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1.
Angew Chem Int Ed Engl ; 59(45): 19961-19965, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32749032

RESUMO

A biosynthetic gene cluster from Streptomyces mobaraensis encoding the first cases of a bacterial geranylfarnesyl diphosphate synthase and a type I sesterterpene synthase was identified. The structures of seven sesterterpenes produced by these enzymes were elucidated, including their absolute configurations. The enzyme mechanism of the sesterterpene synthase was investigated by extensive isotope labeling experiments.


Assuntos
Gefarnato/análogos & derivados , Ligases/metabolismo , Família Multigênica , Sesterterpenos/metabolismo , Streptomyces/enzimologia , Gefarnato/metabolismo , Estereoisomerismo
2.
Nat Prod Commun ; 11(2): 163-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27032191

RESUMO

The enzymatic reactions of geranylfarnesol (8) and its acetate 9, classified as sesterterpenes (C25), using squalene-hopene cyclase (SHC) were investigated. The enzymatic reaction of 8 afforded 6/6-fused bicyclic 20, 6/6/6-fused tricyclic 21, and 6/6/6/6-fused tetracyclic compounds 22 and 23 as the main products (35% yield), whereas that of 9 afforded two 6/6/6-fused tricyclic compounds 24 and 25 in a high yield (76.3%) and a small amount (5.0%) of 26 (the acetate of 22). A significantly higher conversion of 9 indicates that the arrangement of the substrate in the reaction cavity changed. The lipophilic nature and/or the bulkiness of the acetyl group may have changed its binding with SHC, thus placing the terminal double bond of 9 in the vicinity of the DXDD motif of SHC, which is responsible for the proton attack on the double bond to initiate the polycyclization reaction. The results obtained for 8 are different to some extent than those reported by Shinozaki et al. The products obtained in this study were deprotonated compounds; however, the products reported by Shinozaki et al. were hydroxylated compounds.


Assuntos
Alicyclobacillus/enzimologia , Proteínas de Bactérias/metabolismo , Gefarnato/análogos & derivados , Regulação Bacteriana da Expressão Gênica/fisiologia , Transferases Intramoleculares/metabolismo , Proteínas de Bactérias/química , Gefarnato/química , Regulação Enzimológica da Expressão Gênica , Transferases Intramoleculares/química , Estrutura Molecular
3.
Biosci Biotechnol Biochem ; 77(11): 2278-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24200803

RESUMO

Aleuritopteris ferns produce triterpenes and sesterterpenes with tricyclic cheilanthane and tetracyclic 18-episcalarane skeletons. The structural and mechanistic similarities between both classes of fern terpene suggest that their biosynthetic enzymes may be closely related. We investigate here whether a triterpene synthase is capable of recognizing geranylfarnesols as a substrate, and is able to convert them to cyclic sesterterpenes. We found that a bacterial triterpene synthase converted all-E-geranylfarnesol (1b) into three scalarane sesterterpenes with 18αH stereochemistry (5, 7 and 8), as well as mono- and tricyclic sesterterpenes (6 and 9). In addition, 2Z-geranylfarnesol (4) was converted into an 18-episcalarane derivative (10), whose skeleton can be found in sesterterpenes isolated from Aleuritopteris ferns. These results provide insight into sesterterpene biosynthesis in Aleuritopteris ferns.


Assuntos
Alicyclobacillus/enzimologia , Proteínas de Bactérias/metabolismo , Gleiquênias/enzimologia , Gefarnato/análogos & derivados , Ligases/metabolismo , Sesterterpenos/metabolismo , Alicyclobacillus/genética , Proteínas de Bactérias/genética , Ciclização , Escherichia coli/enzimologia , Escherichia coli/genética , Gleiquênias/química , Gefarnato/metabolismo , Ligases/genética , Estrutura Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Especificidade por Substrato , Triterpenos/metabolismo
4.
Biochem Biophys Res Commun ; 436(2): 230-4, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23726912

RESUMO

Cis-prenyltransferase from a hyperthermophilic archaeon Aeropyrum pernix was expressed in Escherichia coli and purified for characterization. Properties such as substrate specificity, product chain-length, thermal stability and cofactor requirement were investigated using the recombinant enzyme. In particular, the substrate specificity of the enzyme attracts interest because only dimethylallyl diphosphate and geranylfarnesyl diphosphate, both of which are unusual substrates for known cis-prenyltransferases, are likely available as an allylic primer substrate in A. pernix. From the enzymatic study, the archaeal enzyme was shown to be undecaprenyl diphosphate synthase that has anomalous substrate specificity, which results in a preference for geranylfarnesyl diphosphate. This means that the product of the enzyme, which is probably used as the precursor of the glycosyl carrier lipid, would have an undiscovered structure.


Assuntos
Aeropyrum/enzimologia , Alquil e Aril Transferases/metabolismo , Proteínas Arqueais/metabolismo , Temperatura Alta , Aeropyrum/genética , Alquil e Aril Transferases/genética , Proteínas Arqueais/genética , Eletroforese em Gel de Poliacrilamida , Estabilidade Enzimática , Escherichia coli/genética , Gefarnato/análogos & derivados , Gefarnato/metabolismo , Organofosfatos/metabolismo , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
5.
Chin Med J (Engl) ; 125(16): 2878-84, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22932084

RESUMO

BACKGROUND: The role of gastro-protecting agents on symptomatic chronic gastritis is unclear. This multicenter, open, randomized trial was designed to compare the comprehensive effects of gefarnate with sucralfate on erosive gastritis with dyspeptic symptoms. METHODS: Totally 253 dyspepsia patients confirmed with erosive gastritis were enrolled from six centers in China. They randomly received either daily 300 mg gefarnate or 3 g sucralfate for six weeks. The primary endpoint was the effective rate of both treatments on endoscopic erosion at week six. RESULTS: Gefarnate showed an effective rate of 72% and 67% on endoscopic score and dyspeptic symptom release, which is statistically higher than sucralfate (40.1% and 39.3%, P < 0.001, intension-to-treat). For histological improvement, gefarnate showed both effective in decreasing mucosal chronic inflammation (57.7% vs. 24.8%, P < 0.001, intension-to-treat) and active inflammation (36.4% vs. 23.1%, P < 0.05, intension-to-treat) than the control. A significant increase of prostaglandins and decrease of myeloperoxidase in mucosa were observed in gefarnate group. Severity of erosion is non-relevant to symptoms but Helicobacter pylori (H. pylori) status does affect the outcome of therapy. CONCLUSIONS: Gefarnate demonstrates an effective outcome on the mucosal inflammation in patients with chronic erosive gastritis. Endoscopic and inflammation score should be the major indexes used in gastritis-related trials.


Assuntos
Antiulcerosos/uso terapêutico , Dispepsia/tratamento farmacológico , Gastrite/tratamento farmacológico , Gefarnato/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sucralfato/uso terapêutico , Resultado do Tratamento , Adulto Jovem
6.
J Gastroenterol ; 47(11): 1186-97, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22526273

RESUMO

BACKGROUND: Patients using low-dose aspirin (LDA) have an increased risk of gastroduodenal mucosal lesions and upper gastrointestinal symptoms. We aimed to clarify the efficacy of rabeprazole for preventing peptic ulcer, esophagitis, and gastrointestinal symptoms associated with LDA. METHODS: Patients with a history of peptic ulcers who were receiving LDA for cardiovascular or cerebrovascular disease were randomly assigned to receive rabeprazole at 10 mg daily, rabeprazole at 20 mg daily, or gefarnate (a cytoprotective anti-ulcer agent) at 50 mg twice daily. The primary endpoint was the development of gastric and/or duodenal ulcer at 12 weeks. The modified Lanza score (MLS) and gastrointestinal symptoms were evaluated at baseline and at 12 weeks. RESULTS: The full analysis set comprised 261 patients (rabeprazole 10 mg: n = 87, rabeprazole 20 mg: n = 89, gefarnate 100 mg: n = 85). The cumulative incidences of gastroduodenal ulcers at 12 weeks in the 10 mg rabeprazole group, 20 mg rabeprazole group, and gefarnate group were 7.4, 3.7, and 26.7 %, respectively (rabeprazole group 5.5 % vs. gefarnate group 26.7 %, hazard ratio [HR] 0.179; 95 % confidence interval [CI] 0.082-0.394; p < 0.0001). The proportions of patients with an MLS of ≥1 and erosive esophagitis were significantly lower in the rabeprazole group than in the gefarnate group at 12 weeks (gastric lesions 33.5 vs. 62.4 %, p < 0.0001; duodenal lesions 5.7 vs. 24.7 %, p < 0.0001; erosive esophagitis 5.8 vs. 19.4 %, p < 0.0001). Rabeprazole was significantly more effective than gefarnate for the resolution and prevention of gastrointestinal symptoms (resolution 53.6 vs. 25.0 %, p = 0.017; occurrence 9.2 vs. 28.3 %, p = 0.0026). CONCLUSIONS: Rabeprazole is more effective than gefarnate for reducing the risk of recurrence of peptic ulcer, esophagitis, and gastrointestinal symptoms in LDA users.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Antiulcerosos/uso terapêutico , Aspirina/efeitos adversos , Úlcera Péptica/prevenção & controle , Idoso , Aspirina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/tratamento farmacológico , Relação Dose-Resposta a Droga , Esofagite/induzido quimicamente , Esofagite/prevenção & controle , Feminino , Gefarnato/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/induzido quimicamente , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Rabeprazol , Prevenção Secundária
7.
J Gastroenterol ; 47(5): 540-52, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22388884

RESUMO

BACKGROUND: Low-dose lansoprazole has not been intensively evaluated for its efficacy in the prevention of recurrent gastric or duodenal ulcers in patients receiving long-term non-steroidal anti-inflammatory drug (NSAID) therapy for pain relief in such diseases as rheumatoid arthritis, osteoarthritis, and low back pain. METHODS: This multi-center, prospective, double-blind, randomized, active-controlled study involving 99 sites in Japan was designed to compare the efficacy of lansoprazole (15 mg daily) with gefarnate (50 mg twice daily). Patients with a history of gastric or duodenal ulcers who required long-term NSAID therapy were randomized to receive lansoprazole 15 mg daily (n = 185) or gefarnate 50 mg twice daily (n = 181) and followed up for 12 months or longer prospectively. RESULTS: The cumulative incidence of gastric or duodenal ulcer at days 91, 181, and 361 from the start of the study was calculated by the Kaplan-Meier method as 3.3, 5.9, and 12.7%, respectively, in the lansoprazole group versus 18.7, 28.5, and 36.9%, respectively, in the gefarnate group. The risk for ulcer development was significantly (log-rank test, P < 0.0001) lower in the lansoprazole group than in the gefarnate group, with the hazard ratio being 0.2510 (95% CI 0.1400-0.4499). A long-term follow-up study showed an acceptable safety profile for low-dose lansoprazole therapy, with diarrhea as the most frequent adverse event. CONCLUSION: Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term NSAID therapy.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/uso terapêutico , Úlcera Duodenal/prevenção & controle , Úlcera Gástrica/prevenção & controle , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Antiulcerosos/efeitos adversos , Artrite/tratamento farmacológico , Método Duplo-Cego , Úlcera Duodenal/induzido quimicamente , Feminino , Gefarnato/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Lansoprazol , Dor Lombar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Prevenção Secundária , Úlcera Gástrica/induzido quimicamente , Resultado do Tratamento
8.
Eksp Klin Gastroenterol ; (5): 56-60, 2011.
Artigo em Russo | MEDLINE | ID: mdl-21916236

RESUMO

We assessed the effects of some gefarnate analogs on gastric ulcer prophylaxis (adrenaline ulcers) and ulcer healing (acetic ulcers) and some secretory parameters in rats. Acute ulcers were induced in male Wistar rats by intraperitoneal injection of 2 mg/kg adrenaline hydrochloride. Rats were killed after 24 hours. Chronic gastric ulcers were induced in rats by application of 100% acetic acid to the serosal surface of the stomach on 60 sec. Gefarnate analogs introduced intraperitoneally or intragastrically. Gefarnate analogs dose-dependently increase the healing of gastric ulcers and have a marked prophylaxis effects especially in the case of adrenaline ulcers.


Assuntos
Antiulcerosos/uso terapêutico , Gefarnato/análogos & derivados , Gefarnato/uso terapêutico , Oxigênio/química , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/química , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Gefarnato/química , Masculino , Estrutura Molecular , Ratos , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
9.
J Gastroenterol ; 46(6): 724-35, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21499703

RESUMO

BACKGROUND: The efficacy of low-dose lansoprazole has not been established for the prevention of recurrent gastric or duodenal ulcers in those receiving long-term low-dose aspirin (LDA) for cardiovascular and cerebrovascular protection. This study sought to examine the efficacy of low-dose lansoprazole (15 mg once daily) for the secondary prevention of LDA-associated gastric or duodenal ulcers. METHODS: Patients were randomized to receive lansoprazole 15 mg daily (n = 226) or gefarnate 50 mg twice daily (n = 235) for 12 months or longer in a prospective, multicenter, double-blind, randomized active-controlled trial, followed by a 6-month follow-up study with open-label lansoprazole treatment. The study utilized 94 sites in Japan and 461 Japanese patients with a history of gastric or duodenal ulcers who required long-term LDA therapy for cardiovascular and cerebrovascular disease. RESULTS: The primary endpoint was the development of gastric or duodenal ulcers. The cumulative incidence of gastric or duodenal ulcers on days 91, 181, and 361 from the start of the study was calculated by the Kaplan-Meier method as 1.5, 2.1, and 3.7%, respectively, in the lansoprazole group versus 15.2, 24.0, and 31.7%, respectively, in the gefarnate group. The risk of ulcer development was significantly (log-rank test, P < 0.001) lower in the lansoprazole group than in the gefarnate group, with the hazard ratio being 0.099 (95% confidence interval [CI] 0.042-0.230). CONCLUSION: Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term LDA therapy.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Antiulcerosos/uso terapêutico , Aspirina/efeitos adversos , Idoso , Aspirina/uso terapêutico , Método Duplo-Cego , Úlcera Duodenal/induzido quimicamente , Úlcera Duodenal/prevenção & controle , Feminino , Seguimentos , Gefarnato/uso terapêutico , Humanos , Incidência , Japão , Estimativa de Kaplan-Meier , Lansoprazol , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Prevenção Secundária , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle
10.
Biol Pharm Bull ; 28(8): 1424-30, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16079487

RESUMO

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.


Assuntos
Antiulcerosos/farmacologia , Degranulação Celular/efeitos dos fármacos , Diterpenos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Gefarnato/farmacologia , Mastócitos/efeitos dos fármacos , p-Metoxi-N-metilfenetilamina/toxicidade , Animais , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/enzimologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Hexosaminas/metabolismo , Histamina/sangue , Masculino , Peroxidase/metabolismo , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Serotonina/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Xantina Oxidase/metabolismo
11.
Cornea ; 21(3): 292-9, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11917179

RESUMO

PURPOSE: To investigate the ability of gefarnate (geranyl farnesylacetate) to stimulate goblet cell function in the primate eye after a mild alkali injury of the tarsal conjunctiva. METHODS: A bilateral injury was created on the conjunctival surface of the lower eye lid of squirrel monkeys by means of a 30-second application of a 4-mm diameter piece of filter paper wetted with 0.5% NaOH. Gefarnate drops (1%) were administered to one eye of each monkey and vehicle alone in the contralateral eye six times a day, 5 days a week for 4 weeks. Slit-lamp biomicroscopy, impression cytology staining of the ocular surface, fluorescein and rose bengal staining, and Western blot for mucin were performed before injury and weekly thereafter. Light microscopy was used to evaluate the lower conjunctiva. RESULTS: Topical application of gefarnate was not associated with any adverse ocular surface effects. Goblet cell repopulation after injury was significantly greater in the gefarnate-treated eyes compared with the vehicle-treated eyes. In the gefarnate-treated eyes, tear mucin content was significantly greater at 1 week after injury. Fluorescein staining was significantly reduced at 3 weeks after injury, and rose bengal staining was significantly reduced in the area of the wound at 2 weeks in the gefarnate-treated eyes compared with the vehicle-treated eyes; at other times, conjunctival staining in the two groups of eyes was not significantly different. CONCLUSIONS: Gefarnate promotes goblet cell repopulation and increases mucin production after a conjunctival injury. No adverse affects of the treatment were found. Thus, this agent may be useful in conditions that diminish goblet cell function.


Assuntos
Antiulcerosos/uso terapêutico , Queimaduras Químicas/tratamento farmacológico , Doenças da Túnica Conjuntiva/tratamento farmacológico , Queimaduras Oculares/induzido quimicamente , Gefarnato/uso terapêutico , Células Caliciformes/efeitos dos fármacos , Animais , Western Blotting , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Contagem de Células , Doenças da Túnica Conjuntiva/metabolismo , Doenças da Túnica Conjuntiva/patologia , Queimaduras Oculares/metabolismo , Queimaduras Oculares/patologia , Fluorofotometria , Células Caliciformes/patologia , Immunoblotting , Masculino , Mucinas/metabolismo , Soluções Oftálmicas , Rosa Bengala , Saimiri , Hidróxido de Sódio , Lágrimas/metabolismo
13.
Anticancer Res ; 20(6B): 4307-13, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11205263

RESUMO

Cytotoxic activity of 9 polyprenylalcohols and 6 vitamin K2 derivatives (MK-1 to MK-6) with various lengths of prenyl units was investigated. Among these compounds, geranylgeraniol with 4 prenyl units, and MK-2 with 2 prenyl units, showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), without induction of internucleosomal DNA fragmentation. Higher molecular weight compounds showed selective cytotoxicity against tumor cell lines than normal human gingival fibroblasts HGF. ESR spectroscopy showed that all polyprenylalcohols did not produce radical, nor scavenged O2- generated by hypoxanthine and xanthine oxidase reaction, and only slightly enhanced the radical intensity of sodium ascorbate. Vitamin K2 derivatives scavenged O2- more efficiently, but did not produce radical (except MK-3) and only slightly modified the ascorbate radical intensity. Cytotoxic activity of these compounds might be affected by the molecular weight, hydrophobicity, van der Waals area and stabilization of hydration of the molecule.


Assuntos
Apoptose , Farneseno Álcool/farmacologia , Gefarnato/análogos & derivados , Gefarnato/farmacologia , Terpenos/farmacologia , Vitamina K/análogos & derivados , Monoterpenos Acíclicos , Linhagem Celular/efeitos dos fármacos , Fragmentação do DNA , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Tumorais Cultivadas/efeitos dos fármacos , Vitamina K/farmacologia
14.
Lipids ; 34(11): 1151-7, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10606037

RESUMO

The triterpene alcohol constituents of the non-saponifiable lipids of two Theaceae seed oils, sasanqua and camellia oils, and two Gramineae seed oils, wheat germ and rice bran oils, were investigated. This led to the isolation and characterization of one acyclic and eight incompletely cyclized triterpene alcohols. They are camelliol A, camelliol B, camelliol C, achilleol A, helianol, isohelianol, sasanquol, graminol A [(13R, 14R)-3,4-seco-25(10->9)abeo-8alpha,9beta,10al phapodioda-4,17,21 -trien-3-ol], and (2Z,6Z,10Z,14E,18E)-farnesyl-farnesol. Two other compounds isolated were characterized as (2Z,6Z,10E,14E)-geranylfarnesol, a sesterterpene alcohol, and phytol, a diterpene alcohol. Graminol A and (2Z,6Z,10E,14E)-geranylfarnesol are considered to be new natural products.


Assuntos
Álcoois/análise , Ericales/química , Óleos Vegetais/química , Poaceae/química , Sementes/química , Triterpenos/análise , Álcoois/química , Cromatografia Líquida de Alta Pressão , Ciclização , Gefarnato/análogos & derivados , Gefarnato/análise , Gefarnato/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Estrutura Molecular , Triterpenos/química
16.
Nihon Yakurigaku Zasshi ; 112(5): 323-31, 1998 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-10098214

RESUMO

To evaluate the effects of teprenone on acute gastritis, its inhibitory effects on gastric mucosal damage were compared to that of gefarnate in taurocholate/hydrochloric acid-induced acute gastric mucosal lesions in rats. After oral administration of 160 mM taurocholic acid and 250 mM hydrochloric acid, hemorrhage and erosion were macroscopically observed in the gastric mucosal surface layer. Edema in the submucosal tissue and decreased PAS staining in the mucosa were histomorphologically observed. Concerning macroscopic findings, pretreatment with teprenone at a dose of 50 mg/kg or more significantly reduced pathological changes in the mucosa of the fundic glandular area. However, gefarnate slightly inhibited these changes in at a dose of 50 mg/kg and significantly inhibited them at a dose of 200 mg/kg. With regards to histomorphological findings in the fundic glandular area, teprenone slightly inhibited erosion at a dose of 50 mg/kg, and it significantly and slightly inhibited the decrease in PAS staining in this area at doses of 50 and 200 mg/kg, respectively. Gefarnate at doses of 50 and 200 mg/kg showed significant inhibition of decreased PAS staining in the fundic glandular area. In the pyloric mucosa, decreased PAS staining was slightly inhibited by teprenone at both doses but not by gefarnate at either dose. The differences between teprenone and gefarnate observed in this model appear to be due to their differences in mucus production ability. These results suggest that teprenone was more effective than gefarnate for the treatment of gastritis.


Assuntos
Antiulcerosos/administração & dosagem , Diterpenos/administração & dosagem , Gastrite/prevenção & controle , Gefarnato/administração & dosagem , Ácido Clorídrico , Ácido Taurocólico , Doença Aguda , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/patologia , Masculino , Muco/metabolismo , Ratos , Ratos Wistar
17.
Br J Ophthalmol ; 82(11): 1320-3, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9924342

RESUMO

AIMS: The effects of three drugs for the treatment of gastritis and gastric ulcer--gefarnate, ecabet sodium, and troxipide--on periodic acid Schiff (PAS) positive cell density in rabbit conjunctiva in vivo were investigated. METHODS: Eye drops containing gefarnate (0.1%, 1%), ecabet sodium (0.1%, 1%), or troxipide (0.1%, 1%) were instilled in both eyes of rabbits, six times a day for 7 days. On the eighth day, filter paper was gently pressed on the bulbar and palpebral conjunctiva, and impression cytology was performed with PAS staining. Three points in each specimen were selected randomly, and PAS stained cells were counted. RESULTS: The instillation of gefarnate increased PAS positive cell density significantly at the concentration of 1% (p < 0.05). In contrast, instillation of ecabet sodium or troxipide failed to change PAS positive cell density. CONCLUSIONS: These results demonstrated that gefarnate stimulates PAS positive cell density in rabbit conjunctiva.


Assuntos
Abietanos , Antiulcerosos/farmacologia , Túnica Conjuntiva/efeitos dos fármacos , Gefarnato/farmacologia , Animais , Contagem de Células/efeitos dos fármacos , Túnica Conjuntiva/citologia , Diterpenos/farmacologia , Soluções Oftálmicas , Piperidinas/farmacologia , Coelhos
18.
Leukemia ; 11(6): 779-87, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9177427

RESUMO

Geranylgeraniol, a polyprenylalcohol composing the side chain of vitamin K2 (VK2), was previously reported to be a potent inducer of apoptosis in tumor cell lines (Ohzumi H et al, J Biochem 1995; 117: 11-13). We examined the apoptosis-inducing ability of VK2 (menaquinone 3 (MK3), MK4 and MK5) and its derivatives such as phytonadione (VK1), as well as polyprenylalcohols with side chains of various lengths including farnesol (C15-OH; FO), geranylgeraniol (C20-OH; GGO), and geranylfarnesol (C25-OH; GFO) toward leukemia cells in vitro. MK3, MK4, MK5 and GFO (at 10 microM) showed a potent apoptosis-inducing activity for all freshly isolated leukemia cells tested and for leukemia cell lines such as NB4, an acute promyelocytic leukemia (APL)-derived cell line and MDS92, a cell line derived from a patient with myelodysplastic syndrome, although there were some differences depending on the cells tested. In contrast, VK1 showed no effect on any of the leukemia cells. The combination of MK5 plus all-trans retinoic acid (ATRA) resulted in enhanced induction of apoptosis in both freshly isolated APL cells and NB4 cells as compared to each reagent alone. These data suggest the possibility of using VK2 and its derivatives for the treatment of myelogenous leukemias, including APL.


Assuntos
Apoptose/efeitos dos fármacos , Leucemia/patologia , Tretinoína/farmacologia , Vitamina K/análogos & derivados , Vitamina K/farmacologia , Medula Óssea/patologia , Diterpenos/farmacologia , Sinergismo Farmacológico , Farneseno Álcool/farmacologia , Citometria de Fluxo , Gefarnato/análogos & derivados , Gefarnato/farmacologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Leucemia Promielocítica Aguda , Estrutura Molecular , Síndromes Mielodisplásicas , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vitamina K 1/farmacologia , Vitamina K 2/análogos & derivados
19.
Exp Eye Res ; 65(4): 569-74, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9464189

RESUMO

The effect of drugs for gastritis and gastric ulcer (ecabet sodium, gefarnate, teprenone, and troxipide) on the secretion of mucin-like glycoproteins from rat cornea were investigated in vitro and on a short-term, rabbit dry eye model in vivo. For the studies in vitro, cultured rat cornea sections (3 mm diameter) were incubated with radiolabeled sodium sulfate, rinsed, and then incubated for 30 min in the presence of one of the drugs. The culture media were reacted with Dolichos biflorus agglutinate (DBA)-lectin, and the radioactivity of DBA-bound mucin-like glycoproteins was measured. A cytotoxicity assay confirmed that mucin-like glycoproteins had not leaked from damaged cells. For studies in vivo, eye drop vehicle or drops containing gefarnate were instilled in the eyes of nine anesthetized rabbits, and then the eyes were kept open with specula for two hours. These rabbits and two control rabbits not subjected to ocular drying were killed, and their eyes were enucleated and stained with methylene blue. Corneal epithelial damage from desiccation was evaluated based on the extent of methylene blue staining. Among the four kinds of drugs for gastritis and gastric ulcers, only gefarnate significantly increased the mucin-like glycoprotein secretion from cultured rat corneas in vitro; this stimulatory effect of gefarnate was dose-dependent. In vivo, the instillation of gefarnate reduced corneal epithelial damage from desiccation in a dose-dependent fashion. These results suggest that gefarnate reduces desiccation of corneal epithelium, perhaps by stimulating secretion of mucin-like glycoproteins from corneal epithelium.


Assuntos
Endotélio Corneano/metabolismo , Gefarnato/farmacologia , Mucinas/metabolismo , Animais , Células Cultivadas , Dessecação , Masculino , Ratos , Ratos Sprague-Dawley
20.
Scand J Gastroenterol ; 26(5): 457-64, 1991 May.
Artigo em Inglês | MEDLINE | ID: mdl-1871538

RESUMO

We observed the quantitative estimation of the transmural changes associated with gastric ulcer healing by using endoscopic ultrasonography (EUS). It was possible to diagnose the depth of ulcer by EUS. Forty-eight patients were divided into three treatment groups. Group A (n = 16) was treated with 800 mg cimetidine daily, group B (n = 22) with 20 mg omeprazole daily, and group C (n = 10) with 400 mg cimetidine + 300 mg gefarnate daily. EUS was performed before and after 2, 4, and 8 weeks of treatment. The groups were compared from the viewpoints of endoscopic findings and contraction rate of the length and the cross-sectional area of the ulcer in EUS pictures. The best healing of both the endoscopic and EUS findings was seen in group B. By estimating the changes inside the ulcer, EUS may provide useful information for choice of anti-ulcer agents.


Assuntos
Antiulcerosos/uso terapêutico , Úlcera Gástrica/diagnóstico por imagem , Cimetidina/administração & dosagem , Cimetidina/uso terapêutico , Quimioterapia Combinada , Feminino , Gastroscopia , Gefarnato/administração & dosagem , Gefarnato/uso terapêutico , Humanos , Masculino , Métodos , Pessoa de Meia-Idade , Omeprazol/uso terapêutico , Estômago/diagnóstico por imagem , Estômago/patologia , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Ultrassonografia
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