Anti-ulcerogenic Drug Research Articles

Phyto-constituents profiling of Prosopis cineraria and in vitro assessment of antioxidant and anti-ulcerogenicity activities

BackgroundThe Fabaceae family's Prosopis cineraria L. Druce (PC) is a tiny to medium-sized, thorny and irregularly branching tree used in Indian traditional medicine. PurposeThe current study has been investigated of Prosopis cineraria bark for mycochemical screening and evaluating their pharmacological activities by using two antiulcer models. After that isolation of active constituent present in hydroalcoholic bark crude extract. Study designIn the present analysis, qualitative and quantitative studies were analyzed. On the basis of this assay we choose hydro-alcoholic bark extract (HABE) for pylorus ligation ulcer model and an ethanol-induced ulcer model on female albino wistar rats. The volume of gastric juice, pH, total and free acidity and ulcer index were all investigated. The hydroalcoholic extracts of bark were selected and further undergo the seclusion of bioactive compounds by using Gas chromatography-mass spectrometry (GC–MS) analyses and Liquid chromatography–mass spectrometry (LC-MS) of the extracts. ResultsPhytochemical screening of the bark extract showed that phenol, terpenoids, flavonoids, saponins, alkaloids, steroids, amino acids and proteins, reducing sugars and carbohydrates were present. However, a greater dose of the extract lowered gastric ulcer index and increased percent protection from pylorus ligation (75.05%) and ethanol (76.05%)-induced aberrations, as measured by altered biochemical markers such as a decrease in stomach volume, free, and total acidity. In contrast, GC–MS analyses of the hydroalcoholic bark extracts identified 42 compounds in which gallic acid is mainly present and in LC-MS analyses ferulic acid, chlorogenic acid and caffeic acid are found by use of the (NIST) library. ConclusionsBased on the present findings, it was revealed that the bark of Prosopis cineraria may be used as potent bio resource for natural antioxidants and antiulcerogenic drug. As a result, more research is needed on elucidation of individual phytochemicals, as well as their mechanism of action.

Gastrin, Histamine Prostaglandin: Indicators for assessing efficacy of cimetidine, Omeprazole and Ranitidine in Gastric Ulcer Treatment

Background and Objectives: There is increase prevalence of gastric ulcer in the society, but the drugs that are sensitive for radical cure are not screened with physiologic markers such which affect proper management of the disease. The objective of the study is to relate various sources or organ specific templates: gastrin, histamine and prostaglandin relating with the disease in evaluating the potencies of cimetidine, ranitidine and omeprazole for best choice of the drugs in gastric ulcer disease treatment.Material and Methods: Plasma, gastric and antral prostaglandins, histamine and gastrin levels were studied in ninety-six (96), male and female Swiss albino rats for 28 days, using high performance liquid chromatography.Results: Male and female rats with gastric ulcer treated with cimetidine, omepraszole and ranitidine showed no significant difference (P>0.5) in gastrin and the drug groups in plasma, gastric and antral concentrations. But, there was significant difference (P<0.05) in histamine levels between cimetidine, omeprazole and ranitidine in their gastric and plasma concentration. There was no significant difference (P>0.05) in prostaglandin values between cimetidine, omeprazole and ranitidine. Also there was no significant difference (P>0.05) in gastric and plasma levels of gastrin, histamine and prostaglandin between 7, 14, 21 and 28 days treatment period. But, there was significant difference (P<0.05) in antral concentration of gastrin, histamines and prostaglandin between the drug groups. However, there was no significant difference (P>0.05) in antral gastrin between male and female rats in cimetidine and ranitidine treatment. The three drugs were associated with high levels of gastrin, histamine, low prostaglandin though cimetidine showed higher concentration of prostaglandin.Conclusion: It is concluded that gastrin, histamine and prostaglandin are sensitive indicators in evaluating anti-ulcerogenic drugs efficacies.Janaki Medical College Journal of Medical Sciences (2017) Vol. 5(2): 5-12

Study of drug utilization pattern in emergency medicine ward at a tertiary care teaching hospital

Background: The emergency department represents an important platform for conducting drug utilization studies as patients present with a wide spectrum of diseases in acute form. An irrational prescription adversely affects the prognosis and recovery of patients. Hence, the objective of our study was to evaluate the drug utilization pattern and to determine the rationality of prescription using WHO prescribing indicators in emergency medicine ward.Methods: After obtaining Institutional Ethical Committee approval, a prospective observational study was conducted over 2 months. The case records of 150 patients admitted to the emergency medicine ward, with a hospital stay of more than 24hrs were reviewed to analyze the prescription pattern during the initial 48hrs of admission. Case records of patients irrespective of age, sex and diagnosis were included in the study. Descriptive statistics were used to analyze the results (SPSS version 20).Results: A total of 1014 drugs were prescribed from 150 case records with a mean age of 47±18 years. An average of 6.76 drugs was prescribed per prescription; percentage of encounters with at least an antimicrobial was 115 (76.66%). Injections were prescribed in all patients (100%) and only 416 (41.02%) drugs were prescribed by generic name and 657 (64.79%) drugs abided to the WHO essential drug list. Majority of patients received anti-ulcerogenic drugs followed by antimicrobials.Conclusions: There was a tendency of polypharmacy with overuse of PPIs and antimicrobials. There is need to rationalize the drug therapy in terms of increasing prescription of drugs from essential drug list by generic name.

Novel Anti-ulcerogenic Effects of Total Extract and Isolated Compounds from Cakile arabica

Abstract: Background and Objective: Natural products take a special interest in the discovery of new anti-ulcerogenic drugs. Family Brassicaceae is one of the most important families in use for many investigations. Cakile arabica (Velen) was used in folk medicine in treatment of gastric disorder with no scientific approve, so the aim of this study was to investigate its contents and prove their biological activities. Materials and Methods: Different chromatographic equipment and instrument were used for isolation such as column chromatography. Identification of compounds were done by several spectroscopic methods; 1H-NMR. The 13C-NMR and DEPT COSY, HSQC and HMBC. Absolute ethanol-induced ulcer model in rats were used to evaluate the anti-ulcerogenic activity using reference standard drug ranitidine (100 mg kg–1). Results: Ten compounds were isolated from C. arabica for the first time and were identified as: (1) ?-amyrin, (2) ?-sitosterol, (3) Tetracosanoic acid, (4) 4-hydroxy-5-n-butoxy-5-oxopentanoic acid, (5) Scopoletine, (6) Umbelliferone, (7) Esculetin, (8) Kaempferol, (9) Quercetin and (10) Quercetin-3-O-rutninoside. The total alcohol extract (1000 mg kg–1) and the isolated compounds (50 mg kg–1) showed anti-ulcerogenic activity with different potentials. The total alcohol extract was the most effective agent in this study, as it showed 98.5% protection of control ulcer followed by compounds tetracosanoic acid and 4-hydroxy-5-n-butoxy-5-oxopentanoic acid, which produced 80 and 55.5%, respectively while standard ranitidine produced 46.2%. The total alcohol extract was safe up to 4000 mg kg–1 and showed no side effects on liver and kidney functions when administrated orally for 15 consecutive days at dose 1000 mg kg–1. Conclusion: The cytoprotective mechanism may explain the potent anti-ulcerogenic activity of the Cakile arabica extract and the isolated compounds. Compounds tetracosanoic acid and 4-hydroxy-5-n-butoxy-5-oxopentanoic acid could be the main active constituents as they showed highest activities between compounds. But it is clear that there was a synergistic activity between compounds as the activity of the total extract exceeds the activity of any compound alone.

Further Pharmacological Evidence Supporting the Development of an Antiulcerogenic Drug Based on Rhizophora mangle L. Aqueous Extract. HPLC Method Proposed for Determinating a Chemical Marker

Rhizophora mangle L. is a vegetal species with high disponibility in Cuba for guarantying economical factibility by drug development. Preview studies showed promissory pharmacological results by the use of this plant in the treatment of gastroduodenal ulce...

Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model

The effects of anti-ulcerogenic drugs are dependent on the increase in prostaglandin production and reduction in leukotriene production in the gastric mucosa. Montelukast is an anti-asthmatic drug, a selective reversible cysteinyl leukotriene D4 receptor antagonist. In this study, we aimed to evaluate the anti-ulcerogenic effect of montelukast and to investigate the relationship between its anti-ulcerogenic effect and polymorphonuclear leukocyte infiltration in the gastric tissues. Male Sprague-Dawley rats were separated into five groups. Distilled water (control group), famotidine (40 mg/kg), and montelukast (5, 10 and 20 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered to all the groups. Six hours later, the animals were sacrificed by decapitation. The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, and the stomachs were later evaluated histopathologically (polymorphonuclear leukocyte infiltration). Ulcer inhibition rates were as follows: famotidine 96.14% and montelukast 59.96%, 72.65% and 76.97% (5, 10 and 20 mg/kg, respectively). Montelukast (10 and 20 mg/kg) showed effects similar to those of famotidine histopathologically. In this study, it was observed that there was a relationship between the anti-ulcerogenic effect of montelukast and polymorphonuclear leukocyte infiltration in the gastric mucosa, and montelukast behaved as an anti-ulcerogenic drug both macroscopically and microscopically.

Pharmacological and toxicological evaluation of Rhizophora mangle L., as a potential antiulcerogenic drug: Chemical composition of active extract

Rhizophora mangle L. is a vegetal species widely distributed in Cuba and other Caribbean countries. This species is characterized by several ethnobotanical activities as antiseptic, astringent, as well for treating skin ulcers. In the present work, we describe a pharmacological, toxicological and chemical evaluation of this plant by its use in human medicine for the treatment of gastroduodenal ulcers. The acute gastric ulcer’s models were: acute gastric ulcers induced by ethanol; indomethacin; pyloric ligation; stress and immobility in cool in mice. The antisecretor effect of the extract was evaluated by pyloric ligation model. Other pharmacological tests were planned with the freeze - dried extract of R. mangle , as part of the evaluation on other systems to known secondary or adverse effects. These tests included the activity of the antiulcer active extract on intestinal transit, activity over arterial pressure, ileum activity and absorption of glucose in gut. The chemical profile of this extract by fatty acids was studied by Gas Chromatography/Mass Spectrometry. Some toxicological studies (genotoxicity) were carried out. The aqueous extract of R. mangle bark showed gastroprotective, antisecretor effects, and it induced a recovery of PGE 2 levels in doses-dependence manner comparable of knowledge antiulcerogenic medicaments. No effect was observed by arterial pressure in rats and the intestinal transit was inhibited by R. mangle . The intestinal motility was stimulated. Antiulcer active extract inhibit the glucose absoprtion in gut. This extract presented 4% of saturated and not saturated long chain’s fatty acids (C10:0 at C24:0). No toxicological signs were obtained by this extract.

Effects of Bidens pilosa L. var. radiata Scherff on experimental gastric lesion

Bidens pilosa L. var. radiata Scherff: (BP) is a plant used as a traditional folk medicine. BP, cultivated with only green manure on Miyako Island, Okinawa prefecture, was processed to powder and is referred to as MMBP. We have reported that MMBP has antioxidant, anti-inflammatory, and anti-allergy properties. In this study, we investigated the effects of MMBP on several experimental gastric lesions induced by HCl/EtOH, a non-steroidal anti-inflammatory drug, or cold-restraint stress, comparing these results with those of rutin or anti-ulcerogenic drugs (cimetidine or sucralfate) based on the lesion index and hemorrhage from the gastric lesions. Orally administered MMBP prevented the progression of the gastric lesions. Moreover, treatment with MMBP, rutin, or sucralfate, which had potent antioxidative activity, inhibited increases in the levels of thiobarbituric acid reactive substances (TBARS) in the gastric mucosal lesions. The inhibition of the gastric mucosal TBARS content by MMBP may have been due to the antioxidant effects of MMBP. These results indicate that MMBP prevents the progression of acute gastric mucosal lesions, possibly by suppressing oxidative stress in the gastric mucosa.

Effects of an essential oil from the bark of Croton cajucara Benth. on experimental gastric ulcer models in rats and mice.

Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. The essential oil from its bark was investigated for acute toxicity in mice and for its ability to prevent the formation of ulceration of the gastric mucosa in different models of experimentally induced gastric ulcer in mice and rats. When previously administered orally at a dose of 100 mg kg(-1), the essential oil significantly reduced (P < 0.01) the gastric injury induced by hypothermic restraint stress (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 200 mg kg(-1), the essential oil from C. cajucara significantly reduced (P < 0.01) the formation of gastric lesions by 52% and 67%, respectively, when compared with the control group. In rats submitted to pylorus ligature, the essential oil given orally increased the volume of gastric juice when compared with the control group (P < 0.01). When the essential oil (100 mg kg(-1)) was administered intraduodenally to mice, significant modifications were found in gastric parameters such as pH and total acid content after oil treatment. We observed significant changes (P < 0.01) in gastric juice parameters such as an increase in volume and a decrease in gastric acidity (pH and total acid content). The acute toxicologic effects of the essential oil from C. cajucara were assessed in mice. The LD50 values were 9.3 g kg(-1) by the oral route and 680 mg kg(-1) by the intraperitoneal route. The good yield of essential oil obtained from dried C. cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity suggest that pharmacological studies of this substance as a potential new anti-ulcerogenic drug are warranted.

Gastroprotective activity of a new semi-synthetic solidagenone derivative in mice

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.

Differences in Gastroprotective and Mutagenic Actions Between Polar and Apolar Extracts ofAnanas ananassoides

Several plants are used in folk medicine to treat gastrointestinal disorders. Ananas ananassoides (Baker) L.B. Smith (Family Bromeliaceae) is a medicinal plant commonly used in the central region of Brazil against gastric pain. We evaluated two extracts (methanol [MeOH] and dichloromethane [DCM]) obtained from the leaves of A. ananassoides for their ability to protect the gastric mucosa against injuries caused by necrotizing agents (0.3 M HCl/60% ethanol, absolute ethanol, non-steroidal anti-inflammatory drugs, and pylorus ligation) in mice and rats. The best results were obtained after pretreatment with the DCM extract, whereas the MeOH extract did not show any significant anti-ulcerogenic activity but presented mutagenic action. The mechanism of action of the DCM extract suggested the effective participation of endogenous sulfhydryl group in the gastroprotective action. The data, taken together with the absence of acute toxicity and mutagenicity, indicate the apolar extract, instead of the polar, extract of A. ananassoides as a safe and potential new anti-ulcerogenic drug.

Gastroprotective and ulcer healing effect of ferruginol in mice and rats: Assessment of its mechanism of action using in vitro models

The gastroprotective activity of the diterpene ferruginol isolated from Prumnopitys andina wood and bark was determined on HCl/EtOH-induced gastric lesions in mice. The effect of the compound on the healing of subacute gastric lesions in rats was also studied. The mode of action of the diterpene was assessed using human gastric epithelial cells (AGS) and MRC-5 fibroblasts. The effect of ferruginol on the prostaglandin E 2 content, protection against sodium taurocholate induced-damage and reduced glutathione content was evaluated on AGS cells as well as on the growth of AGS and fibroblast cultures. The free radical scavenging effect of ferruginol was assessed by the 1,1-diphenyl-2-picryl-hydrazil radical and superoxide anion assays. The effect of ferruginol on human erythrocyte membrane lipoperoxidation was determined. The cytotoxicity of the compound was assessed by means of the neutral red uptake. At 25 mg/kg, ferruginol inhibited the appearance of gastric lesions by 60% showing similar effects than lansoprazole at 20 mg/kg. Additionally, the compound displayed a significant ulcer healing activity in rats at 25 and 50 mg/kg with curative ratios of 36.0% and 92.5%, respectively, while the reference compound ranitidine at 50 mg/kg showed a curative ratio of 79.6%. At 6 and 12 μM, ferruginol increased significantly the prostaglandin E 2 content. A strong inhibition of lipoperoxidation was found (IC 50: 1.4 μM), but no effect was observed on the sodium taurocholate induced-damage or reduced glutathione content. Ferruginol stimulated cell proliferation at 1–2 μM in AGS cells and at 4–8 μM in fibroblasts, with cytotoxicities (IC 50) of 24 and 26 μM, respectively. Our results support that ferruginol acts as gastroprotective increasing the PGs content, protecting the cells against lipid peroxidation and improving the gastric ulcer healing by a stimulating effect on the cell proliferation. These findings encourage further pharmacological studies of ferruginol as a potential new anti-ulcerogenic drug.

Effects of tea from Turnera ulmifolia L. on mouse gastric mucosa support the Turneraceae as a new source of antiulcerogenic drugs.

Turnera ulmifolia is a plant belonging to the family Turneraceae, popularly known in Brazil as chanana. This species is distributed from Guyana to southern Brazil where it is considered a weed. The plant occurs in tropical rain forest, fields, and gardens. Chanana tea is used in Brazilian folk medicine for the treatment of diseases related mainly to gastric dysfunction including gastric and duodenal ulcers. In this study, the ability of a lyophilized infusion, as an aqueous fraction (AqF) of the aerial parts of T. ulmifolia, was investigated for its ability to prevent ulceration of the gastric and duodenal mucosa was examined in mice and rats, respectively. The AqF significantly reduced the formation of lesions associated with HCl/ethanol administration by 39% and 46%, respectively, at doses of 500 mg/kg and 1000 mg/kg, p.o. The AqF also significantly reduced the incidence of gastric lesions induced by a combination of indomethacin and bethanechol by 58% and 72% at doses of 500 mg/kg and 1000 mg/kg, respectively. In stress-induced gastric ulcer, the inhibition by the AqF was 48%, 57%, and 58% at doses of 250 mg/kg, 500 mg/kg, and 1000 mg/kg, respectively (p<0.05). A pyloric ligature experiment showed that the highest dose of the AqF significantly affected the gastric juice parameters by increasing the pH from 2.5 (control) to 5.3 and decreasing the acid output from 11.3 (control) to 3.7 mEq/ml/4 h. The AqF had no significant effect on duodenal ulcers induced by cysteamine. Preliminary phytochemical screening confirmed that flavonoids were the major constituents of the AqF of T. ulmifolia. These results indicate that this extract has a significant antiulcerogenic effect, as popularly believed.

On a possible new intracellular signal-system in rat gastric mucosa

It is known that cAMP and cGMP, as an “intracellular second messenger system” play a significant role as a signal system, in the mechanism of action of anti-ulcerogenic (cytoprotective) drugs. According to our present, preliminary investigations it seems that during different experimental circumstances the gastric mucosal 3′-5′-cyclic-cytidine-mono-phosphate (cCMP) 3′-5′-cyclic-uridine-monophosphate and (cUMP) levels were changed—similarly to CAMP and cGMP—and these changes might be a possible indicator of a further, most probably secondary, signal- system role.

Evaluation of the Gastroprotective Activity of Cordatin, a Diterpene Isolated from Aparisthmium cordatum (Euphorbiaceae).

Aparisthmium cordatum (Juss.) BAIL. (Euphorbiaceae) is a medium sized tree native to the North Brazilian coastal region, which is known in the State of Pará as "ariquena queimosa." To our knowledge it has no popular use. Phytochemical studies of the benzene extract of the bark of A. cordatum yielded a furan diterpene with a clerodane skeleton, called cordatin. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), another furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of cordatin, another compound of the clerodane diterpene group present in A. cordatum bark. When previously administered (p.o.) at the dose of 100 mg/kg, cordatin significantly reduced (p<0.01) gastric injury induced by the indomethacin/bethanechol (78%), ethanol (76%), and hypothermic restraint-stress models (66%) and by pylorus ligature (50%) in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 250 mg/kg, cordatin from A. cordatum significantly reduced (p<0.001) the formation of gastric lesions by 70% and 77%, respectively, when compared to the control. In the pylorus-ligature model, cordatin (p.o.) only decreased the volume of gastric juice compared to the control (p<0.001). When cordatin (100 mg/kg) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity compared to the control (p<0.05). In the animals pre-treated with cordatin, free mucus production was not altered when compared with the control group. The results suggest that cordatin from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an anti-secretory property but the involvement of mucosal defensive mechanisms are not to be ignored. The good yield of cordatin obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.

Binding ability of impromidine, a potent H2 agonist of histamine

Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 ○C. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications.

A possible molecular basis for the effect of gastric anti-ulcerogenic drugs.

The exact mechanism of action of the anti-ulcerogenic drugs is still under debate. According to the literature, under normal conditions the cAMP:cGMP ratio in the rat gastric mucosa is approximately 8:10. Following prostacyclin administration, this ratio transiently decreases but later shows a strong elevation, indicating profound changes in the intracellular cyclic nucleotide balance. There is evidence that this elevation or 'shift' in the cAMP:cGMP ratio is linked, on a cellular or molecular level, to the anti-ulcerogenic, cytoprotective processes in the stomach. Cimetidine and ranitidine (widely used H2 receptor-blocking drugs) administered at doses that are too low to interfere with gastric acid secretion, cause an elevation in the cAMP:cGMP ratio, an effect that is also observed with other prostaglandin derivatives and anti-ulcerogenic drugs. In this article, Gabor A. Balint discusses these data and how the elevation of the gastric mucosal cAMP:cGMP ratio is a useful molecular marker that could provide insights into the effects of anti-ulcerogenic drugs.

Antiulcerogenic activity of trans-dehydrocrotonin from Croton cajucara.

trans-Dehydrocrotonin (DHC), the major diterpene isolated from Croton cajucara Benth, was assayed for antiulcerogenic activity in four induced gastric ulcer models in the rat. At an oral dose of 100 mg/kg DHC showed a significant antiulcerogenic effect on ulcers induced by hypothermic restraint stress, ethanol, and pylorus ligature. No significant changes in indomethacin-induced gastric lesions or modifications in gastric parameters such as wall mucus, secretion rate, pH, and total acid content were found after DHC treatment. The acute toxicological effects of DHC were assessed in mice. The LD50 values were 876 mg/kg and 47.2 mg/kg for oral and intraperitoneal administrations, respectively. The cytotoxicity of DHC was also studied. A dose-dependent inhibition of cell viability was observed in V-79 fibroblast cell cultures with an IC50 of 240 microM. The high yields of DHC obtained from dried C. cajucara barks as well as its good antiulcerogenic activity and low toxicity support the pharmacological study of this compound as a potential new antiulcerogenic drug.

Famotidine, the new antiulcero-genic agent, a potent ligand for metal ions

Potentiometric, polarographic, and spectroscopic results obtained for Cu 2+ and Ni 2+-famotidine systems clearly indicated that this anti-ulcerogenic drug is a very potent chelating agent able to coordinate cupric ion that was at pH below 2. This drug exhibits excellent histamine H 2 receptor blocking effects and its effective coordination to metal ions may have significant biological implications. Famotidine is found to be a very effective ligand for Ni 2+ ions also.

Depression of membrane-bound hydrolases by cimetidine in mouse renal basolateral and brush border

Oral administration of the antiulcerogenic drug, cimetidine, was studied on kidney-bound hydrolytic enzymes at three different dose levels (30 mg, 100 mg, and 2000 mg/kg body weight) and for single administration for 2 and 24 h, and daily administration for 15 days in mice. It significantly inhibited Na+, K(+)-ATPase, Mg(2+)-ATPase, and Ca2+, Mg(2+)-ATPase in the isolated basolateral membrane (BLM). Brush-border-membrane-(BBM)-associated enzymes, sucrase, lactase, maltase, leucine aminopeptidase, and alkaline phosphatase also showed a marked reduction. Substrate saturation kinetics revealed the nature of inhibition was of mixed type in the case of sucrase, lactase, maltase, and alkaline phosphatase (Km was increased, while Vmax decreased), whereas it was of non-competitive type for leucine aminopeptidase (Km was unchanged, while Vmax decreased). In vitro addition of cimetidine (5-20 mM) to the BBM also inhibited the enzyme activity. Dixon plot produced the inhibition constant (Ki) for cimetidine in the case of maltase, alkaline phosphatase, and leucine aminopeptidase in the order of 14.83, 32.83 and 11.5 mM, respectively. Analysis of lipids revealed a significant reduction in BBM-associated phospholipid and phospholipid/cholesterol molar ratio, while the neutral lipid fraction, i.e., cholesterol and triglycerides were not altered. Free fatty acid exhibited an increase after drug treatment, which was significant at higher dose after 24 h of single and 15 days of daily treatment. BLM-associated lipids did not exhibit any significant change. Cimetidine-induced depression in renal BLM- and BBM-associated disaccharidases and ATPases, at least at the higher dose level, may have serious consequences in the absorption of end-product nutrients.