolox equivalents/g DW) assays showed parallel seasonal trends with maxima in September and October. As the subsequent correlation studies confirmed the determinative impact of polyphenols on the leaf antioxidant activity and its seasonal fluctuations, the Fall season could be recommended as optimal for harvesting the plant material for medicinal purposes and cost-effective production of natural health products.
... Gaultheria procumbens L (Wintergreen) is a small ericaceous plant cultivated for use in the landscape industry, and it is the source of the essential oil from wintergreen (WO) [1,2]. WO is obtained commercially by steam distillation; however, the most commonly used form of WO is synthetic. ...
... and pains because of their analgesic activity. In fact, MS, the most common salicylate in commercial wintergreen preparations, is routinely used in topical ointments for the treatment of inflammation [2]. It has been demonstrated that some plants produce salicylic acid (SA) as a response to the infection by tobacco mosaic virus (TMV) [3]. ...
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Methyl Salicylate (MS), the principal constituent of Wintergreen oil (WO) was obtained from acetyl salicylic acid (ASA) by sequential transesterification-esterification reaction promoted by NbCl5for the first time. The reagents were added simultaneously, and the reaction process involved the transesterification and esterification reactions, which were accompanied by thin layer chromatography and gas chromatography. The conversion rate via GC was 100%, and the MS yield was 94%. A cytotoxicity of 50% and 64% for cultured S. aureus and metastatic melanoma cells, respectively, was observed for a concentration of 0.6 mg/mL, whereas no cytotoxicity for non-tumor cells was observed for this concentration, and it is considered to be the optimum concentration.
... It is also extensively used in the synthesis of solvents, perfumes, cosmetics, food preservatives, chiral auxiliaries, plasticizers, drugs, and pharmaceuticals [6,7]. Ribnicky et al., (2003) determined the presence of salicylates, other than methyl salicylate, that could act as alternatives for aspirin [8]. Recently, the authenticity of methyl salicylate (MS) in the essential oils from Gaultheria procumbens L. and Betula lenta L. was determined using isotope ratio mass spectrometry [9]. ...
... It is also extensively used in the synthesis of solvents, perfumes, cosmetics, food preservatives, chiral auxiliaries, plasticizers, drugs, and pharmaceuticals [6,7]. Ribnicky et al., (2003) determined the presence of salicylates, other than methyl salicylate, that could act as alternatives for aspirin [8]. Recently, the authenticity of methyl salicylate (MS) in the essential oils from Gaultheria procumbens L. and Betula lenta L. was determined using isotope ratio mass spectrometry [9]. ...
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SiO2–SO3H, with a surface area of 115 m2/g and pore volume of 0.38 cm3g−1, and 1.32 mmol H+/g was used as a 20% w/w catalyst for the preparation of methyl salicylate (wintergreen oil or MS) from acetylsalicylic acid (ASA). A 94% conversion was achieved in a microwave reactor over 40 min at 120 °C in MeOH. The resulting crude product was purified by flash chromatography. The catalyst could be reused three times.
... Phenolic acids were represented by simple hydroxybenzoic and hydroxycinnamic acids (1, 2, 3, 16) and quinic acid pseudodepsides (4,5,9). Among the analytes, only one representative of lignans was found, lyoniresinol hexoside (26), and two methyl salicylate derivatives (12,18) with the dominant gaultherin (18,GT). Most of the compounds were detected in all extracts (Table S1) but significant differences in their concentration levels and extraction yields were observed depending on the extraction solvent. ...
... Effect of AE at 25, 50, 100, 150 µg/mL(6,12,24,36 µg GAE/mL), model polyphenols (PB2 and GT), and positive controls (QU and DEX) on: (A) ROS level; and secretion of (B) IL-8; (C) IL-1β; (D) TNF-α; (E) MMP-9; and (F) ELA-2 by stimulated human neutrophils. Data expressed as means ± SD of three independent experiments performed with cells isolated from five independent donors. ...
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Salicylate-rich plants are an attractive alternative to synthetic anti-inflammatory drugs due to a better safety profile and the advantage of complementary anti-inflammatory and antioxidant effects of the co-occurring non-salicylate phytochemicals. Here, the phytochemical value and biological effects in vitro and ex vivo of the stems of one of such plants, Gaultheria procumbens L., were evaluated. The best extrahent for effective recovery of the active stem molecules was established in comparative studies of five extracts. The UHPLC-PDA-ESI-MS3, HPLC-PDA, and UV-photometric assays revealed that the selected acetone extract (AE) accumulates a rich polyphenolic fraction (35 identified constituents; total content 427.2 mg/g dw), mainly flavanols (catechins and proanthocyanidins; 201.3 mg/g dw) and methyl salicylate glycosides (199.9 mg/g dw). The extract and its model components were effective cyclooxygenase-2, lipoxygenase, and hyaluronidase inhibitors; exhibited strong antioxidant capacity in six non-cellular in vitro models (AE and procyanidins); and also significantly and dose-dependently reduced the levels of reactive oxygen species (ROS), and the release of cytokines (IL-1β, IL-8, TNF-α) and proteinases (elastase-2, metalloproteinase-9) in human neutrophils stimulated ex vivo by lipopolysaccharide (LPS) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The cellular safety of AE was demonstrated by flow cytometry. The results support the application of the plant in traditional medicine and encourage the use of AE for development of new therapeutic agents.
... Gaultherin demonstrated its outstanding analgesic and anti-inflammatory effects in a variety of studies: administered in vivo as a pure compound (Zhang et al., 2006), in the form of its derivatives (Wang et al., 2011) or as fractions of wintergreen (Gaultheria yunnanensis) extract containing large quantities of gaultherin (Zhang et al., 2007). Scientific studies on gaultherin concluded that its anti-inflammatory and analgesic activities are similar to aspirin, but without the side effects on the gastrointestinal tract known for aspirin, namely the formation of lesions and ulcers because of aspirin's COX-1 inhibitory action in the gastric epithelium, leading to reduced levels of cytoprotective prostaglandins (Ribnicky et al., 2003;Zhang et al., 2006). After ingestion, gaultherin is hydrolyzed to methyl salicylate by intestinal β-glycosidase, followed by ester cleavage mediated by esterases in the intestine, blood, and liver, thereby, releasing its active metabolite, salicylic acid. ...
... A considerably slower rate of gaultherin hydrolysis provides an effective concentration of salicylates over a longer period of time without an extreme increase of salicylate quantity. Therefore, salicylic acid does not affect COX-1 activity in the stomach, because it is not released in this part of the digestive tract, and thus does not cause undesirable effects on gastric mucosa (Ribnicky et al., 2003;Wang et al., 2011;Zhang et al., 2006). ...
Article
Filipendula vulgaris (dropwort) is used in traditional medicine for relieving various inflammation-related diseases. In the present study, the phytochemical profile of the aerial part (FVA) and root (FVR) methanolic extracts was evaluated by LC-DAD-HRMS analysis. Furthermore, their in vitro and in vivo anti-inflammatory effects, as well as their potential cytotoxicity, were assessed. Results showed that the extracts mainly contain phenolics like flavonoids, hydrolyzable tannins, procyanidins, and phenolic acid derivatives, including gaultherin. No in vitro cytotoxicity was found at the highest concentration (50 μg/mL). FVA extract (50 μg/mL) significantly inhibited cyclooxygenase-1 and -2 (COX-1 and COX-2) activities in vitro (>50% inhibition), and FVR extract considerably inhibited COX-2 activity (52.5 ± 2.7%) without affecting COX-2 gene expression in LPS-stimulated THP-1 cells. The extracts demonstrated prominent in vivo anti-inflammatory potential upon oral administration in rats. Especially FVA extract at 100 and 200 mg/kg, significantly inhibited carrageenan-induced edema formation. From these results, it can be concluded that F. vulgaris extracts possess interesting anti-inflammatory properties.
... The most commonly used plant organs of G. procumbens are the leaves, traditionally valued as anti-inflammatory and analgesic agents as well as a source of wintergreen essential oil [1]. Methyl salicylate, constituting over 95% of the essential oil [2], and its glycosidic precursor-gaultherin [3]-are the main representatives of salicylates, so far considered as the primary active constituents of Gaultheria plants [4][5][6]. However, plant extracts are usually multicomponent and their activity is rarely due to one, single constituent. ...
... However, plant extracts are usually multicomponent and their activity is rarely due to one, single constituent. In fact, our previous studies [7] demonstrated that the anti-inflammatory activity of wintergreen leaves is also largely influenced by other polar compounds, among which thirty-five representatives of flavonoids, proanthocyanidins, and caffeoylquinic acids were identified by UHPLC-PDA-ESI-MS 3 profiling. The concept of metabolite profiling evolved recently in the most preferable characterization procedure of bioactive plant fractions, but it is generally confined to hydrophilic compounds alone [8], while lipophilic components are often studied only fragmentarily, either by classic techniques such as isolation, or after separation of less complex, specific sub-fractions, e.g., essential oils. ...
Article
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The phytochemical profile and anti-inflammatory activity of Gaultheria procumbens dry lipophilic leaf extracts were evaluated. Forty compounds were identified by GC-MS, representing 86.36% and 81.97% of the petroleum ether (PE) and chloroform (CHE) extracts, respectively, with ursolic acid (28.82%), oleanolic acid (10.11%), methyl benzoate (10.03%), and methyl salicylate (6.88%) dominating in CHE, and methyl benzoate (21.59%), docosane (18.86%), and octacosane (11.72%) prevailing in PE. Three components of CHE were fully identified after flash chromatography isolation and spectroscopic studies as (6S,9R)-vomifoliol (4.35%), 8-demethyl-latifolin (1.13%), and 8-demethylsideroxylin (2.25%). Hyaluronidase and lipoxygenase inhibitory activity was tested for CHE (IC50 = 282.15 ± 10.38 μg/mL and 899.97 ± 31.17 μg/mL, respectively), PE (IC50 = 401.82 ± 16.12 μg/mL and 738.49 ± 15.92 μg/mL), and nine of the main constituents versus heparin (IC50 = 366.24 ± 14.72 μg/mL) and indomethacin (IC50 = 92.60 ± 3.71 μg/mL) as positive controls. With the best activity/concentration relationships, ursolic and oleanolic acids were recommended as analytical markers for the extracts and plant material. Seasonal variation of both markers following foliar development was investigated by UHPLC-PDA. The highest levels of ursolic (5.36–5.87 mg/g DW of the leaves) and oleanolic (1.14–1.26 mg/g DW) acids were observed between August and October, indicating the optimal season for harvesting.
... The essential oil of wintergreen is usually obtained from the Gaultheria, and most commonly from the two wintergreen species G. procumbens and G. fragrantissima [9] because these species yield a high concentration of methyl salicylate, which is an aromatic ester structurally related to aspirin. It is found at high concentration in WEO, and is an active ingredient that efficiently relieves pain caused by muscle fever [10]. Methyl salicylate represents more than 99% of the composition of most wintergreen species oils after distillation [9,11,12]. ...
Article
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The chemical composition of wintergreen (Gaultheria procumbens L.) essential oil (WEO) was identified by gas chromatography-mass spectrometry (GC-MS) and evaluated for its biological activities. Methyl salicylate (100%) was the main compound in the wintergreen essential oil. The herbicidal efficacy of the WEO was confirmed by germination inhibition, radical and shoot length reduction, and phytotoxicity assessment with Echinochloa crus-galli and Amaranthus tricolor seedlings. The WEO significantly reduced the germination and seedling growth of both weeds. It showed highly significant inhibition of seed germination (93.37%) and seedling growth of A. tricolor at the highest dose (6 µL/petri dish) assayed. The WEO was formulated as an emulsifiable concentrate (EC-EO) for post-emergence application, and was applied at a range of concentrations from 10 to 80 mL/L. Both treated plant leaves appeared wilted and slightly discolored within 1 day of application (DAA). The visible weed control efficacy was most remarkable at 80 mL/L treatment, which was a level that ultimately killed the seedlings of both species at 3 DAA, suggesting promising herbicidal potential for the WEO. The WEO showed weak scavenging activity with a high IC50 value (IC50 >2×10 4 and >5×10 4 ppm) for DPPH scavenging and metal chelating assays, respectively. The WEO showed moderate antibacterial activity, and its zones of inhibition against bacterial test strains were 7.90±0.8 mm and 23.9±0.9 mm for Escherichia coli TISTR 780 and Staphylococcus aureus TISTR 1466, respectively. Therefore, the results suggest the possibility of using WEO as an active ingredient to produce natural herbicides. Keywords essential oil; EC-EO; Gaultheria procumbens; bioactivity; herbicidal activity; antibacterial activity; antioxidant activity Curr. Appl. Sci. Technol. Vol. 23 No. 5 S. Jintanasirinurak et al. 2
... Kết quả nghiên cứu này hoàn toàn phù hợp với các nghiên cứu trước đây về thành phần tinh dầu của các loài thuộc chi Gaultheria trên thế giới. Theo các nghiên cứu trước đây về thành phần hoá học của tinh dầu loài G. procumbens, G. yunnanensis và G. fragrantissima thì methyl salicylate cũng là thành phần chính trong tinh dầu của các loài này và chiếm tỷ lệ trên 90% [14]- [16]. ...
Article
Trong nghiên cứu này, thành phần hóa học của tinh dầu chiết xuất từ lá loài Gaultheria sleumeri Smitinand & P.H.(Benth.) ở Việt Nam đã được phân tích và đánh giá hoạt tính sinh học của chúng. Tinh dầu lá loài G. sleumeri thu được thông qua quá trình chưng cất lôi cuốn hơi nước, sau đó phân tích thành phần bằng phương pháp sắc ký khí khối phổ (GC-MS). Kết quả cho thấy, tinh dầu chủ yếu bao gồm hai thành phần: methyl salicylate (99,92%) và eugenol (0,08%). Để đánh giá hoạt tính kháng khuẩn của tinh dầu, phương pháp khuếch tán giếng thạch được sử dụng trong nghiên cứu này. Kết quả cho thấy, tinh dầu loài này thể hiện hoạt tính kháng vi sinh vật chống lại hai chủng vi khuẩn bao gồm Escherichia coli, Staphylococcus aureus và một loại nấm men gây bệnh (Candida albicans) ở các nồng độ khác nhau. Nghiên cứu cung cấp những hiểu biết có giá trị về thành phần hóa học và hoạt tính kháng vi sinh vật của tinh dầu chiết xuất từ lá loài G. sleumeri ở Việt Nam.
... WO is extracted from Gaultheria procumbens L., and belongs to the family Ericacea. 8 Remarkably, the anti-inflammatory effect of Gaultheria species is believed to be due to the presence of 96.9-98% of methyl salicylate as the main active ingredient. 9 It also contains tannin, resin, α-pinene, myrcene, delta-3-carene, 3, 7-guaiadiene, and delta cadinene which gives the plant a distinct medicinal tannins odour. ...
... The aromatic and herbaceous wintergreen fragrance can be used in perfumery and in the cosmetic and food industries, but the main uses are in aromatherapy, oral care, and natural preservatives for cosmetics. Many medical ointments used in aromatherapy are composed of wintergreen essential oil (Mukhopadhyay et al., 2016) because of its analgesic and anti-inflammatory properties (Delplancq, 2015;Liu et al., 2013;Michel et al., 2014;Park et al., 2011), which efficiently relieve pain caused by muscle fever (Ribnicky et al., 2003). Antispasmodic, vasodilators, and liver stimulant properties of the essential oil have also been reported (Franchomme et al., 2012). ...
Thesis
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Les matières naturelles aromatiques, telles que les huiles essentielles, que l’on retrouve sur le marché, ne sont pas toujours authentiques, bien que ces produits soient vendus comme étant 100% purs et naturels. Certains fournisseurs fraudent leurs produits afin de réduire les coûts de production, d’améliorer la qualité des huiles essentielles ou encore pour augmenter artificiellement les volumes de production. Les huiles essentielles sont adultérées en ajoutant des produits à moindre coût, incluant des matières naturelles moins chères et des molécules d’origine pétrochimique. Des méthodes d’authentification appropriées sont nécessaires pour contrôler la naturalité et la pureté des huiles essentielles. La détermination des ratios isotopiques stables et l’analyse énantiosélective de composés spécifiques, associées à la recherche de traces de précurseurs de synthèses, permettent d’authentifier de nombreuses huiles essentielles (gaulthérie, alliacées, néroli, menthe crépue, cannelle et cypriol). Le contrôle de ces produits naturels requiert l’établissement de banques de données, constituées d’échantillons parfaitement tracés pour l’authenticité de leurs origines. La méthodologie mise en place a permis de développer de nouveaux outils pertinents pour l’authentification, comprenant le développement de l’analyse isotopique de composés ciblés pour la mesure du δ18O et du δ34S, et d’identifier de nouvelles fraudes, comprenant les ajouts de composés enrichis en 14C et les molécules issues d’hémisynthèses.
... Leaves, stems, and whole aerial parts of G. procumbens are anti-inflammatory, analgesic, and antioxidant agents recommended for treating rheumatoid arthritis, influenza, cold, fever, tracheitis, pharyngitis, pain of various aetiology, and some skin and periodontal diseases [7,8]. The genus Gaultheria is known for salicylate glycosides, a rare class of natural analogues of aspirin [7][8][9]. The leading compound, gaultherin (GT), exerts potent anti-inflammatory activity by modulation of pro-inflammatory functions of immune cells, especially secretion of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α [10,11]. ...
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Aerial parts, leaves, and stems of Gaultheria procumbens are polyphenol-rich herbal medicines with anti-inflammatory and antioxidant effects. The present study focused on identifying active markers of the G. procumbens extracts in an integrated approach combining phytochemical and biological capacity tests. The target compounds, representing all classes of Gaultheria polyphenols, were pre-selected by LC-ESI-PDA-MS/MS. For unambiguous identification, the key analytes, including a rare procyanidin trimer (cinnamtannin B-1), miquelianin potassium salt, and two new natural products: quercetin and kaempferol 3-O-β-d-xylopyranosyl-(1→2)-β-d-glucuronopyranosides, were isolated by preparative HPLC and investigated by spectroscopy (HR-ESI-MS, UV-vis, CD, 1D- and 2D-NMR), thiolysis, flame photometry, optical rotation experiments, and absolute configuration studies. The significant contribution of the pre-selected compounds to the biological effects of the extracts was confirmed in vitro: the analytes significantly and in a dose-dependent manner down-regulated the pro-oxidant and pro-inflammatory functions of human neutrophils ex vivo (inhibited the release of reactive oxygen species, IL-1β, TNF-α, and neutrophils elastase, ELA-2), inhibited two key pro-inflammatory enzymes (cyclooxygenase, COX-2, and hyaluronidase), and most of them, except gaultherin, exerted potent direct antioxidant activity (ferric reducing antioxidant power and superoxide anion scavenging capacity). Moreover, cellular safety was confirmed for all compounds by flow cytometry. Eventually, as these mechanisms have been connected to the health benefits of G. procumbens, 11 polyphenols were accepted as active markers, and a simple, accurate, reproducible, and fully validated RP-HPLC-PDA method for standardisation of the target extracts was proposed.
... This process is known as the defense system of gandapura. Gaultherin has some characterictics which make it potential to become a natural aspirin, anti-cancer, antiinflamatory dan cardiopulmonary [4]. As a natural aspirin, gaultherin has a high healing power, yet, it has minimum negative effect than synthetic aspirin. ...
... Gaultherin memiliki sifat-sifat yang menjadikannya sebagai kandidat terbaik natural aspirin, anti kanker, anti inflamatory, dan cardiopulmonary (Ribnicky et al., 2003). Secara empirik tanaman dari keluarga gaultheria telah digunakan dalam pengobatan kanker dan leukimia (Hoffman, 2007). ...
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This study purposed the optimization of gaultherin production from “gandapura” by inactivating the gaultherase enzyme, including gaultherin productivity and process parameters. This research applied the combination processes of extraction-dryer, simultanously. The productivity of gaultherin was improved by adding the drying agent, such as magnesium sulfate, sodium sulfate, calcium chloride, and calcium sulfate. The optimization was conducted using a factorial design 2n. Dependent variables determined by calculating the main effects and interactions, following by the application of probability plots. During the research, the content of gaultherin, methyl salicylate, salicylic acid were measured by using a spectrophotometer and HPLC-MS. The results shows that the higher concentration of drying agent (especially calcium chloride) and ethanol, increased the content of gaultherin. However, the most influenced factor to this conducted process was pH, regarding to the concentration of ethanol. During extraction, the higher the pH, increased the active compound of gaultherin. The optimum condition of enzyme inactivation was found at pH 8 with the content of gaultherin at 14.46%. The higher the solvent concentration of ethanol, the higher content of gaultherin can be extracted. The maximum process condition regarding to ethanol concentration found at 90% with active compound concentration at 13.10%.
... The essential oil of Gaultheria procumbens contains methyl salicylate, an aspirin-like compound. This oil is marketed for external treatment of neuralgia, malign, arthralgia and other pains (Ribnicky et al., 2003;Wei-Rui et al., 2013). Recent studies have shown that Schisandra chinensis is known for its various biological and therapeutic properties, e.g. ...
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Background. In line with the current tendency towards the production of the so-called safe foods, the use of environmentally-friendly methods for the extraction of polyphenols from fruits has been sought. Citric acid is a good solvent in the preparation of phenolic compounds for the food and pharmaceutical industries because it is a natural antioxidant and is non-toxic for the environment. Furthermore, new sources of polyphenols from fruit of orchard plants that are less known in Poland have been looked for. The aim of this study was to assess the content and antiradical activity of polyphenolic compounds in fruit extracts, depending on the extraction method employed. In addition, the yield of extraction processes was assessed. Material and methods. The experimental materials were fruits of the following plants: Actinidia arguta, Crataegus monogyna, Gaultheria procumbens, Schisandra chinensis. For the extraction, aqueous solutions of citric acid (CAE) and methanol (ME) were used. The following were determined in fruit extracts: the con- tent of total phenols (TP) and anthocyanins (A), and antiradical activity (DPPH and ABTS). Results. In general, the C. monogyna fruit extracts were distinguished by the highest TP and A content. The TP and A content was significantly higher in fruit extracts obtained with the CAE method than in the ones produced with the ME method. The highest mean A/TP ratio was determined for S. chinensis fruit extracts. The antiradi- cal activity (DPPH and ABTS) in fruit extracts did not depend on an extraction method, but on fruit species. Overall, a higher yield of extraction processes was achieved for the CAE method than for the ME method. Conclusions. The present study indicates that the selected extraction methods are able to obtain polyphenolic extracts from fruits with a high antiradical activity and high yield. The use of citric acid in order to extract polyphenols from fruits may be an alternative to the conventional extraction method, while being eco-friend- ly and more effective than the latter.
... Gaultherin possesses all the beneficial activities of salicylic acid, with minimal gastric side-effects, which explains its effectiveness as a pain reliever (Ribnicky et al., 2003). Since then, wintergreen oil has become popular as an anti-inflammatory, antiseptic, and soothing agent for the digestive system, and is also known to have fungicidal properties (Ribnicky et al., 2001). ...
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Leaves of mature of Gaultheria fragrantissima Wall. plants (Indian wintergreen) were collected from various locations in the Eastern Himalayan region on the Indo-China border and were analysed by steam distillation and gas chromatography to identify an elite line that contained 1.79% (v/v) essential oils, 98% of which was methyl salicylate. Subsequently, a highly reproducible micropropagation protocol using adult shoot tips from this elite genotype was developed in order to conserve this highly-valued, endangered, woody oil-bearing aromatic shrub in India. Among several plant growth regulator (PGR) combinations tested for in vitro multiplication, up to 35 shoots per explant could be induced within 14 weeks of culture on woody plant medium (WPM) fortified only with 0.22 mg l -1 thidiazuron (TDZ). These shoots could elongate on WPM containing 1.0 mg l -1 kinetin. Rooted plantlets were acclimatised ex vivo, with 70% success. Random amplified polymorphic DNA (RAPD) analysis indicated the genetic uniformity of both the micropropagated plantlets and the donor plants. This is the first report on in vitro micropropagation of G. fragrantissima.
... In the United States, these oils are used in the food (to make chewing gums and sweets), cosmetics and pharmaceutical industries. This plant is very popular in Central and South Americas, where it is known as teaberry and used to make aromatic infusion (CLARC 1999, HUFF-MAN et al. 1994, RIBNICKY et al. 2003, SENETA, DOLATOWSKI 1997. Fruits of Eastern teaberry, owing to their content of polyphenols (catechins, quercetins), have antixodative properties (ACUNA et al. 2002, MA et al. 2001. ...
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Eastern teaberry (Gaultheria procumbens L.) is known for its high content of essential oils in leaves and fruits, which are used in the pharmaceutical, food and cosmetics industries. Recently, teaberries have been attracting more interest owing to their content of polyphenolic compounds. The purpose of our study has been to determine the content of polyphenolic compounds (anthocyanins and total phenols) as well as their antioxidative activity and the concentration of several bioelements (Ca, Mg, Fe and Zn) in extracts from fruits of Eastern teaberry harvested in three different fruit maturity stages. The content of polyphenolic compounds depended on the harvest date. The highest level of these compounds was found in extracts from teaberries collected in the full maturity phase. All teaberry extracts, independently of the harvest date, demonstrated high antioxidative activity. Among the bioelements determined, teaberry extracts contained more calcium than magnesium and more iron than zinc. The content of such bioelements as Mg, Fe and Zn (in contrast to Ca) found in teaberry extracts did not depend on the harvest date.
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Methyl salicylate (MS), the principal constituent of Wintergreen oil (WO), was obtained from salicylic acid (SA) by regioselective methylation of the carboxyl group. A new procedure involved exclusive capture of carboxylic hydrogen (-COOH) through the use of the selective base, NaHCO 3 . and methylation via an S N 2 mechanism employing the previously formed carboxylate as a nucleophile and the dimethyl sulfate [(CH 3 ) 2 SO 4 or DMS] as the electrophilic reagent or substrate in a solvent-free reaction process. The reagents were added separately. SA and NaHCO 3 was added, followed by DMS after 30 min. The reaction involved the esterification by nucleophilic substitution in Csp ³ with heating by a heating mantle. The reaction was accompanied by thin layer chromatography and gas chromatography. The conversion rate via GC was 100%, and the MS yield was 96%. The DMS used in excess was transformed into MeOH and H 2 SO 4 during the washing with water. The MeOH was stored, and H 2 SO 4 was transformed in Na 2 SO 4 by neutralization with NaOH. Na 2 SO 4 can be used as a desiccant. The simplicity of the procedure, readily available MS, short reaction times, excellent yield and mild reaction condition are other advantages of this protocol. Cytotoxicities of 50% and 64% for cultured S. aureus and metastatic melanoma cells, respectively, were observed for a concentration of 0.6 mg/mL of the MS produced, whereas no cytotoxicity against non-tumor cells was observed at this concentration, and this is considered to be the optimum concentration.
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Gaultheria procumbens L. is a medicinal plant whose aerial parts (leaves, stems, and fruits) and methyl salicylate-rich essential oil (wintergreen oil) are used in phytotherapy to treat inflammation, muscular pain, and infection-related disorders. This overview summarises the current knowledge about ethnobotany, phytochemistry, pharmacology, molecular mechanisms, biocompatibility, and traditional use of G. procumbens and the wintergreen oil distilled from different plant organs. Over 70 hydrophilic compounds, including methyl salicylate glycosides, flavonoids, procyanidins, free catechins, caffeoylquinic acids, and simple phenolic acids, have been identified in G. procumbens plant parts. Moreover, aliphatic compounds, triterpene acids, and sterols have been revealed in lipophilic fractions. Furthermore, over 130 volatile compounds have been detected in wintergreen oil with dominating methyl salicylate (96.9–100%). The accumulated research indicates that mainly hydrophilic non-volatiles are responsible for the pharmacological effects of G. procumbens, primarily its potent anti-inflammatory, antioxidant, and photoprotective activity, with mechanisms verified in vitro and ex vivo in cellular and cell-free assays. The biological effectiveness of the dominant methyl salicylate glycoside—gaultherin—has also been confirmed in animals. Wintergreen oil is reported as a potent anti-inflammatory agent exhibiting moderate antioxidant and antimicrobial activity in vitro and significant insecticidal and larvicidal capacity. Together, G. procumbens accumulate a diverse fraction of polyphenols, triterpenes, and volatiles with validated in vitro and ex vivo biological activity but with the absence of in vivo studies, especially clinical trials concerning effective dose determination and toxicological verification and technological research, including drug formulation.
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Gandapura extraction process using ethanol as a polar compound has two functions, namely: deactivating the gaultherase enzyme and extracting the active compound gaultherin. This study examines the effect of extraction using UV from the concentration of ethanol in the extraction process of gandapura leaves into gaultherin on the extraction time, with a ratio of solvent and feed of 5:1, the rotational speed of the stirrer and the rotational speed of the chopper blades are 75 and 125 rpm, respectively. Drying agent is added according to the experimental variables; the independent variables includes ethanol concentrations of 85, 90, and 96%, while the extraction times are 10, 30 and 50 min, respectively. Gaultherin concentration was obtained from HPLC Alliance 2695 (Waters) analysis with Photodiode Array Detector 2996 (Waters) at a wavelength of 254 nm. The effect of UV photo extraction on the acquisition of gaultherin compounds has succeeded in deactivating the gaultherase enzyme and opening when it is penetrated with ethanol. In this study, the peak of the dominant gaultherin compound was found at the retention time of 5.8 min, and the highest area was at 90% ethanol concentration variable with an extraction time of 50 min; the area was 22.783% of the total gaultherin area.
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This study investigates the antifungal activities of the essential oils (EO) obtained from Myrtus communis L. and Gaultheria procumbens L. leaves on foodborne yeasts, isolated from sourdough samples and the chemical compositions of the oils. The main constituents of the Myrtus communis L. EO. were 1,8-cineole (35.62 %), α-pinene (29.14 %) and α-terpineol (10.04 %). Methyl salicylate (96.87 %) and limonene (2.05 %) were identified as the major constituents in the G. procumbens L. EO. M. communis L. and G. procumbens L. EOs showed the highest antifungal activity against Torulaspora delbrueckii (27.86 mm zone diameter) and Pichia polymorpha (40.23 mm zone diameter) respectively. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of the M. communis L. and G. procumbens L. EOs were in the range of 46,87-562.50 μg/mL / 23.44-375.0 μg/mL and 4.39-562.50 μg/mL / 2.93-156.25 μg/mL, respectively.
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Gaultheria longibracteolata (Ericaceae) has been traditionally used by different linguistic groups in Yunnan Province, China, but it has not been well studied. Through our ethnobotanical study in Lüchun County of Yunnan, we found that this species has multiple traditional uses including food, medicine, and worship. The essential oils from the root, stem, and leaf were investigated by both GC–MS and anti-bacterial assays. The GC–MS study showed that methyl salicylate is the main (>90%) component of the essential oil, and the oil composition extracted from different plant parts showed some similarities. The oil of G. longibracteolata displayed antimicrobial activity against Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus, which is likely due to its methyl salicylate content. Gautheria longbracteolata appears to be a useful natural wintergreen oil substitute, but further studies are needed to develop this product.
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The fruits of Gaultheria procumbens are traditionally used for culinary and healing purposes as anti-inflammatory agents. In the present work, the active components of the fruits were identified (UHPLC-PDA-ESI-MS³, preparative HPLC isolation, and NMR structural studies), and their biological capacity was evaluated in vitro in cell-based and non-cellular models. The fruits were revealed to be the richest known dietary source of salicylates (38.5 mg per g fruit dw). They are also rich in procyanidins (28.5 mg per g fruit dw). Among five tested solvents, acetone was the most efficient in concentrating the phenolic matrix (39 identified compounds; 191.3 mg g⁻¹, 121.7 mg g⁻¹, and 50.9 mg g⁻¹ dry extract for total phenolics, salicylates, and procyanidins, respectively). In comparison to positive controls (dexamethasone, indomethacin, and quercetin), the extract (AE) and pure salicylates exhibited strong inhibitory activity towards pro-inflammatory enzymes (cyclooxygenase-2 and hyaluronidase). The analytes were found to be non-cytotoxic (flow cytometry) towards human neutrophils ex vivo. Moreover, they significantly, in a dose-dependent manner, downregulated the release of ROS, TNF-α, IL-1β, and elastase-2 and slightly inhibited the secretion of IL-8 and metalloproteinase-9 in the cells. The observed effects might support the usage of G. procumbens fruits as functional components of an anti-inflammatory diet and indicate the potential of AE for use in adjuvant treatment of inflammatory disorders cross-linked with oxidative stress and associated with the excessive production of TNF-α, IL-1β, and elastase-2.
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The essential oil of wintergreen, which is extracted by steam distillation from Gaultheria genus leaves, is mainly used in aromatherapy. However, due to its adulteration easiness with synthetic material, it is necessary to control samples naturalness with accuracy. The purpose of this work was to develop a methodology to authenticate the essential oil of wintergreen. Wintergreen essential oil is composed of more than 99% methyl salicylate. This aromatic ester can be easily synthesized and used to adulterate wintergreen essential oil. Authentic wintergreen essential oil can be distinguished from adulterated oils by examining their compositions. The detection of methyl salicylate synthetic marker compounds (methyl 4-hydroxybenzoate, dimethyl 4-hydroxyisophthalate or dimethyl 2-hydroxyisophthalate) or the absence of several naturally occurring minor secondary metabolites (ethyl salicylate and vitispirane) contribute to the authentication. Isotopic values of bulk wintergreen essential oil have also been determined using an isotope ratio mass spectrometer (IRMS): the δ¹³C values of authentic samples range from −36.78 to −33.36‰, the δ²H values range from −173 to −115‰ and the δ¹⁸O values range from −1.3 to 5.7‰. However, these analytical methods cannot account for the natural variability in the essential oils. To determine the boundaries of the natural isotopic values, ¹⁴C radioactive isotope activity assessment was undertaken, which allows for the determination of the genuineness of samples that are not assessed using multistable isotope approaches. Additional studies evaluating ¹⁴C activity of a noncompliant sample using IRMS identified a ¹⁴C-labeled synthetic methyl salicylate adulteration.
Thesis
Dans le contexte actuel de méfiance de la population vis-à-vis des médicaments allopathiques (affaire du Mediator®, déremboursements massifs), on enregistre logiquement à l'officine un intérêt croissant des patients pour l'homéopathie et la phytothérapie. Les plantes médicinales bénéficient en général d'une excellente réputation concernant leur innocuité. La croyance naïve qui implique que « naturel » est par définition inoffensif, relayée par les médias et par une certaine confusion avec l'agriculture biologique,doit être appréhendée par le pharmacien d'officine afin d'éviter les accidents médicamenteux.Ce document entreprend d'inventorier les plantes médicinales dont l'utilisation pourrait modifier l'efficacité d'une certaine classe thérapeutique, les antithrombotiques. Parmi eux, les antagonistes de la vitamine K, dont on mesure très facilement les variations d'efficacité in vivo, sont qualifiés demédicaments à marge thérapeutique étroite, ce qui signifie que les conséquences d'un mauvais dosage ou d'une interaction peuvent être gravissimes pour la santé du patient (thrombose ou hémorragie).Cette liste de plantes, non exhaustive, est regroupée alphabétiquement en tableau à la fin du document, afin d'en faciliter la consultation.
Chapter
Salicylic acid (SA) and its derivatives are the most widely known drugs in the world used to reduce pain and fever, helping to treat many inflammatory diseases, in the prevention of coronary heart disease and heart attacks, and in tumor suppression. This substance is also characterized by a high metabolic and physiological activity, which enables it to perform regulatory functions in plant development and reaction to biotic and abiotic stress factors. Under non-stress conditions, SA is present in plant tissues in quantities of several mg to several ng in one g of fresh mass. Its level substantially increases in plants exposed to water deficit. The accumulation of SA may result from its de novo synthesis through activation of enzymes involved in the synthesis of SA from phenylalanine, i.e. phenylalanine ammonia lyase (PAL) and benzoic-acid-2-hydroxylase (BA2H). SA accumulated in plants growing under the conditions of water shortage may be involved in the regulation of mechanisms responsible for resistance to drought through the control of water balance and activation of antioxidant system. Large body of evidences revealed that exogenous application of SA was effective in modeling plant responses to water deficit. Plant pre-treatment with SA resulted in higher tissue water content, increased activity of antioxidant enzymes, decreased level of lipid peroxidation and membrane injury and it also protected nitrate reductase activity against inhibition under water deficit conditions. These changes enable plants to survive under drought and play an essential role in countering the adverse effects of stress on growth and yield.
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Indian winter green (Gaultheria fragrantissima) is an endengered aromatic plant containing highest amount of methyl salicyate among the plant kingdom. Earlier, wide ranging oil bearing capabilities of the populations of G. fragrantissima were identified by us. Therefore, random amplified polymorphic DNA (RAPD) was used to fingerprint 23 genotypes of eastern Himalayas. A high degree of polymorphism was detected with 5 informative primers, namely OPE-3, OPE4, OPE-7, OPE-18 and OPE-20. Among these, OPE-03 produced the highest (87.5%) while OPE-07 produced the lowest (53.85%) degree of polymorphism. While the extent of total variability was recorded to be 68.25%, the inter- and intra- population variability was found to be 53% and 46%, respectively. A resemblance matrix was developed, using Simple Matching Coefficient, to compute cluster analysis. It was concluded that the RAPD markers detected a sufficient degree of polymorphism to differentiate among the Gaultheria genotypes, which will be useful for conservation of this endengered plant species.
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Humans have two isoforms of Prostaglandin H Synthase or cyclooxygenase: COX-1 and COX-2. COX-1 is cytoprotective. COX-2 inhibitors reduce inflammation without the risk of ulceration and kidney damage. The ideal nutraceutical would inhibit COX-2 synthesis while preserving COX-1 synthesis. The hypothesis for this research was that COX inhibitors would fall primarily into three categories: COX-2 specific inhibition, non-specific inhibition (COX-1 and COX-2), and minimal inhibition. The human Cayman COX inhibitor screening assay was used to determine the inhibitory concentration 50 (IC50) of COX-1/ COX-2 activity of each nutraceutical. The assay was run, in duplicate, with three concentrations of a suspected inhibitor, a standard curve of eight concentrations, a non-specific binding sample, and a maximum binding sample. The inhibition and concentration of each sample was then put on a multiple regression best-fit line and the IC50 determined. For comparison, ibuprofen, rofecoxib, naproxen, and indomethacin were used. Positive results were seen for ipriflavone, resveratrol, MSV-60, amentoflavone, ruscus extract and notoginseng. Glucosamine, nexrutine, and berberine did not inhibit either isoform.
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The natural trigger for heat production in the thermogenic inflorescences of Sauromatum guttatum Schott (voodoo lily) was recently identified as salicylic acid (SA), which induced heat production at levels as low as 13 ng g f. wt -1. Since then the levels of SA were determined in other thermogenic and non-thermogenic plant species. In thermogenic inflorescences of five aroid species, and in male cones of at least four thermogenic cycads SA levels during heat production exceeded 1 μg g f. wt -1. SA was not detected in the thermogenic flowers of a water lily, Victoria regia Lindl. (Nymphaeaceae), and Bactris major Jacq. (Palmae). Levels of salicylic acid varied substantially in the floral parts of seven non-thermogenic species and in the leaves of 27 non-thermogenic species.
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Salicylic acid (SA) is hypothesized to be a natural signal that triggers the systemic induction of pathogenesis-related proteins and disease resistance in tobacco. When Xanthi-nc (NN genotype) tobacco was inoculated with tobacco mosaic virus (TMV) there was an increase in endogenous SA in both inoculated and virus-free leaves. The highest levels of SA were detected in and around necrotic lesions that formed in response to TMV. Chemical and enzymatic hydrolysis of extracts from TMV-inoculated leaves demonstrated the presence of a SA conjugate tentatively identified as O-beta-D-glucosyl-SA. The SA conjugate was detected only in leaves that contained necrotic lesions and was not detected in phloem exudates or uninoculated leaves of TMV-inoculated Xanthi-nc tobacco. When exogenous SA was fed to excised tobacco leaves, it was metabolized within 10 hr. However, this reduction in free SA did not prevent the subsequent accumulation of the PR-1 family of pathogenesis-related proteins. The absence of SA accumulation in TMV-inoculated tobacco plants incubated at 32 degrees C was not a result of the glucosylation of SA. The addition of SA to the medium elevated levels of SA in the leaves of virus-free tobacco grown hydroponically. Increasing the endogenous level of SA in leaves to those naturally observed during systemic acquired resistance resulted in increased resistance to TMV, expressed as a reduction in lesion area. These data further support the hypothesis that SA is a likely natural inducer of pathogenesis-related proteins and systemic acquired resistance in TMV-inoculated Xanthi-nc tobacco.
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Lipid bodies, cytoplasmic inclusions that develop in cells associated with inflammation, are inducible structures that might participate in generating inflammatory eicosanoids. Cis-unsaturated fatty acids (arachidonic and oleic acids) rapidly induced lipid body formation in leukocytes, and this lipid body induction was inhibited by aspirin and nonsteroidal antiinflammatory drugs (NSAIDs). Several findings indicates that the inhibitory effect of aspirin and NSAIDs on lipid body formation was independent of cyclooxygenase (COX) inhibition. First, the non-COX inhibitor, sodium salicylate, was as potent as aspirin in inhibiting lipid body formation elicited by cis-fatty acids. Second, cis-fatty acid-induced lipid body formation was not impaired in macrophages from COX-1 or COX-2 genetically deficient mice. Finally, NSAIDs inhibited arachidonic acid-induced lipid body formation likewise in macrophages from wild-type and COX-1- and COX-2-deficient mice. An enhanced capacity to generate eicosanoids developed after 1 hr concordantly with cis-fatty acid-induced lipid body formation. Arachidonic and oleic acid-induced lipid body numbers correlated with the enhanced levels of leukotrienes B4 and C4 and prostaglandin E2 produced after submaximal calcium ionophore stimulation. Aspirin and NSAIDs inhibited both induced lipid body formation and the enhanced capacity for forming leukotrienes as well as prostaglandins. Our studies indicate that lipid body formation is an inducible early response in leukocytes that correlates with enhanced eicosanoid synthesis. Aspirin and NSAIDs, independent of COX inhibition, inhibit cis-fatty acid-induced lipid body formation in leukocytes and in concert inhibit the enhanced synthesis of leukotrienes and prostaglandins.
Chapter
This chapter discusses salicylic acid and its derivatives in plants. The medicinal uses of concoctions of the bark of willow, spiraea, and related plants, were the cause of salicylates receiving early attention from both chemists and pharmacologists. The medicinal uses of these barks seems to have been appreciated by “pre-industrial” cultures as far apart as South Africa and North America and were known in a more systematic way to the medical philosophers of classical Greece and Rome. Salicylates, especially aspirin, but also salicylic acid itself, its sodium salt, its methyl ester and its amide are important medicinally because of their analgesic, anti-inflammatory, and anti-pyretic properties. They are comparatively safe, non-sedative, non-narcotic, nonaddictive, and cheap. More recently aspirin has been used to decrease the likely occurrence of secondary thromboses in people with appropriate cardiovascular diseases and its use as a prophylactic against the occurrence of cardiovascular and cerebrovascular thrombotic events has been the source of much study and comment. Because of their widespread use, often in massive doses, the toxicity of salicylates has also received much attention. Therapeutic doses of aspirin can induce gastric bleeding in sensitive patients. This had led to changes of tablet formulation, including more rapidly disintegrating, more readily soluble and buffered, effervescent preparations. Other acute symptoms of salicylate toxicity, occurring in long-term medication with very high doses, include deafness, tinnitus and extreme nausea, and vomiting. Chronic, event fatal, salicylate poisoning, either accidental or deliberate, has been comparatively common.
Article
Salicylic acid (SA) is an important component of systemic-acquired resistance in plants. It is synthesized from benzoic acid (BA) as part of the phenylpropanoid pathway. Benzaldehyde (BD), a potential intermediate of this pathway, was found in healthy and tobacco mosaic virus (TMV)-inoculated tobacco (Nicotiana tabacum L. cv Xanthi-nc) leaf tissue at 100 ng/g fresh weight concentrations as measured by gas chromatography-mass spectrometry. BD was also emitted as a volatile organic compound from tobacco tissues. Application of gaseous BD to plants enclosed in jars caused a 13-fold increase in SA concentration, induced the accumulation of the pathogenesis-related transcript PR-1, and increased the resistance of tobacco to TMV inoculation. [¹³C6]BD and [²H5]benzyl alcohol were converted to BA and SA. Labeling experiments using [¹³C1]Phe in temperature-shifted plants inoculated with the TMV showed high enrichment of cinnamic acids (72%), BA (34%), and SA (55%). The endogenous BD, however, contained nondetectable enrichment, suggesting that BD was not the intermediate between cinnamic acid and BA. These results show that BD and benzyl alcohol promote SA accumulation and expression of defense responses in tobacco, and provide insight into the early steps of SA biosynthesis.
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The formation rate of aspirin from the prodrug was determined as a function of the pH, temperature, and dielectric constant of the solvent spectrophotometrically and was confirmed by high-pressure liquid chromatography. Aspirin formation was first order with respect to the prodrug and zero order with respect to the hydroxide-ion concentrations. The hydrolysis rate was independent of buffer concentration but very sensitive to the dielectric constant of the solvents. The half-life for the formation of aspirin at 37° was 7 min. The activation energy for the hydrolysis was 23.7 kcal/mole. The results suggest that the hydrolysis of the prodrug to aspirin proceeds by an SN1-type mechanism.
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A new mass spectrometric assay is described for the accurate quantification of salicylic acid in plant tissues, using [2H3]-labelled salicylic acid as an internal standard.
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The pharmacokinetics of acetylsalicylic acid (ASA, 650 mg.) and salicylic acid (SA, 500 mg.) were studied following intravenous administration in males. The resultant plasma concentration-time curves were described by bi-exponential equations. The half-life of the first exponent was 2–5 min. for both compounds while that of the second exponent was 13–19 min. and 3.5–4.5 hr. for ASA and SA, respectively. Over the dose range 0.3–1.2 g. ASA, the area under the ASA plasma concentration-time curve was proportional to the dose administered. Also SA was shown to be the exclusive metabolite of ASA. Analysis of the present results, over the dose range and duration of study, showed that the data could best be fitted by conceiving the body to act as a two-compartmental open system with respect to these drugs. The significance of these findings on measurement of the rate constants of metabolism, volume of distribution, and other pharmacokinetic parameters are discussed.
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A review with 102 references to literature, with the following chapters: introduction; chemistry; pharmacologic effects, absorption, distribution, metabolism, excretion, side effects and toxicology; drug interactions involving acetyl salicylic acid and a list of medications containing aspirin is given.
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The effect of a new aspirin derivative, aspirin-isopropylantipyrine (AIA), with very little gastric ulcerogenic activity and very slight acute toxicity and with analgesic, antipyretic anti-inflammatory, and platelet aggregation inhibitory activities was evaluated in vitro and ex vivo and compared with those of aspirin and isopropylantipyrine (IA). In vitro, AIA, aspirin and IA (50-200 microM) caused concentration-dependent inhibition of collagen-induced aggregation in rabbit platelets although AIA was several-fold more active than the others Arachidonic acid-induced aggregation was inhibited by all three agents (200 microM) in the following magnitude; IA greater than aspirin greater than AIA. Three agents did not influence primary ADP-induced aggregation. The in vitro effects on the release-inducing aggregants were confirmed by ex vivo experiments in rats. These demonstrated that AIA and aspirin (50 mg/kg) exhibited almost identical inhibitory potencies in the extent and the rate of collagen-induced aggregation 4 h after subcutaneous injection. AIA was still effective 24 h after administration as well as aspirin. IA was less effective, differing from the results in vitro. AIA had no effect on plasmin activity and blood flow through the common carotid artery. AIA (1 mM) maintained spreading and beating of myocardial cells in a serum-free culture. As special toxicity trials on AIA mutagenecity tests were made by the Rec-assay with Bacillus subtilis, by the plate culture with Escherichia coli, and by the Ames system with Salmonella typhimurium. AIA was found to have no mutagenic effect under any of those methods and to have no effect on the mutagenic action of 3, 4-benzopyrene under the liver microsome test using the Ames system.
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A triglyceride of aspirin, A-45474: [2-(1,3-didecanoyloxy)-propyl]2-acetyloxybenzoate, was developed to reduce the direct gastric irritant properties of aspirin. Studies in the rat show that oral administration of A-45474 produces anti-inflammatory activity comparable to aspirin with negligible gastric irritation. Compared with aspirin, plasma salicylate levels of A-45474 appeared less rapidly and were more sustained. It is concluded that incorporation of aspirin in the 2-position of a triglyceride bearing n-decanoyl groups in the 1- and 3-positions markedly reduces the gastric irritating properties of aspirin while maintaining its pharmacological effects.
Article
The methyl and some other esters of acetylsalicylic and salicylic acids and their derivatives were found to have much lower gastric ulcerogenic activity (when assayed in the stress-sensitized rat) compared with their corresponding acids. There was little or no loss in therapeutic potencies of these salicylate esters as determined by assessment of anti-inflammatory activity (against the carrageenan-induced oedema) and antipyretic activity (against yeast-induced fever in rats. The methyl ester of acetylsalicylic acid (=AME) was almost devoid of gastric irritancy/ulcerogenicity (as observed with acetylsalicylic acid) when given orally to pigs for 10 days. AME had appreciable anti-inflammatory activity in the adjuvant-arthritis model and at high doses (200 mg/kg t.i.d.) was without the lethal effects seen with acetylsalicylic acid. Moreover, no toxic effects were seen after long-term administration of 100–1000 mg/kg/day AME for 3–4 months. The results provide further evidence for the hypothesis that the carboxylic acid moiety of salicylates is a major factor in the gastric ulcerogenic activity of these drugs. The methyl esters of these salicylates may be considered as models for the development of pro-drugs and in some cases may be therapeutic alternatives to acetylsalicylic acid or salicylate.
Article
A series of 1,3-dialkanoyl-2-(2-methyl-4-oxo-1,3-benzodioxan-2-yl)glycerides ("cyclic aspirin triglycerides") was synthesized. They demonstrated essentially all the systemic antiinflammatory activity associated with aspirin in the carrageenin-induced rat paw edema test. Examination of the rat stomachs showed that the 1,3-didecanoyl derivative did not cause gastric lesions.
Article
There is much (renewed) interest about the effects of salicylates on food intolerance, attention-deficit disorders, and cardiovascular disease. Current evidence for the efficacy of salicylate-elimination diets in the treatment of attention-deficit disorders and hyperactivity is weak, and further investigation is required on the relationship between salicylates and cardiovascular disease.
Article
Aspirin, along with its analgesic-antipyretic uses, is now also being considered for prevention of cardiovascular disease, cancer, and treatment of human immunodeficiency virus infection. Although many of aspirin's pharmacological actions are related to its ability to inhibit prostaglandin biosynthesis, some of its beneficial therapeutic effects are not completely understood. Transcription factor activator protein 1 (AP-1) is critical for the induction of neoplastic transformation and induction of multiple genes involved in inflammation and infection. We have used the JB6 mouse epidermal cell lines, a system that has been used extensively as an in vitro model for the study of tumor promotion and anti-tumor promotion, to study the anti-carcinogenesis effect of aspirin at the molecular level. Aspirin and aspirin-like salicylates inhibited the activation of AP-1 in the same dose range as seen for the inhibition of tumor promoter-induced transformation. The inhibition of AP-1 and tumor promoter-induced transformation in JB6 cells occurs through a prostaglandin independent- and an Erk1- or Erk2-independent pathway. The mechanism of AP-1 and transformation inhibition in this cell culture model may involve the elevation of H+ concentration. The inhibition effects on the activation of AP-1 activity by aspirin and aspirin-like salicylates may further explain the anti-carcinogenesis mechanism of action of these drugs.
Article
The history of aspirin can be traced back to ancient Egypt where extract of willow bark was used to treat inflammation. The active component of the extract was identified as the glucoside of salicylic alcohol. The severe gastric side effects associated with the use of sodium salicylate prompted the synthesis of the o-acetyl-derivative as a possible pro-drug. In fact, acetylsalicylic acid was antiinflammatory, analgesic and antipyretic but also ulcerogenic to the stomach. Acetylsalicylic acid was synthesized one hundred years ago, and was mass-produced under the commercial name of 'Aspirin' (Dreser, 1899) by the German company Bayer for the treatment of fever and rheumatism.
Article
The first clinical reports on the treatment of fever and pain with salicylate-containing natural willow bark remedies were made by the English clergyman Edward Stone in 1763. The pharmacologically active principles were isolated from natural sources by Italian, German and French scientists between 1826 and 1829. Salicylic acid was first synthesised by the German Gerland in 1852 and a year later the Frenchman Gerhardt synthesised acetylsalicylic acid. The first reports on the clinical use of salicylic acid in rheumatic disorders were made independently by the two German physicians Stricher and Reiss in 1876. Acetylsalicylic acid was rediscovered by Hoffmann in 1897 and by the turn of the century it had gained worldwide recognition in the treatment of pain and rheumatological disorders. Reports on adverse events relating to gastrointestinal intolerance and bleeding appeared early, but were largely neglected until the 1950s. Today, salicylates are still widely used as analgesic, antipyretic and anti-inflammatory drugs. New indications, such as thrombosis prophylaxis, have emerged during the last decades, and yet others are being explored.
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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.
Article
The potential use of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancers has been highlighted recently. However, it is not known whether NSAIDs could also be useful for preventing esophageal cancer, although regular users of these drugs appear to have a decreased incidence of esophageal cancer. Therefore, we examined the effect of aspirin on growth and apoptosis in 10 esophageal cancer cell lines as well as the expression and modulation of its target enzymes, cyclooxygenases (COXs), and their product prostaglandin E2. Growth inhibition of these cells by aspirin was dose- and time-dependent and associated with the induction of apoptosis. COX-1 and COX-2 were expressed in 7 of the 10 cell lines. Bile acids could induce COX-2 expression in six of eight cell lines tested, which was correlated with prostaglandin E2 production, and aspirin could inhibit COX-2 enzymatic activity even after bile acid stimulation but was unable to change the COX-2 protein level in these cell lines. Down-regulation of bcl-2 by aspirin was found in the two cell lines tested. These results suggest that induction of apoptosis by aspirin may be a mechanism by which it can intervene in esophageal carcinogenesis and may be indicative of the potential of NSAIDs as chemopreventive agents in esophageal cancer.
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A debate has emerged about how NSAIDs - nonsteroidal anti-inflammatory drugs - protect against colon and other cancers.
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To determine serum salicylic acid concentrations in non-vegetarians and vegetarians not taking salicylate drugs, and to compare these concentrations with those found in patients taking aspirin, 75 mg daily. Serum samples were obtained from vegetarians (n = 37) and non-vegetarians (n = 39) not taking salicylate drugs. Non-vegetarians and vegetarians were recruited from the community and from a Buddhist monastery, respectively, in Dumfries and Galloway, Scotland. Patients (n = 14) taking aspirin (75 mg daily) were recruited from the Dumfries diabetic clinic. Serum salicylic acid concentrations were determined using a high performance liquid chromatography method with electrochemical detection. Salicylic acid was detected in every serum sample analysed. Higher serum concentrations of salicylic acid were found in vegetarians than non-vegetarians: median concentrations of 0.11 (range, 0.04-2.47) micromol/litre and 0.07 (range, 0.02-0.20) micromol/litre, respectively; the median of the difference was 0.05 micromol/litre (95% confidence interval for difference, 0.03 to 0.08; p < 0.0001). The median serum concentration of salicylic acid in patients taking aspirin (75 mg daily) was 10.03 (range, 0.23-25.40) micromol/litre, which was significantly higher than that found in non-vegetarians and vegetarians. There was overlap in serum salicylic acid concentrations between the vegetarians and patients taking aspirin. Salicylic acid, a non-steroidal anti-inflammatory drug, is present in fruits and vegetables and is found in higher concentrations in vegetarians than non-vegetarians. This suggests that a diet rich in fruits and vegetables contributes to the presence of salicylic acid in vivo. There is overlap between the serum concentrations of salicylic acid in vegetarians and patients taking aspirin, 75 mg daily. These findings may explain, in part, the health promoting effects of dietary fruits and vegetables.
History, uses, labeling and poison-prevention packaging
  • B Bharat
Aspirin, after more than 200 years, the mechanisms by which this venerable drug and its relatives achieve their wide range of effects have yet to be fully elucidated
  • Weissman Gerald
Pharmacokinetics of salicylates
  • J J Theissen
  • Barnett
  • Hjm
  • Hirsh
  • J Mustard
13C6-[benzene ring]-indole-3-acetic acid
  • J D Cohen
  • B Baldi
  • J Slovin
Observations on the volatile oil of Betula lenta, and on gaultherin, a substance which, by its composition, yields that oil
  • W Proctor
Le primeverose, les primeveroides et la prime-verosidase
  • M Bridel
  • M Guignard
Sur la preparation et les propietes du monotropitoside
  • M M Bridel
  • Picard
  • M L Guignard
Pharmacological studies in the rat with [2-(1,3-didecanoyloxy)-propyl]2-acetyloxybenzoate (A-45474): An aspirin pro-drug with negligible gastric irritation
  • G W Carter
  • P R Young
  • L R Swett
  • G Paris
Salicylates inhibit adhesion and transmigration of T lymphocytes by preventing integrin activation induced by contact with endothelial cells
  • R Gerli
  • C Paolucci
  • P Gresele
  • O Bistoni
  • S Fiorucci
  • C Muscat
  • S Belia
  • Bertotto
  • V Constantini
Synthesis of glucosides. Part VII, the synthesis of monotropidoside (gaultherin)
  • Robertson
  • R Walters
Methyl salicylate, or oil or win-tergreen
  • Clark Iv George Stuart
Potent platelet anti-aggregant activity and no mutagenicity of aspirin-isopropylantipyrene (AIA)
  • S Aounuma
  • Y Kohama
  • Fujimoto
  • T Makino
Health effects of sa-licylates in food and drugs
  • C A Perry
  • J Dwyer
  • J A Gelfand
  • Couris
  • W W Mcclosky
Etude biochimique sur la composition du Mono-tropa hypopitys L. Obtention d un nouveau glucoside a salicylate de methyle, la monotropitine
  • M Bridel
  • M Guignard
Sur l hydrolyse fermentaire de la monotropitine
  • M Bridel
  • M Guignard
Caracteres et composition du prime-verose
  • A Goris
  • Vischniac
  • M L Guignard
Le glucoside a salicylate de methyle du Gaultheria procumbens L. este le monotropitoside
  • M Bridel
  • S Grillon
Sur un complexe glucosidique instable de l ecorce de tige de nerpun purgati
  • M Bridel
  • M Guignard