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To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p0.001). Treatment with esomeprazole was generally well tolerated.Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.NCT01069939.

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.

Irsogladine, a mucosal protective drug, was developed in Japan for the treatment of peptic ulcer disease and acute gastritis. This drug is superior to gefarnate, the same therapeutic category drug, in a randomized, controlled and double-blind clinical study in 1987. The mechanisms of irsogladine's actions are apparently different from those of antisecretory drugs. Irsogladine increases intracellular cyclic adenosine 3',5'-monophosphate content via non-selective inhibition of phosphodiesterase isozymes and exhibits gastric cytoprotection partly mediated by endogenous nitric oxide. These effects may account for a variety of actions of irsogladine in the gastrointestinal tract, including facilitation of gap junctional intercellular communication, inhibition of the reduced gastric mucosal blood flow response, suppression of reactive oxygen generation and so on. Since 1984, more than 60 papers have been published to further verify the effects of irsogladine on gap junctional intercellular communication, tight junction, nitric oxide production and neutrophil migration as well as Helicobacter pylori-related pathological changes in the stomach as well as the adverse reactions induced in the stomach or the small intestine by various drugs, including nonsteroidal anti-inflammatory drugs, bisphosphonates or selective serotonin re-uptake inhibitors. In this article, we review recent advances in understanding the mechanisms of irsogladine's actions and the most recent data in experimental as well as clinical studies.

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.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.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; p0.0001). 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 %, p0.0001; duodenal lesions 5.7 vs. 24.7 %, p0.0001; erosive esophagitis 5.8 vs. 19.4 %, p0.0001). 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).Rabeprazole is more effective than gefarnate for reducing the risk of recurrence of peptic ulcer, esophagitis, and gastrointestinal symptoms in LDA users.

Epadel S®,a seamless capsule form of ethyl icosapentate (EPA-E),was made into a suspension in 20 ml of hot water (55°C) and stirred with a polystyrene (PS) disposable spoon.When left in the suspension,the surface of the spoon started to dissolve after 45 minutes,and was completely dissolved after 12 hours.We also investigated the dissolution of PS utensils in suspensions made from teprenone (Selbex®) capsules or powder,or gefarnate (Gefanil®) capsules.Up till now,there have been no reports of toxicity due to PS or the non-reactants and/or by-products produced in the PS production process.However,as the dissolution of spoons,cups or other common utensils made of PS in drug suspensions could cause concern among patients,caregivers,and medical staff,it is important to instruct them to avoid the use of such utensils when preparing drug suspensions.

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.

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.

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.

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.

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.

Atsuyoshi Dota, Yuko Takaoka-Shichijo, Masatsugu NakamuraOphthalmic Research and Development Center, Santen Pharmaceutical Co, Ltd, Ikoma-shi, Nara, JapanPurpose: The aim of this study was to evaluate the effect of gefarnate on mucin-like glycoprotein secretion in isolated rabbit conjunctival tissue, and on corneal epithelial damage in rabbit and cat dry-eye models.Methods: Conjunctival tissue isolated from rabbits was treated with gefarnate. Mucin-like glycoprotein was detected in the culture supernatant by an enzyme-linked lectin assay. Gefarnate ointment was topically applied to eyes once daily for 7 days in the rabbit dry-eye model, in which the lacrimal glands, Harderian gland, and nictitating membrane were removed, or for 4 weeks in the cat dry-eye model, in which the lacrimal gland and nictitating membrane were removed. Corneal epithelial damage was evaluated by measurement of corneal permeability by rose bengal in the rabbit model or by fluorescein staining in the cat model.Results: Gefarnate stimulated mucin-like glycoprotein secretion in conjunctival tissue in a dose-dependent manner. In the rabbit dry-eye model, application of gefarnate ointment to the eyes resulted in a dose-dependent decrease in rose bengal permeability in the cornea, with the effect being significant at concentrations of ≥0.3%. In the cat dry-eye model, application of gefarnate ointment resulted in a significant decrease in the corneal fluorescein staining score.Conclusion: These results suggest that gefarnate stimulates in vitro secretion of mucin-like glycoprotein in conjunctival tissue and ameliorates corneal epithelial damage in animal dry-eye models. Gefarnate may therefore be effective for treating dry eye.Keywords: gefarnate, fluorescein staining, rose bengal permeability, rabbit, cat, dry eye

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.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.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%, P0.001, intension-to-treat). For histological improvement, gefarnate showed both effective in decreasing mucosal chronic inflammation (57.7% vs. 24.8%, P0.001, intension-to-treat) and active inflammation (36.4% vs. 23.1%, P0.05, 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.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.

Deterpens (plaunotol, gefarnate and teprenone) and isoprenyl chalcone derivatives of sofalcone have been extensively employed as a gastric protective agents. The role of these drugs in cytoprotec-tion have been reported, e. g. mucous secretion, macromolecular synthesis, gastric blood flow, bicarbonate secretion and newly formed capillaries and granulation tissue. Furthermore, it is recently indicated that these gastric protective agents promote increase of the migration of fibroblast and epithelial cells. Accordingly, we investigated the accelerating effect of topical preparation of gastric protective agents on healing of ducubitus and skin ulcers caused by vasculitis. Each topical preparation contained same dosage as orally administration dosage and was once a daily administered to ulcerative lesion.In 20 cases of patients with intractable decubitus, the wound area was significantly reduced within 1 week and re-epithelization of the ulcer edge and the increase of granulation tissue were also observed in 2 weeks after treatment. Healing acceleration rate by these drugs were about the same. In cases of patients with skin ulcers, healing acceleration was also comfirmed.These results suggest that topical preparation of gastric protective agents are useful for the treatment of wound healing.

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

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.

The antifungal and antibacterial activity of both anti-ulcer terpens and sofalconein vitrowere studied.Among them, plaunotol has proved to show the strongest antibacterial and antifungal activity. It exhibits a wide spectrum activity against dermatophytes and Gram positive bacterias. The weakin vitroactivity of sofalcone against dermatophytes and Gram positive bacterias was recognized and also gefarnate revealed the clinically useful MIC values, whereas teprenone didn't indicate antifungal and antibacterial activityin vitro.Mechanism of fungicidal action is not clear, but present study suggests that surplus C20unit inhibits the transport of several glycoprotein of cytoplasm and/or metabolites of plaunotol having aldehyde may inhibit the growth of various dermaphytes and bacterias. These results indicate that anti-ulcer terpens and sofalcone may be useful for the treatment of superficial fungal infections.

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

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.

Geranyl farnesylacetate (gefarnate) has been used to stimulate mucin production from goblet cells of patients who have gastritis and/or gastric ulcer.1,2 In previous studies, Nakamura et al.3 reported that gefarnate increased the mucin-like glycoprotein secretion from cultured rat corneas in vitro in a dose-dependent manner. The ability of topically applied gefarnate to increase goblet cell density in vivo was reported in normal4,5 and dry eye rabbit.5,6 In the present study, we investigated the effect of topical gefarnate treatment in a rabbit model of dry eye on goblet cell repopulation of the tarsal conjunctiva after a mild alkali injury.

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.

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.

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

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.

Recently, some antiulcer agents have been reported to have antibacterial activity against Helicobacter pylori, which is highly associated with gastritis and peptic ulcers. In-vitro and in-vivo activity of plaunotol, a cytoprotective antiulcer agent, against H. pylori was investigated. Antibacterial activity of plaunotol against a standard strain (NCTC 11637) and 14 clinical isolates was compared with those of other cytoprotective antiulcer agents: benexate, sofalcone, teprenone, cetraxate, and gefarnate, by an agar dilution method. The MIC50 and MIC90 of plaunotol against 15 strains were 6.25 and 12.5 mg/L, respectively, making it the most potent of the cytoprotective antiulcer agents. The bactericidal effect of plaunotol was investigated using an in-vitro killing assay. Plaunotol at concentrations of more than 6 mg/L induced a rapid reduction of culture turbidity, with an extensive loss of viability, within 30 min. Observation by scanning electron microscopy revealed that plaunotol caused autolysis and treated cells were deformed. In-vivo activity of plaunotol against H. pylori was examined in a nude mouse gastritis model. Plaunotol significantly decreased the number of H. pylori in the stomach of nude mice. In addition, the antiulcer agent enhanced the antibacterial activity of amoxycillin or clarithromycin in the infection model.

In the healing test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., at doses of 3 and 10 mg/kg, twice a day, for 14 consecutive days from the day after acetic acid injection not only reduced the size and depth of the ulcers, but also promoted the regeneration of the defective mucosa. In the hydrocortisone-induced relapse test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., twice a day, at doses of 3 and 10 mg/kg for 20 consecutive days from the 40th day after the acid injection strongly prevented the exfoliation of the regenerated mucosa. Cimetidine (100 mg/kg x 2/day, p.o.), like Z-103, showed a marked relapse-preventive action in addition to the healing-promoting action. However, it was more effective on the healing. Gefarnate (300 mg/kg x 2/day, p.o.) markedly reduced the size and depth of the ulcers and strongly prevented the steroid-induced relapse, but showed no apparent effect on the regeneration of the defective mucosa. These results suggest that Z-103 may be a new therapeutic agent sharing both healing-promoting and relapse-preventive actions on gastric ulcers.

This paper describes a possibility that a metabolite of orally administered gefarnate (GF), an antiulcerative agent, is an acting substance, instead of GF.When GF was orally administered in rabbits or rats, its metabolites, farnesylacetic acid (FAA), geraniol etc. were clearly detected in portal or lymphatic flow, while mother compound GF was not detectable. FAA revealed about 100 times potent increase in the O2 consumption of mitochondria of rat liver than that of GF. When FAA (4 mg/kg) was intraperitoneally administered in rats, it showed a potent inhibitory effect on the stress ulcer, while oral administrations (1-260mg/ kg) were inactive or slightly adverse.These findings may be related to the assumption that FAA, a main metabolite, acts as a main pharmacologically active substance, but when it was directly applied to the surface of gastric mucosa with higher concentrations, it may inhibit the cellular respiration.

Quality tests were made on 10 different commercial gefarnate preparations in fine granules as well as granule, which are drugs for gastric or duodenal ulcer. The availability in handling was evaluated on each preparation by examinations of physical properties, such as angle of repose, loose bulk density, packed bulk density, dispersibility and particle size distribution. The stability was also examined by measuring content, hydrolysis rate, peroxide value, because gefarnate is the ester of geraniol and farnecyl acetate of isoprene structure. In addition study was done on the relation between the results of the examinations and the methods of granulation.From the results of the physical property tests, all the preparations were within acceptable range in actual dispensing. But in 4 preparations out of 10, the amount of gefarnate decreased on the measurement of the content. Peroxide values of these preparations were remarkably high, whereas hydrolysis rate indicated no significant value when these were compared with other commercial preparations. Therefore, it is concluded that degradation process was mainly due to the oxidation. These 4 preparations were produced by extruding granulation procedure. Gefarnate is degraded easily, and its preparations may show great difference in pharmaceutical quality when produced in different techniques.

Lipase becomes soluble and active in organic solvents by covalently binding with polyethylene glycol. The polyethylene glycol-modified lipase, PEG-lipase, catalyzed the reverse reaction of hydrolysis, ester synthesis reaction, in benzene or in chlorinated hydrocarbon. Using PEG-lipase, gefarnate was synthesized with 87% yield from farnesylacetic acid and geraniol in 1,1,1-trichloroethane at 25°C. The PEG-lipase can be reused without loss of enzymic activity after recovery from the reaction system.

The effects of geranylgeranylacetone (GGA), a new acyclic polyisoprenoid with a novel antiulcer action on gastrointestinal secretion were studied in rats. Intraduodenal administration of GGA (1-30 mg/kg) dose-relatedly reduced the gastric acid secretion caused by pentagastrin, histamine or insulin. On the other hand, GGA (3-30 mg/kg i.d.) dose-relatedly increased pancreatic secretion but did not affect biliary secretion. The above-mentioned findings seem consistent with the further findings that GGA depressed a plasma gastrin level enhanced by insulin while in increased the basal level of plasma secretin. These pharmacological features found in the present studies may partially, at least, account for the mechanism of GGA antiulcer action.

Cost-benefit analysis (CBA) and cost-effectiveness analysis (CEA) are increasingly being used in medical practice and in health policy making. The choice among alternative treatments, the aim of a more efficient use of limited resources and the wider goal of cost containment, are so many reasons for CBA and CEA. This paper addresses the rather unexplored field of long-term cost-benefit analysis. Gastric ulcer, which is a recurrent disease is taken as a case study. Mathematical modelling is used for situation analysis of alternative long-term intervention strategies. The use of recurrence in the model makes the results of earlier CBA's based on the healing of a single episode, open to question. The paper holds important lessons for both the theoretical aspects of CBA and for its utilization in health policy formulation.

The anti-ulcer effect of sofalcone, an isoprenyl chalcone derivative, on acetic acid-induced gastric ulcers in rats was studied histologically and histochemically. After administrations of sofalcone at 50 and 200 mg/kg twice daily for 10 days, contraction of the ulcer, mucosal regeneration, accelerated development of the collagen fibers in the granulation tissue at the base of the ulcer, and increase of acid mucopolysaccharides, an alcian blue stain-positive substance covering the regenerated mucosa, were noted. The healing effect of sofalcone was balanced in mucosal regeneration and connective tissue proliferation (formation of the collagen fibers). Sofalcone of 50 mg/kg showed a greater healing effect than gefarnate at the same dose and had a similar healing effect as L-glutamine at 200 mg/kg.

Anti-ulcer effects of cetraxate, a new compound possessing anti-plasmin, anti-casein and anti-trypsin actions were investigated by using experimental gastric ulcer models in rats. Cetraxate, 300 mg/kg p.o. showed significant inhibitory effects of 65.3 %, 70.0 %, 30.2 % and 67.1% against acute types of ulcers producing by aspirin, phenylbutazone, indomethacin, and pyloric ligature (Shay's ulcer), respectively. These effects were greater than those obtained by gefarnate and aluminum sucrose sulfate and may be mainly attributed to the protecting action of this drug on gastric mucosa. Cetraxate further revealed remarkable inhibitory effects on chronic types of ulcers produced by acetic acid, clamping, and clamping-cortisone. In acetic acid ulcer in particular, cetraxate was found to have a dose-dependent inhibitory effect at doses over 50 mg/kg. Of test drugs including L-glutamine and methylmethionine sulfonium chloride, cetraxate showed the most remarkable inhibitory effect on β-glucuronidase activity in ulcer tissue of these three types of ulcers. These findings suggest that cetraxate may prevent the connective tissue in the ulcer location from decomposition due to lysosomal enzymes such as β-glucuronidase, thereby accelerating the recovery from ulcer.

Farnesylacetic acid was efficiently labelled with 14C at the 5-position and gefarnate, a potent ulcer inhibitor, was prepared from it in radioactive form for use in metabolic studies. Condensation of [carbonyl-14C]acetyl chloride (5) with t-butyl 2-ethoxymagnesiomalonate (6) followed by acid-catalyzed deprotection and decarboxylation gave ethyl 3-oxo[3-14C]butanoate (8). Alkylation of the keto ester (8) with geranyl bromide (9) afforded the unsaturated keto ester (10), which was hydrolyzed and decarboxylated to give geranyl[2-14C]acetone (11). Grignard reaction of 11 with cyclopropylmagnesium bromide followed by treatment with hydrobromic acid yielded [4-14C]homofarnesyl bromide (13). Cyanation of 13 with potassium cyanide and subsequent hydrolysis gave [5-14C]farnesylacetic acid (1) in 6.1% yield from barium [14C]carbonate (3). Chlorination of 1 followed by esterification with geraniol afforded [5-14C]gefarnate (2) in 88% yield.

Farnesylacetic acid and its geraniol ester (gefarnate) labelled with 14C at the carbon-chain were prepared via methyl cyclopropyl ketone-14C. The intermediate, ketone-14C was obtained in 63 % radiochemical yield from barium carbonate-14C and from this ketone-14C, farnesylacetic acid-14C and gefarnate-14C having a specific radioactivity of 1.0 mCi/mmole were prepared in 48.4 % and 37.2 % yield, respectively.

SummaryA study to investigate the mechanism of action of gefarnate (treatment: 600 mg. daily by mouth for 30 days) was carried out in 25 patients with gastric ulcer.The following parameters were evaluated before and after treatment: a) the macroscopic (endoscopy), microscopic (optic microscopy and histochemistry) and ultra-structural appearance (electron microscopy) of the gastric mucosa; b) mucous secretion (hexosamines); c) hydrochloric acid and peptic secretion; and d) serum levels ofgastrin (radioimmunoassay).Endoscopic examination after treatment showed that the ulcer was completely healed in 32% of cases with re-epithelising in the remaining patients: satellite gastritis was considerably improved in all patients. The normalisation of the histological, histochemical and ultrastructural picture of the mucoid cells was the main morphological change induced by the treatment. This was associated on a functional level with a statistically significant increased production of hexosamines. The hydrochloric a...

Hexosamine content of pyloric tissue of the stomach in rats exposed to fasting, water immersion and restraint stress, and cortisone treatment was determined. Water immersion and restraint stress, and cortisone treatment resulted in the decreased hexosamine content. Anti-ulcer drugs were administered to these animals orally. In the water immersion and restraint stress the hexosamine content of pyloric tissue of the rats was increased by tyrosine, threonine, glutamine, gefarnate, synthetic aluminum silicate and sodium copper chlorophylline. Glutamine, gefarnate and sodium copper chlorophylline also induced the increase in hexosamine content of the rat pyloric tissue treated with cortisone acetate.

The effects of various therapeutic drugs for ulcer on oxygen consumption and anaerobic glycolysis of the gastric mucosa and the ulcer tissue were investigated utilizing Warburg manometer, the oxygen consumption and the glycolysis were markedly promoted with 3 types of drugs, namely Calf Blood Ex., Gefarnate and Human Placenta Ex. Accordingly, it seems that the results mentioned above can be one of the guides for the clinical treatment of peptic ulcer.