Ferulic acid nanoemulsion as a promising anti-ulcer tool: in vitro and in vivo assessment.

OBJECTIVE: Ferulic acid (FA) is a promising nutraceutical molecule which exhibits antioxidant and anti-inflammatory properties, but it suffers from poor solubility and bioavailability. In the presented study, FA nanoemulsions were prepared to potentiate the therapeutic efficacy of FA in prevention of gastric ulcer. METHODS: FA nanoemulsions were prepared, pharmaceutically characterized, and the selected nanoemusion was tested for its ulcer-ameliorative properties in rats after induction of gastric ulcer using ethanol, by examination of stomach tissues, assessment of serum IL-1ß and TNF-α, assessment of nitric oxide, prostaglandin E2, glutathione, catalase and thiobarbituric acid reactive substance in stomach homogenates, as well as histological and immunohistochemical evaluation. RESULTS: Results revealed that the selected FA nanoemulsion showed a particle size of 90.43 nm, sustained release of FA for 8 h, and better in vitro anti-inflammatory properties than FA. Moreover, FA nanoemulsion exhibited significantly better anti-inflammatory and antioxidant properties in vivo, and the gastric tissue treated with FA nanoemulsion was comparable to the normal control upon histological and immunohistochemical evaluation. CONCLUSION: Findings suggest that the prepared ferulic acid nanoemulsion is an ideal anti-ulcer system, which is worthy of further investigations.

Design, synthesis, biological evaluation, and computational studies of novel thiazolo-pyrazole hybrids as promising selective COX-2 inhibitors: Implementation of apoptotic genes expression for ulcerogenic liability assessment.

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation.

New γ-pyrone glycoside from Pachira glabra and assessment of its gastroprotective activity using an alcohol-induced gastric ulcer model in rats.

Pachira glabra is a medium sized tree that is famous for its delicious edible seeds and leaves. Phytochemical investigation of Pachira glabra leaf alcohol extract led to the isolation of a new γ-pyrone glycoside, 7-hydroxy maltol-3-O-ß-d-glucoside (HMGlu). In vivo assessment of the gastro-protective activity of HMGlu demonstrated superior gastro-protection at a dose of 100 mg kg-1, close to the value triggered by the standard reference omeprazole drug (evidenced by morphological and histopathological examinations). This was further confirmed by immunohistochemical staining where pretreatment with HMGlu (100 mg kg-1) markedly reduced NFκB, COX-2 and BAX positively-stained cells. Thus, it can be concluded that 7-hydroxy maltol-3-O-ß-d-glucoside can be a new pharmaceutically active agent with promising gastro-protective activity of natural origin.

Assessment of the Gastroprotective Effect of the Chaga Medicinal Mushroom, Inonotus obliquus (Agaricomycetes), Against the Gastric Mucosal Ulceration Induced by Ethanol in Experimental Rats.

The chaga medicinal mushroom (Inonotus obliquus) was traditionally used to treat various ailments. To establish the pharmacological properties of I. obliquus, studies were performed to show the antiulcer activity of the ethanolic extract. The ethanolic extract of I. obliquus was prepared. The antiulcer activity of I. obliquus was determined using gastric ulcerated rats (ulceration induced by ethanol). The ethanolic extract of I. obliquus (200 mg/kg) did not cause any sign of toxicity or sensitivity to rats when the extracts were administered by oral feed. Oral administration of ethanolic extract of I. obliquus exhibited antiulcer activity in all models used. The ethanolic extract of I. obliquus showed an effective antiulcer activity, which could be due to the presence of various biologically active compounds. This confirmed the traditional uses of I. obliquus in the treatment of ailments.

A Comprehensive Review on the Screening Models for the Pharmacological Assessment of Antiulcer Drugs.

BACKGROUND: Due to inappropriate diet, smoking, alcohol consumption, regular use of drugs like NSAIDs and sedentary lifestyle, one may feel upper abdominal pain which may be the predictor of the gastrointestinal disorder called Peptic Ulcer. When an imbalance occurs between the defensive factor and aggressive factor of the stomach, ulcer formation in the esophageal lining, stomach, or duodenum takes place. This leads to the formation of small sores that cause pain. Another condition that synergizes the abdominal pain is vomiting materials which look like coffee grounds, blood in the stool, black or tarry stools. This pain may increase after lunch or dinner. This problem persists, that often leads to the gastroenterologist's consultation. OBJECTIVE: There are many antiulcer screening models present for the determination of antiulcer activity of the drug molecule. The main objective of this study is to find which model is best for the determination of antiulcer activity. METHODS: A literature search was conducted on the databases namely Science direct and PubMed with the help of different keywords such as "Anti-ulcer", "In-vitro models" and "In-vivo models". The search was customized by applying the appropriate filters so as to get the most relevant articles to meet the objective of this review article. RESULT: There are different research and review papers based on the antiulcer screening models for the determination of antiulcer activity of new drug molecules. CONCLUSION: On the basis of our study, we found some useful models for the antiulcer activity of drugs and suggested that, if we use in-vitro and in-vivo methods together, then we may obtain the most relevant result in our research area.

Cognitive impact after short-term exposure to different proton pump inhibitors: assessment using CANTAB software.

INTRODUCTION: Studies have shown that proton pump inhibitors (PPIs) increase the brain burden of amyloid-beta (Aß) and also create vitamin B12 deficiency. However, these two phenomena have deleterious effect on cognition and Alzheimer's disease (AD). Since the use of PPIs has increased tremendously for the last few years, it is of great public health importance to investigate the cognitive impact of PPIs. Hence, the purpose of this study was to investigate the degree of neuropsychological association of each PPI with different cognitive functions. METHODS: Sixty volunteers of either gender were recruited and divided randomly into six groups: five test groups for five classes of PPIs and one control group. All the groups participated in the five computerized neuropsychological tests (nine subtests) of the Cambridge Neuropsychological Test Automated Battery twice: at the beginning of the study and 7 days thereafter. RESULTS: We found statistically and clinically significant impairment in visual memory, attention, executive function, and working and planning function. One-way analysis of variance findings showed that all PPIs had a similar negative impact on cognition. However, paired-samples t tests indicated that omeprazole showed significant (p < 0.05) results in seven subtests; lansoprazole and pantoprazole showed significant results in five subtests; and rabeprazole showed significant results in four subtests. Among five classes of PPIs, esomeprazole showed comparatively less impact on cognitive function with significant results in three subtests. CONCLUSIONS: The present study reveals for the first time that different PPIs have varying degrees of influence on different cognitive domains and have associations with AD. These findings should be considered when balancing the risks and benefits of prescribing these medications. A study done for a longer period of time with a larger sample size might yield better results.

Methods used in preclinical assessment of anti-Buruli ulcer agents: A global perspective.

Buruli ulcer (BU) caused by Mycobacterium ulcerans is the third most common chronic mycobacterial infection in humans. Approximately 5000 cases are reported annually from at least 33 countries around the globe, especially in rural African communities. Even though anti-mycobacterial therapy is often effective for early nodular or ulcerative lesions, surgery is sometimes employed for aiding wound healing and correction of deformities. The usefulness of the antibiotherapy nonetheless is challenged by huge restrictive factors such as high cost, surgical scars and loss of income due to loss of man-hours, and in some instances employment. For these reasons, more effective and safer drugs are urgently needed, and research programs into alternative therapeutics including investigation of natural products should be encouraged. There is the need for appropriate susceptibility testing methods for the evaluation of potency. A number of biological assay methodologies are in current use, ranging from the classical agar and broth dilution assay formats, to radiorespirometric, dye-based, and fluorescent/luminescence reporter assays. Mice, rats, armadillo, guinea pigs, monkeys, grass cutters and lizards have been suggested as animal models for Buruli ulcer. This review presents an overview of in vitro and in vivo susceptibility testing methods developed so far for the determination of anti-Buruli ulcer activity of natural products and derivatives.

Assessment of Cedrus deodara root oil on the histopathological changes in the gastrointestinal tissues in rats.

The present study was designed to investigate the effect of Cedrus deodara root oil on the histopathology of different gastrointestinal organs of Wistar rats. This oil was used traditionally as an anti-ulcer agent in the Indus Unic System and extracted from the plant root by destructive distillation method. A total of 90 rats were taken and divided into groups A, B and C, each comprising of 30 animals. The animals of group B and C were given 0.5 ml/kg and 2.5 ml/kg of C. deodara oil respectively while group A served as control and administered vehicle only. The treatment was given to the animals ones only for 24 hours. All animals were sacrificed and the organs like esophagus, stomach and ileum were taken out. Tissue processing and staining procedure was then carried out for any pathological changes in the animal tissues during microscopic examination. The results indicated that Cedurs deodara root oil at both doses 0.5ml/ kg and 2.5 ml/kg exhibited some adverse effects such as erosion of epithelium, edema on sub-mucosal and mucosal layers, congestion of blood vessels as well as presence of inflammatory cells on esophagus, stomach and ileum were seen. Moreover shortening of villi was also seen at both doses. A study conducted on mammalian toxicity previously on rats revealed that the C. deodara root oil used is not very toxic and comes under least toxic group as standardized by toxicologists. Based on the results obtained it was concluded that C. deodara root oil produced some adverse changes in the tissues of GIT when given at 0.5 ml/kg and 2.5 ml/kg doses but the effects were not lethal therapeutically at this dose LC50 16.5 ml/kg. The plant oil showed some toxicity and needs further detailed studies to assess its potential toxicity and therapeutic status before using this material as drug.

Chemical characterization of the lipophilic fraction of Livistona decipiens and Livistona chinensis fruit pulps (Palmae) and assessment of their anti-hyperlipidemic and anti-ulcer activities.

The oil of the dried pulps of Livistona decipiens and L. chinensis palm fruits have been studied for the first time by gas chromatography-mass spectrometry for their unsaponifiable matter (USM) and fatty acid composition (FAME). The antihyperlipidemic and anti-ulcer activities for both oils were also assayed. The principal fatty acid of L. decipiens pulp oil was oleic acid (53.4 %) and of L. chinensis pulp oil palmitic acid (47.4 %). In relation to anti-hyperlipidemic properties, the pulp oil of L. decipiens presented a better profile than that of L. chinensis, in comparison with the reference standard (simvastatin). In addition, both pulp oils showed high anti-ulcer activity using an indomethacin-induced ulceration technique in rat stomach. The relationship between the anti-hyperlipidemic, anti-ulcer and chemical composition of the pulp oils is also discussed.

Incremental cost effectiveness of proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug ulcers: a pharmacoeconomic analysis linked to a case-control study.

INTRODUCTION: We estimated the cost effectiveness of concomitant proton pump inhibitors (PPIs) in relation to the occurrence of non-steroidal anti-inflammatory drug (NSAID) ulcer complications. METHODS: This study was linked to a nested case-control study. Patients with NSAID ulcer complications were compared with matched controls. Only direct medical costs were reported. For the calculation of the incremental cost effectiveness ratio we extrapolated the data to 1,000 patients using concomitant PPIs and 1,000 patients not using PPIs for 1 year. Sensitivity analysis was performed by 'worst case' and 'best case' scenarios in which the 95% confidence interval (CI) of the odds ratio (OR) and the 95% CI of the cost estimate of a NSAID ulcer complication were varied. Costs of PPIs was varied separately. RESULTS: In all, 104 incident cases and 284 matched controls were identified from a cohort of 51,903 NSAID users with 10,402 NSAID exposition years. Use of PPIs was associated with an adjusted OR of 0.33 (95% CI 0.17 to 0.67; p = 0.002) for NSAID ulcer complications. In the extrapolation the estimated number of NSAID ulcer complications was 13.8 for non-PPI users and 3.6 for PPI users. The incremental total costs were euro 50,094 higher for concomitant PPIs use. The incremental cost effectiveness ratio was euro 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. CONCLUSIONS: Concomitant use of PPIs for the prevention of NSAID ulcer complications costs euro 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. The price of PPIs highly influenced the robustness of the results.

Experimental model in the qualitative and quantitative assessment of non-Helicobacter gastric microflora under proton pump inhibitors action.

PURPOSE: To evaluate models of gastric material collection from Wistar rats with and without using proton pump inhibitors(PPIs). METHODS: Twenty-four rats underwent intraperitoneal omeprazol treatment, and other 12 received similar treatment with 0.9% saline. All animals underwent collection of gastric material samples, after stomach removal, by either biopsies, or aspirates, or swabs. Samples were bacteriologically processed in order to identify species and strains. Values are described as natural logarithm of colony former units per mL [Ln(CFU/mL)]. Kruskal-Wallis and Mann-Whitney non-parametric tests were used, and p<0.05 was set as statistically significant. RESULTS: Significant difference was not seen for Ln (UFC/mL) values among the three methods of collection irrespective of using or not omeprazol. Also, significant difference was not seen in Ln (UFC/mL) values when comparing a method with each others, either using omeprazol or placebo. A significant increase of bacteria strains occurred when PPI was used, and this was seen on the three ways of collection, mainly in biopsy and swab. CONCLUSION: No difference occurred among the three methods of collecting bacteria samples from stomachs of rats, either when using placebo or omeprazol. A remarkable change is seen on animals bacterial microflora when PPIs are used, and bacteria are better identified when swab and biopsy are used.

Risk assessment in elderly for sensitization to food and respiratory allergens.

For elderly people, epidemiological data are rare for respiratory allergies and completely missing for food allergies. The aim of this study was to examine the prevalence and risk factors for sensitizations in 109 people with a mean age of 77 years, who are living in a geriatric nursing home. The cross-sectional study included a detailed interview, skin prick tests, and serum tests for specific and total IgE, IFN-gamma, and ST2, a marker for Th2-lymphocyte activity. Almost all study subjects (n=101) suffered from co-morbidity, 14 from type I allergy, 25 from gastrointestinal disorders treated with anti-ulcer drugs, 25 were chronic alcoholics and 21 were smokers. The total IgE levels were significantly higher in men (P=0.025), and not affected by smoking or alcohol consumption. Skin prick tests were positive in 41.7% of tested patients. Specific IgE to respiratory allergens was found in 40.4% of all patients and was elevated in men (P=0.013), with a significant correlation to smoking (P=0.029). Specific IgE to food allergens was detected in 24.8%, apparently without connection to the investigated risk factors. However, positive skin prick tests with food allergens could be correlated with chronic alcohol consumption (P=0.036). The intake of anti-ulcer medication was significantly correlated with elevated ST2 levels as an indirect readout for Th2-cell activity (P<0.001). The risk factors for sensitization in elderly to respiratory allergens were chronic damage of respiratory epithelia due to smoking, and for sensitization to food allergens chronic alcohol consumption.

The role of proton pump inhibitors in acute stress ulcer prophylaxis in mechanically ventilated patients.

This article reviews the use of proton pump inhibitors, other pharmacological therapies, and nonpharmacological therapies for the prevention of acute stress ulcers in critically ill patients.

Anti-ulcerogenic activity of xanthanolide sesquiterpenes from Xanthium cavanillesii in rats.

The preventive effect of natural xanthanolides as well as a series of synthetic derivatives on ulcer formation induced by absolute ethanol in rats was examined. Among the compounds tested, xanthatin gave the strongest protective activity. The inhibitory action exerted by this molecule on the lesions induced by 0.6N HCl and 0.2N NaOH was highly significant, reducing ulceration in the range of 58-96% at a dose from 12.5 to 100mg/kg. These results appear to confirm that the presence of a non-hindered alpha,beta-unsaturated carbonyl group seems to be an essential structural requirement for the gastric cytoprotective activity of these compounds. In order to explore this possibility, a theoretical conformational analysis was performed. We suggest that the mechanism of protection would involve, at least in part, a nucleophylic attack of the sulfhydryl group from the biological molecules present in the gastric mucosa to electrophylic carbons accessible in suitable Michael acceptors.

Comparison of two management strategies for Helicobacter pylori treatment: clinical study and cost-effectiveness analysis.

BACKGROUND: First-line proton pump inhibitor-based triple and quadruple therapies for Helicobacter pylori eradication present similar levels of efficacy. Cross-over treatment (quadruple following triple failure, and triple following quadruple failure) seems the most sensible approach to treatment failures, but the two strategies -'quadruple first' versus 'triple first'- have not been previously compared. The aims of our study were to assess the usefulness and the cost-effectiveness of the two treatment strategies. MATERIAL AND METHODS: Forty-nine out of 344 patients included in a previous study comparing triple therapy - 7 days of omeprazole, amoxicillin and clarithromycin twice a day - with quadruple therapy - 7 days of omeprazole twice a day, plus tetracycline, metronidazole and bismuth subcitrate three times a day - failed initial treatment and were assigned to cross-over therapy. Cure was determined by urea breath test. A decision analysis was performed to compare the two eradication strategies. RESULTS: Intention to treat cure rates were 46% (10/22 patients; 95% CI 24-68%) for second-line triple therapy and 63% (17/27 patients; 95% CI 42-81%) for second-line quadruple therapy. Per protocol cure rates were 71% and 85%, respectively. Intention to treat cure rates were 87% (95% CI 81-92%) for the 'triple first' versus 86% (95% CI 80-91%) for the 'quadruple first' strategy (p = .87). The 'quadruple first' strategy was more cost-effective. The incremental cost of 'triple first' strategy per person was 19 in the low-cost area and 65 US dollars in the high-cost area. CONCLUSIONS: The effectiveness of 'triple first' and 'quadruple first' strategies is similar, although the latter seems slightly more cost-effective.

Prescribing proton pump inhibitors for initial treatment of acid-related gastrointestinal diseases in a managed care population.

OBJECTIVE: To determine whether health services use by patients with selected acid-related gastrointestinal disorders (peptic ulcer disease, gastroesophageal reflux disease, and gastritis or dyspepsia) is lower after initial treatment with proton pump inhibitors (PPIs) than with histamine2 receptor antagonists (H2RAs). STUDY DESIGN: Retrospective, 2-year longitudinal study. PATIENTS AND METHODS: Among continuous enrollees from December 1, 1996, to June 1, 2002, in a group model health maintenance organization, 13,971 members were electronically selected who began receiving antisecretory therapy during that period and who had no previous drug therapy, endoscopy, or hospitalization for gastrointestinal disease. Adjusted medical costs and healthcare use related to gastrointestinal disease (measured by office visits, endoscopy, or imaging and hospital admissions) and factors associated with initial and subsequent drug therapy were analyzed using a 2-stage model. This method adjusted for unobservable confounders, primarily drug selection bias, an inherent limitation of retrospective database studies. RESULTS: Drug costs were more than 4-fold higher (P < .001) when PPIs rather than H2RAs were prescribed initially, but non-drug costs and health services use showed no decrease. A history of physicians' prescribing PPIs in the prior 12 months was associated with prescribing PPIs as initial therapy (odds ratio, 4.29; 95% confidence interval, 3.74-4.90) and with step-up therapy (change from H2RAs to PPIs). A history of physicians' prescribing H2RAs in the prior 12 months was associated with step-down therapy (change from PPIs to H2RAs). CONCLUSION: Prescribing PPI compared with H2RA therapy as initial therapy for acid-related gastrointestinal disease produced no decrease in nondrug costs or health services use.

A cost-effectiveness analysis of stress ulcer prophylaxis.

OBJECTIVE: To evaluate the efficacy, safety, and cost of using cimetidine, famotidine, and lansoprazole for stress ulcer prophylaxis (SUP) at our institution and determine which agent was most cost-effective. METHODS: An observational study of adults admitted to the medical, surgical, or cardiovascular intensive care unit was conducted to compare the cost and effectiveness of cimetidine, famotidine, and lansoprazole for SUP. Patients were identified for inclusion during three 2-week periods in 2000. Medical record reviews were conducted to gather data regarding the costs associated with the administration of SUP drugs and the treatment of any adverse events or therapeutic failures. Decision analysis was used to determine the average cost per patient for each treatment arm. A cost-effectiveness analysis was then conducted to determine which of the SUP agents was associated with the least cost without adversely affecting patient outcomes. A sensitivity analysis was applied to determine the robustness of the data. RESULTS: Eighty-eight patients were included in the analysis. Five of the patients started on cimetidine experienced therapeutic failure, whereas no patients receiving lansoprazole experienced therapeutic failure. For these reasons, and because lansoprazole is an oral agent, the average costs associated with lansoprazole use were lower than with the use of cimetidine. Lansoprazole was found to be the most cost-effective therapy. CONCLUSIONS: This study showed that lansoprazole is a cost-effective agent for the use of SUP at our institution. However, due to the higher cost of intravenous pantoprazole, the model demonstrates that, assuming equal effectiveness, intravenous pantoprazole would not be cost-effective when compared with cimetidine.

Low-dose lansoprazole and clarithromycin plus metronidazole vs. full-dose lansoprazole and clarithromycin plus amoxicillin for eradication of Helicobacter pylori infection.

AIM: To compare, in a randomized controlled trial, the efficacy and tolerability of two 1-week triple therapies for Helicobacter pylori eradication. METHODS: One hundred and thirty-four consecutive patients with non-ulcer dyspepsia and H. pylori infection were randomized to receive lansoprazole 30 mg once daily, clarithromycin 250 mg twice daily, and metronidazole 500 mg twice daily (LCM group), or lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily (LCA group). H. pylori status was assessed by rapid urease test, histology and 13C-urea breath test before and after therapy. RESULTS: At 3 months, H. pylori eradication (intention- to-treat/per protocol analysis) was 92.4%/93.8% in the LCM group and 83.1%/85.7% in the LCA group (P=N.S.). Side-effects were more frequently reported in the LCA group (37.9%) than in the LCM group (19.7%) (P < 0.05). CONCLUSIONS: In this open, randomized controlled trial, eradication of H. pylori by low-dose lansoprazole and clarithromycin plus metronidazole was higher with significantly less side-effects than by full-dose lansoprazole and clarithromycin plus amoxicillin. This finding may be related to the stronger synergism of clarithromycin plus metronidazole, even at lower doses, than of clarithromycin plus amoxicillin. Considering the lower cost as well, LCM should be preferred to LCA in the eradication of H. pylori.

Life cycle of a block buster drug: discovery and development of omeprazole (Prilosec).

Block buster drugs share a variety of common features, among which is the tendency to create entirely new markets. For example, an early "informed" estimate of the potential market size for the hypothetically "perfect" peptic ulcer drug was thirty-five million dollars. Based on current sales, however, we reckon this hypothesis to have underestimated the actual market demand for omeprazole (Prilosec) by about 400-fold. Similarly, prior to the introduction of the "retired" block busters chlordiazepoxide and diazepam (Librium and Valium), the market for "minor tranquilizers" in the treatment of anxiety and neurosis did not exist. Thus, once an emerging block buster seems to be therapeutically working, it is not unusual for diagnostic rates of the disease for which it is indicated and efficacious to actually increase. Top block buster drugs generally have or appear to have a high margin of safety.