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ABSTRACT: The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg(-1), the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(beta-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg(-1), reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18-44 microM). Ferruginol and compounds 5-9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19-56 microM), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg(-1) and cytotoxicity >1000 microM towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time.
Journal of Pharmacy and Pharmacology 02/2007; 59(2):289-300. · 2.17 Impact Factor
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ABSTRACT: The gastroprotective effect of the sesquiterpene cyperenoic acid and seven semi-synthetic derivatives was assessed in the HCl/ethanol-induced gastric ulcer model in mice. At doses of 25, 50 and 100 mg kg(-1), cyperenoic acid showed a dose-dependent gastroprotective effect reducing the lesions by 45 and 75% at 50 and 100 mg kg(-1), respectively. Seven derivatives of the sesquiterpene were prepared and their gastroprotective activity compared at 50 mg kg(-1). The cytotoxicity of the compounds was evaluated in fibroblasts and AGS cells. At 50 mg kg(-1), patchoulan-15-oic acid (compound 8) presented the best gastroprotective effect, reducing the gastric lesions by 86%, with a similar effect to lansoprazole at 20 mg kg(-1). The gastroprotective effect of cyperenol, cyperenoic acid methyl ester and the ethylamide and butylamide from cyperenoic acid were in the same range, reducing the gastric lesions by 72-77%. Cyperenol and cyperenoic acid methyl ester, however, were more cytotoxic with IC50 (concentration that produces a 50% inhibitory effect) values of 44 and 75, 48 and 75 microM against AGS cells and fibroblasts, respectively. The best gastroprotective effect with lower cytotoxicity was found for the compound 8, cyperenoic acid and the p-anisidyl derivative 7.
Journal of Pharmacy and Pharmacology 12/2006; 58(11):1507-13. · 2.17 Impact Factor
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ABSTRACT: The triterpene oleanolic acid 1 and its semisynthetic derivatives 2-7 were assessed for gastroprotective and ulcer-healing effect using human epithelial gastric cells (AGS) and human lung fibroblasts (MRC-5). The ability of the compounds to protect the AGS cells against the damage induced by sodium taurocholate (NaT), to stimulate the cellular reduced glutathione (GSH) and prostaglandin E(2) content, to enhance AGS and MRC-5 cell proliferation and to scavenge superoxide anion in vitro was studied. The cytotoxicity of the compounds was assessed towards MRC-5 and AGS cells. In addition, the gastroprotective activity of the compounds was assessed in vivo using the HCl/EtOH-induced ulcer model in mice. All the assayed compounds displayed a significant reduction of AGS cells damage after incubation with NaT. None of the studied compounds was active as a superoxide anion scavenger nor stimulated the GSH content in AGS cell cultures. Compounds 1, 2, 4 and 6 were able to increase the prostaglandin content in AGS cell cultures. Concerning the proliferation assays, a significant stimulating effect was observed for compounds 3 and 7 on AGS cells and for 1 and 7 on MRC-5 fibroblasts. Regarding cytotoxicity, derivatives 2, 4, 6 and 7 were less toxic than the parent compound oleanolic acid. Our results strongly support the predictive capacity of the in vitro assessment of gastroprotective activity allowing the reduction of experimental animals.
Life Sciences 09/2006; 79(14):1349-56. · 2.53 Impact Factor
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ABSTRACT: An infusion or decoction of the aerial parts of Fabiana imbricata (Solanaceae) is used in traditional medicine in Chile and Argentina as a digestive and diuretic agent. The main sesquiterpene of the plant was identified as 11-hydroxy-4-amorphen-15-oic acid. At doses of 25, 50 and 100 mg/kg, the compound showed a dose-dependent gastroprotective effect in HCl/EtOH-induced gastric lesions in mice reducing the lesions by 68% at 100 mg/kg. Seven derivatives of the terpene were prepared and their gastroprotective effect was assessed in HCl/EtOH-induced gastric lesions in mice. The cytotoxicity of the products was evaluated in fibroblasts and AGS cells. At 100 mg/kg, 11-hydroxy-4-amorphen-15-p-toluidinamide presented the best gastroprotective effect reducing the gastric lesions by 80%, showing a similar effect to lansoprazole at 20 mg/kg. The compound, however, presented higher cytotoxicity than other derivatives with the IC50 ranging between 110 and 145 microm in AGS cells and fibroblasts, respectively. Most compounds proved to be non-toxic showing cytotoxicity values higher than 1000 microm. The spectroscopic data of six 11-hydroxy-4-amorphen-15-oic acid derivatives are presented here for the first time.
Phytotherapy Research 01/2006; 19(12):1038-42. · 2.09 Impact Factor
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ABSTRACT: The labdane diterpene solidagenone 1 and its semisynthetic and biotransformation derivatives 2-10 were assessed for gastroprotective and ulcer-healing effect using human epithelial gastric cells (AGS) and human lung fibroblasts (MRC-5). The ability of the compounds to protect the AGS cells against the damage induced by sodium taurocholate (NaT), to stimulate the cellular reduced glutathione (GSH), prostaglandin E(2) content, enhance AGS and MRC-5 cell proliferation and to scavenge superoxide anion in vitro was studied. The cytotoxicity of the compounds was assessed towards MRC-5 fibroblasts and AGS cells. A significant reduction of cell damage after NaT incubation was observed when the AGS cells were pretreated with compounds 2 and 6. Treatment with compounds 4-6, 8 and 9 significantly stimulated the GSH content in AGS cell cultures. None of the studied compounds was active as a superoxide anion scavenger. In AGS cells treated with compounds 1-10, only compound 5 was able to increase prostaglandin content. Concerning the proliferation assays, a significant stimulating effect was observed for compounds 2, 8, 9 on AGS cells and for 5, 7-9 on MRC-5 fibroblasts. Regarding cytotoxicity, solidagenone showed higher toxicity while compounds 4 and 7 were the less toxic. Our results showed that most of the studied compounds act in vitro as gastroprotectors increasing the cellular GSH content. Additionally, some derivatives exhibited in vitro ulcer-healing effect stimulating the cell proliferation.
Life Sciences 10/2005; 77(17):2193-205. · 2.53 Impact Factor
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ABSTRACT: "Bailahuén" is the common name of a medicinal shrub native to Chile where this resinous herb is widely used for its liver stimulating properties. Although the official species is Haplopappus baylahuen Remy (Asteraceae), other species of the same genus are also used in different regions as "bailahuén". A thin layer chromatography (TLC) method for rapid identification of different species and detection of adulterations is described for four of the species: Haplopappus baylahuen, Haplopappus taeda Reiche, Haplopappus multifolius Phil., and Haplopappus remyanus Wedd. To confirm efficiency in all species antioxidant properties were screened in resins, infusions, and methanolic extracts by tests of lipid peroxidation in erythrocytes and free radical scavenging activity by DPPH. In both studies Haplopappus baylahuen showed the lowest antioxidant capacity. In DPPH analyses, infusion and resins of Haplopappus baylahuen also showed the lowest and Haplopappus remyanus the major inhibiting activity of free radicals, while Haplopappus multifolius proved to have the highest result when the methanolic extracts were used. The chemical characterization of the studied species showed important levels of flavonoids and coumarins, with flavonoids predominating in Haplopappus taeda, coumarins in Haplopappus multifolius and both of them in Haplopappus baylahuen and Haplopappus remyanus.
Journal of Ethnopharmacology 03/2005; 97(1):97-100. · 3.01 Impact Factor
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ABSTRACT: The gastroprotective activity of the new semi-synthetic solidagenone derivative 15,16-epoxy8(9),13(16),14-labdatrien-7 beta-methoxy-6 beta-ol (ELMO) has been assessed on the model of HCl/EtOH-induced gastric lesions in mice. Human gastric epithelial cells (AGS) and fibroblasts (MRC-5) were used to determine its mode of action. The effect of ELMO on the prostaglandin E2 content, cellular reduced glutathione (GSH) and protection against damage induced by sodium taurocholate was assessed against AGS cells. The effect of ELMO on the growth of AGS and fibroblast cultures was evaluated. The superoxide anion scavenging capacity of the compound was studied also. The cytotoxicity of ELMO, expressed as cell viability, was assessed using two independent endpoints: neutral red uptake (NRU) and the reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for MRC-5 fibroblasts and NRU for AGS cells. A single oral dose of ELMO (10 and 20 mg kg(-1)) inhibited the appearance of gastric lesions in mice displaying similar values to lansoprazole at 20 mg kg(-1). At 40 microM ELMO increased the prostaglandin E2 content but not GSH in AGS cells. The compound showed no effect on sodium taurocholate-induced damage and was devoid of superoxide anion scavenging activity. Concentrations of 0.5, 1, 2 and 4 microM stimulated fibroblast but not AGS cell proliferation. The compound showed weak cytotoxicity with values (IC50) of 411 (NRU) and 418 microM (MTT) for fibroblasts and 261 microM (NRU) for AGS cells. The results support further pharmacological study of this compound as a potential new anti-ulcerogenic drug.
Journal of Pharmacy and Pharmacology 03/2005; 57(2):265-71. · 2.17 Impact Factor
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ABSTRACT: Con fines de domesticación se estudiaron seis accesiones de matico, Buddleja globosa Hope, durante dos temporadas, cultivadas en parcelas divididas para dos niveles de riego. Además, se evaluó el efecto del número de cosechas por temporada y la extracción de nutrientes. Las tres accesiones silvestres mostraron menores rendimientos de hojas que las tres cultivadas con 0,17 contra 0,25 kg planta-1 (P £ 0,05), una de ellas con el mayor valor peso hojas:material aéreo, 0,64 contra 0,54 a 0,57. Entre las accesiones se encontraron diferencias significativas (P £ 0,05) en el número de brotes por planta (13,3 contra 28,5), mientras que en la concentración de flavonoides y taninos éstas no fueron significativas. De la primera a la segunda temporada aumentaron el rendimiento de hojas de 0,18 a 0,23 kg planta-1, el número de brotes de 15,8 a 28,0 y los contenidos de flavonoides de 0,20 a 0,48%, y taninos de 1,54 a 2,00% (P £ 0,05). El estrés hídrico afectó al rendimiento (0,16 contra 0,25 kg planta-1) (P £ 0,05). Con tres cosechas se obtuvo el menor rendimiento (0,19 contra 0,29 y 0,25 kg planta-1 para una y dos cosechas, respectivamente). Con el número de cortes aumentó la relación hojas:material aéreo de 0,50 a 0,65 y el contenido de flavonoides, mientras que disminuyó el contenido de taninos de 3,21 a 1,85% (P £ 0,05). Una tonelada de hojas deshidratadas extrajo 18,26 kg N; 2,17 kg P; 12,25 kg K; 7,43 kg Ca; 2,8 kg Mg; 94 g Mn; 24 g Zn y 11 g Cu.
Agricultura técnica, ISSN 0365-2807, Vol. 64, Nº. 4, 2004, pags. 413-420.
