Gastric Side Effects Research Articles

Design, synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity

A new series of novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety has been synthesized and evaluated as orally bioavailable anti-inflammatory agents with anti-ulcerogenic activity. The anti-inflammatory and anti-ulcerogenic activities of these compounds were compared to diclofenac and omeprazole, respectively. In carrageenan-induced paw oedema assay, 2-methyl-N-((3,4-dimethoxypyridin-2-yl)methyl)-1H-benzimidazol-5-amine (12d) and 1-(1,2,3,5-tetrahydroxy-α-d-mannofuranose)-5-(((3,4-dimethoxypyridin-2yl)methyl)amino)-2-methyl-1H-benzimidazole (15d) displayed dose-dependent anti-inflammatory activities by decreasing the inflammation by 62% and 72%, respectively which is comparable to that of diclofenac (73%). In contrast to diclofenac, the anti-inflammatory activity of these compounds was not only free from any side effects on the gastric mucosa but also showed significant anti-ulcerogenic activity in rat pyloric ligation and ethanol-induced gastric ulcer models similar to that of omeprazole. Together, these findings suggest that 12d and 15d are potent anti-inflammatory agents with concurrent anti-ulcerogenic activity and support its clinical promise as a component of therapeutic strategies for inflammation, for which the gastric side effects are always a major limitation.

QUALZICE: A QUALitative exploration of the experiences of the participants from the ZICE clinical trial (metastatic breast cancer) receiving intravenous or oral bisphosphonates

BackgroundThis qualitative sub-study aimed to explore the experiences of participants on the National Cancer Research Institute ZICE clinical trial, a randomised trial assessing two types of bisphosphonate treatment in breast cancer patients with bone metastases. Participants in the clinical trial were randomly allocated to receive either zoledronate, delivered by an intravenous (IV) infusion at clinic, or oral ibandronate, taken at home.MethodsQualitative research interviews were conducted with participant groups organised by treatment and location. Interviews covered experiences and understanding of bisphosphonate treatment, the experience of the delivery mechanisms (IV or oral), side effects and benefits, and quality of life issues. The analytic framework was interpretative phenomenological analysis.ResultsThis paper reports on one of four superordinate themes: participants’ experience of the ZICE trial, which explores the participants’ experiences with clinical trial-related processes. Results show that participants were generally satisfied with their randomised treatment, although most participants had an initial preference for oral bisphosphonates. Some difficulties were reported from participants for both interventions: needle phobia, poor veins, difficulty with swallowing and gastric side effects, but pain control was improved with both modes of delivery. However, the infused bisphosphonate was reported to lose effectiveness after three weeks for some participants, whereas the oral bisphosphonate was reported to give consistent pain control. Geographical location and distance to travel made little difference to convenience of access to clinic as the reported lengths of travel time were similar due to traffic congestion in the urban areas. Most participants understood the trial processes, such as randomisation, and information about bisphosphonates but some participants showed little understanding of certain aspects of the trial. Some participants reported difficulties in accessing dental treatment due to their dentist’s perceptions of bisphosphonate treatment.ConclusionsIn trials of medicinal products, especially when testing for non-inferiority, participants’ preferences and idiosyncrasies in relation to treatments should not be assumed. This study has shown that in a trial context, participants’ views can usefully add to the main trial outcomes and they should be taken into account when prescribing in the real world.Trial registrationISRCTN13914201. Main ZICE MREC: 05/MRE09/57. CRUK E/04/022.

Effect of methanolic extract of Physalis minima on gastric inflammation and gastric ulcers formation

Objective: This study aimed to investigate the effect of methanolic extract of Physalis minima L (MEPM) in gastric inflammation and gastric ulcer formation. Methods: For anti-inflammatory activity, we divided 30 male rats into five groups (n = 6), including the control group, gastric inflammation group, and gastric inflammation + MEPM groups (600, 1200 and 1800 mg/kg BW). Gastric inflammation was performed by oral administration of indomethacin at dose 30 mg/kg BW six hour prior to administration of MEPM. Phospholipase A2 was analysed by Western blotting. For gastric ulcer study, we compared the formation of ulcers between nonsteroidal anti-inflammatory drugs (aspirin) and MEPM. We divided 42 rats into seven groups (n = 6), including the control, aspirin (250, 500 and 750 mg/kg BW) and MEPM (600, 1200 and 1800 mg/kg BW) groups. Twenty four hours later the rats’ gastric and duodenal tissues were removed and ulcers formation were analysed histologically. Results: MEMP inhibit phospholipase A2 at the dose of 1200 mg/kg. The gradation of gastric ulcers was higher in aspirin compared to MEMP. At the dose of 600 mg/kg, MEMP does not induce gastric ulcers, but aspirin induces ulcers just at 250 mg/kg. Conclusion: Methanolic extract of Physalis minima L exerts anti-inflammatory action due to its effect to inhibit phospholipase A2 expression. In addition, the gastric ulcers formation side effect of MEMP was lower compared to aspirin.

Anti‐Inflammatory, Analgesic Evaluation and Molecular Docking Studies of N‐Phenyl Anthranilic Acid‐Based 1,3,4‐Oxadiazole Analogues

A novel series of N‐phenyl anthranilic acid‐based 1,3,4‐oxadiazoles were prepared (4a–h) and subjected to anti‐inflammatory, analgesic activity and molecular docking studies to target cyclooxygenase‐2 enzyme. 1,3,4‐Oxadiazole derivatives were screened for anti‐inflammatory activity in carrageenan‐induced rat paw edema and analgesic activity by tail immersion method. In synthesized compounds, the free carboxylic group, which is responsible for gastric side effects, was derivatized by heterocyclic 1,3,4‐oxadiazole bioactive core, which showed good interaction with COX‐2 receptor with good docking score. Among all the synthesized compounds, 4e and 4f have emerged out as potential COX‐2 inhibitors.

Effects of Nabumetone and Dipyrone on Experimentally Induced Gastric Ulcers in Rats

Nabumetone and dipyrone are non-acidic, nonsteroidal anti-inflammatory drugs. Both of them are known to have weak inhibitory effects of cyclooxygenases. Gastric side effects represent the most common adverse drug effects of the widely used nonsteroidal anti-inflammatory drugs. The gastric effects of these drugs may be comparable in experimental ulcer models. In the present study, the gastric ulcerogenic activity of nabumetone and dipyrone were investigated on stress- and diethyldithiocarbamate-induced experimental ulcer models by determining the ulcer index and gastric mucus secretion in rats. It was found that diethyldithiocarbamate increased both ulcer index and mucus secretion. Nabumetone inhibited dose-dependently the increase of diethyldithiocarbamate-induced mucus secretion. Dipyrone inhibited both stress- and diethyldithiocarbamate-induced ulcer index and mucus secretion. Nabumetone inhibited stress-induced ulcer index at 25-mg/kg dose but stimulated dose-dependently mucus secretion. These effects may be attributed to their non-acidic structures and weak inhibitory effects on gastric mucosal cyclooxygenases.

Pharmacological evaluation of sedative–hypnotic activity and gastro-intestinal toxicity of Rhizoma Paridis saponins

Ethnopharmacological relevanceRhizoma Paridis saponins (RPS) have been well studied for antimicrobial, anti-hemorrhagic, and anticancer effects. However, scientific information on RPS regarding the toxic and neuropharmacological effects is limited. In this study, the acute oral toxicity, sedative–hypnotic activity and gastro-intestinal toxicity of RPS were investigated. Materials and methodsThe acute toxicity was carried out by administering single doses (800–5000mg/kg) of RPS to adult mice. Rotarod test and sodium pentobarbital-induced hypnosis activity were used to evaluate the neuropharmacological effects on mice. Gastric emptying and intestinal transit were used to investigate the gastric–intestinal system effects. ResultsA single oral administration of RPS dose-dependently caused adverse effects on the general behavior and mortality rate of mice. LD50 value of oral acute toxicity was 2182.4mg/kg, with 95% confidence limit of 1718.4–2807.8mg/kg. In the test of sleeping mice, RPS acted in synergy with sodium pentobarbital at doses 250 and 500mg/kg while motor coordination was not influenced within 120min after treatment with RPS. Regarding the gastric–intestinal toxicity, RPS (100, 250, and 500mg/kg) significantly inhibited gastric emptying but did not affect the intestinal transit. ConclusionsRPS, which is a hypotoxic anticancer drug, possesses the sedative–hypnotic activity and gastric stimulus side effect.

Clinical Response and Side Effects of Metoclopramide

Metoclopramide is associated with variable efficacy and side effects when used in the treatment of gastroparesis. To determine associations of clinical and pharmacogenetic parameters with response and side effects to metoclopramide in patients with upper gastrointestinal symptoms suggestive of gastroparesis. Gastroparetic patients treated with metoclopramide were enrolled. Clinical parameters recorded were age, sex, weight, diabetic status, gastric emptying result, daily dose, effectiveness, and side effects. DNA was isolated from salivary samples; 20 single nucleotide polymorphisms were genotyped in 8 candidate genes (ABCB1, ADRA1D, CYP1A2, CYP2D6, DRD2, DRD3, HTR4, KCNH2). One hundred gastroparetic patients treated with metoclopramide participated. Dose averaged 33±16 mg/d for 1.1±1.7 years. Responders (53 of 100 patients) were older (48±15 vs. 38±11 y; P=0.0004) and heavier (body mass index of 28±7 vs. 25±7; P=0.0125). Efficacy was associated with polymorphisms in KCNH2 (rs1805123, P=0.020) and ADRA1D (rs2236554, P=0.035) genes. Side effects, occurred in 64 patients, were more common in females (83% vs. 64%; P=0.037), nondiabetics (77% vs. 47%; P=0.004), and patients with normal gastric emptying (41% vs. 17%; P=0.015). Side effects were associated with polymorphisms in CYP2D6 (rs1080985, P=0.045; rs16947, P=0.008; rs3892097, P=0.049), KCNH2 (rs3815459, P=0.015), and serotonin 5-HT4 receptor HTR4 gene (rs9325104, P=0.026). Side effects to metoclopramide were more common in nondiabetic patients with normal gastric emptying. Polymorphisms in CYP2D6, KCNH2, and 5-HT4 receptor HTR4 genes were associated with side effects, whereas polymorphisms in KCNH2 and ADRA1D genes were associated with clinical response. Clinical parameters and pharmacogenetic testing may be useful in identifying patients before treatment with metoclopramide to enhance efficacy and minimize side effects.

Design and Synthesis of New Mefenamic Acid Derivatives as Anti-Inflammatory Agents

This study includes design and synthesis of new non-steroidal anti inflammatory agents (NSAIDs) with expected cyclooxygenase-2 (COX -2) selective inhibition to achieve better activity and low gastric side effects. Two mefenamic acid derivatives were designed and synthesized as potential NSAIDs. In vivo acute anti-inflammatory effect of the synthesized agents (compound 2and 3) was evaluated in the rat using egg-white induced paw edema model of inflammation. Preliminary pharmacological study revealed that compound 2and 3 produced a significant reduction in paw edema with respect to the effect of propylene glycol 50% v/v (control group), moreover compound 2 exhibited comparable anti-inflammatory effect to that of aspirin after 120 and 210 minutes and compound 3 has less antiinflammatory effect, which encourages the continuation of the search to identify their selectivity toward COX-2 isoenzymes.

Design and synthesis of certain mesoionic sydnonyl styrylketones as potential nonsteroidal antiinflammatory agents

In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4-methoxyphenyl) sydnones, containing the structural features of mesoionic sydnone and styrylketone, have been designed and synthesized by condensing 4-acetyl-3-(4-methoxyphenyl) sydnone with various substituted aryl aldehydes and characterized by spectral studies. They have been tested for analgesic activity by acetic acid induced writhing in mice and for anti-inflammatory activity by carrageenan induced rat paw edema at 100 mg/kg body weight p.o. The compounds containing furyl and chloro substituents showed highly significant analgesic effect, while those with dimethylamino, chloro and nitro substituents exhibited highly significant anti-inflammatory effect at the end of 3 h. The compounds that showed good analgesic and anti-inflammatory activities were evaluated for ulcerogenicity in rats to assess their gastric side effects at 100 mg/kg body weight p.o. They were found to be less ulcerogenic than the standard drug.

NSAIDs: take with food or after fasting?

Published and regulatory advice is to take NSAIDs with fluids and/or food irrespective whether NSAIDs are taken over the counter or long-term. The basis for this recommendation is not clear and we sought to establish the reasons for it through a search of published literature and personal files. Results from experimental animals show that fasting increases the gastric side effects of NSAIDs while food increases small bowel damage, but this has not been tested in humans. The possible effects of food in modifying the gastric damage caused by NSAIDs are complex, as food quantity and composition modify the responses substantially. Food usually delays peak levels of NSAIDs (and hence onset of action) without affecting total bioavailability. This may not be important when a steady state is achieved, but rapid onset of action is highly relevant for over-the-counter use of NSAIDs. The safety of over-the-counter use of ibuprofen and naproxen appears to be excellent and comparable with paracetamol. The rapid onset of action of NSAIDs is most important during over-the-counter use, in which case it may be more appropriate to take the drugs on a fasting stomach.

Ibuprofen–phospholipid solid dispersions: Improved dissolution and gastric tolerance

Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen–DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen–DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5 mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 ± 6.2, 3.9 ± 5.3, 5.3 ± 4.9 and 9.1 ± 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p < 0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen.

Abstract 5560: All three positional isomers of acetyl salicylic acids are equally potent in inhibiting colon cancer cell growth: Differences in mode of COX inhibition

Abstract Introduction: Aspirin, 2-(acetyloxy)-benzoic acid or acetyl salicylic acid (o-ASA) is the prototypic chemopreventive agent. The mode of action of o-ASA is irreversible inhibition of cyclo-oxygenases (COX-1 and COX-2). o-ASA has potentially serious gastrointestinal side effects ranging from dyspepsia to gastrointestinal bleeding, obstruction, and perforation. There are 2 other positional isomers of acetyl salicylic acid, 3-(acetyloxy)-benzoic acid (m-ASA) and 4-(acetyloxy)-benzoic acid (p-ASA). In this study we did a head-to-head comparison between these 3 structural isomers in terms of their ulcerogenic properties, mode of COX inhibition, effects on colon cancer growth and cell kinetics. Methods: Cell line: HT-29 human colon adenocarcimoa; Cell growth: MTT; Cell cycle phase distribution: Flow cytometry; Apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms; Proliferation: PCNA. COX-1, -2 enzyme activity: colorimetric kit; Enzyme inhibition reversibility: dialysis. In vivo: 6 hrs after drug administration rats were euthanized, stomachs removed, cut along the greater curvature, rinsed with water, and observed (with magnifying lenses) to count the numbers and measure the lengths (in mm) of all hemorrhagic lesions (ulcer index). Tissue samples were immediately frozen in liquid nitrogen for PGE2, SOD, and MDA determination. Results: All 3 positional isomers inhibited the growth of HT-29 cells with IC50s &amp;gt;3 mM. At 1 mM and 3 mM, the 3 positional isomers showed similar but dose-dependent: (i) increases in apoptosis; (ii) reductions in proliferation; (iii) increases in G0/G1 phase, decreases in S and G2/M phases, suggesting a G0/G1 block. COX-1 inhibition before and after dialysis with 1 mM concentrations were: o-ASA 72 ± 3% and 72 ± 4%; m-ASA 54 ± 2% and 38 ± 2%; p-ASA 48 ± 2% and 29 ± 1%. COX-2 inhibition before and after dialysis with 3 mM concentrations were: o-ASA 83 ± 2% and 81 ± 2%; m-ASA 80 ± 2% and 56 ± 3%; p-ASA 80 ± 3% and 38 ± 2%. For indomethacine (positive control) at 1 µM the corresponding values were: COX-1 69 ± 2% and 24 ± 1%; COX-2 67 ± 2% and 32 ± 2%. In the stomachs all 3 positional isomers reduced PGE2 and SOD levels and increased MDA to the same extent. Ulcer index in o-ASA treated animals was 38 whereas in m-ASA and p-ASA treated animals it was 12 and 8 respectively. However, in the stomachs of the m-ASA and p-ASA treated animals there were significant numbers of micro-hemorrhagic lesions (m-ASA = 45, p-ASA = 37) representing pre-ulcers. Conclusion: m-ASA and p-ASA are reversible inhibitors of COX-1 and COX-2 whereas o-ASA in an irreversible inhibitor. Gastric side effects were qualitatively and quantitatively different possibly because o-ASA inhibits COX-1 to a greater extent than m-ASA or p-ASA. All 3 positional isomers had similar effects on HT-29 cell kinetics. m-ASA and p-ASA may be alternatives to traditional ASA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5560. doi:10.1158/1538-7445.AM2011-5560

Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence

Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world's first proven chemopreventive agent is currently unknown but the evidence looks hopeful.

Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) andO2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as Safe Anti-Inflammatory, Analgesic, Antipyretic, Antioxidant Prodrugs

Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design.

Relationship between feeding schedules and gastric distress during retinopathy of prematurity screening eye examinations

To determine whether a relationship exists between the timing of feeding before retinopathy of prematurity (ROP) eye examinations and gastric side effects or distress associated with this examination. A prospective, randomized, single-masked study was conducted involving infants in the neonatal intensive care unit who required an ROP eye examination and who received normal or full enteral feeding over a 1 year period. Infants were randomly assigned to 1 of 2 study arms: feeding 1 hour before examination (arm 1) or feeding schedule adjusted to ensure no feeding within 2 hours before examination (arm 2). Physiological data, including blood pressure and pulse rate, before, during and after examination, crying time during the examination, presence of vomiting and gastric aspirates, and gastric aspirates volume 24 hours after the examination, were recorded. A total of 34 infants were enrolled, with 57 separate eye examinations conducted. There was 19% less crying (p = 0.016) in arm 1 versus arm 2. Vomiting was 3-fold less in arm 1 versus arm 2 (4.2% vs 12.5%, p = 0.38). Gastric aspirates was less in arm 1 versus arm 2 (p = 0.18). Diastolic blood pressure was lower and respiratory rate greater during the examination in arm 1 (p < 0.05), whereas pulse rate was greater at the start of the examination in arm 1 (p < 0.05). Feeding neonatal intensive care unit infants 1 hour before compared with withholding feeding 2 or more hours before ROP examinations may reduce stress during the examination, as measured by percentage crying during the examination, with no increased incidence of vomiting or gastric aspirates.

Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI(2)) receptor (IP receptor) agonist that is chemically distinct from PGI(2) and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI(2) can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI(2) analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP(1)) > prostaglandin E receptor 3 (EP(3)), IP receptor > prostaglandin D(2) receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10(-3) M. In contrast, the PGI(2) analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10(-4) M). Contraction to all PGI(2) analogs was mediated via activation of EP(3) receptors, although EP(1) receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.

In vitro evaluation of topical gel prepared using natural polymer.

Nimesulide is a second generation non–steroidal anti–inflammatory agent, which is widely used in the long term therapy of rheumatoid arthritis, in alleviating pain and inflammation. But its short half-life (only 3–4 hr), so its causes more fluctuation. After oral administration Nimesulide causes to produces heart burn, nausea, loose motions, pruritus, etc. The present study based on the preparation of bioadhesive topical gel of Nimesulide, so as to avoid all gastric side effects. For the preparation of bioadhesive topical gel natural polymer aegel marmelos (plant Bale) was used. Bioadhesive polymers are the agents which increases the contact between the formulation and biological membrane, so as to avoid the fluctuation of formulation and behave as a sustained release formulation. In the present study, prepared bioadhesive topical gel was evaluated with the help of different parameters like drug content, spreadability, extrudability, swelling index study, in–vitro drug diffusion study, in-vitro drug release kinetic study and ex–vivo bioadhesive measurement. On the basis of in–vitro drug diffusion study and ex–vivo bioadhesive measurement property of gel, we have concluded that natural polymer aegel marmelos is the best polymer for the preparation of sustained release bioadhesive topical gel. Keywords: Topical gel; Bioadhesion; Natural polymer

Optimizing delivery of flurbiprofen to the colon using a targeted prodrug approach

The carboxylic group responsible for the gastric side-effects of the propionic acid derivative, flurbiprofen, was masked temporarily to overcome these side-effects and to accomplish colon-specific delivery of the drug. An amide prodrug (FLU-GLY) was synthesized by coupling flurbiprofen with L-glycine. Confirmation and characterization of the structure of the synthesized prodrug included elemental analysis, Fourier transform (FT)-IR, FT-NMR, mass (FAB) spectroscopy, and determinations of R(f), R(t) and R(M) values, respectively. Aqueous solubility and lipophilicity (logP) value were determined at pH 1.2, 4.0, 6.8 and 7.4. In-vitro reversion of FLU-GLY to flurbiprofen was measured at different pHs and in a simulated colonic environment. Acute toxicity and ulceration potential were evaluated in-vivo in albino rats. Pre-formulation studies showed increased hydrophilicity but a non-significant increase in lipophilicity of the prodrug. In-vitro reversion studies suggested that the prodrug remained intact until colonic pH was attained, when the colonic microfloral enzymes (amidase) hydrolysed the FLU-GLY amide linkage, releasing the free drug. In-vivo evaluation indicated that the prodrug was much less toxic and had less ulcerogenic activity than the parent drug. Selective delivery of drugs to the colon can be useful in terms of reducing the dose administered and reducing undesirable side-effects.

Abstract A42: Comparison between NO-ASA and NONO-ASA as safe anti-inflammatory, analgesic, antipyretic, antioxidant chemopreventive prodrugs

Abstract Introduction: Chronic inflammation is widely recognized as an underlying etiological factor in carcinogenesis; there is enough evidence to support the use of non-steroidal anti-inflammatory drugs (NSAIDs), and more importantly, their chemically-modified NO-releasing prodrugs (NO-NSAIDs) as promising chemopreventive agents. Metabolic activation of organic nitrate-containing NO-aspirins may lead to a cytotoxic “activated” linker (a quinone methide), raising safety concerns. Replacement of organic nitrates with N-diazeniumdiolates as a second-generation NONO-NSAIDs allowed us to conduct a head-to-head comparison between NCX-4016 (NO-aspirin), CVM-01 (NONO-aspirin), and aspirin as analgesic, anti-inflammatory, and anti-pyretic agents with no significant gastrointestinal toxicity. Methods: a) Anti-inflammatory: paw edema induced by intraplantar injection of 100 µL of 1% carrageenan, paw volumes measured up to the tibiotarsal joint immediately prior to carrageenan injection and thereafter at 1hr intervals up to 6hrs. Drugs were administered orally 1 hr before carrageenan; b) Anti-pyretic: body core temperature was measured twice at 15 min intervals before administration of lipopolysaccaride (LPS, 50µg/kg, ip) to induce fever. Drugs administered 1hr before LPS; c) analgesic: the time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered orally 2.5 hours after carrageenan; d) Anti-ulcerogenic: Rats fasted for 48h before drug administration. After 6 hrs animals were euthanized, stomachs removed, cut along the greater curvature, lightly rinsed with water, and observed (with magnifying lenses) to count the numbers and measure the lengths (in mm) of all hemorrhagic lesions (“gastric damage score”) for each stomach. Tissue samples immediately frozen in liquid nitrogen for PGE2, SOD, and MDA determination. Results: NCX-4016 and CVM-01 decreased the carrageenan-induced edema 1h after administration and maintained this anti-inflammatory effect throughout the experiment (up to 7h). Both compounds showed improved anti-inflammatory effect compared to aspirin 3–7h post administration. All test drugs (aspirin, NCX-4016, and CVM-01) were effective anti-pyretics, decreasing the body core temperature starting at 1h post-administration. At the end of the assay (5h) aspirin prodrugs showed slightly improved anti-pyretic effect compared to aspirin. Despite a drastic reduction of PGE2 levels induced by NCX-4016 and CVM-01 in stomach tissue, both prodrugs were devoid of gastric side effects (gastric index &amp;lt; 5) aspirin (GI=48). Lipid peroxidation induced by aspirin (MDA=57 nmol/mg protein) was higher than that observed by the prodrugs NCX-4016 (MDA= 9nmol/mg) and CVM-01 (13 nmol/mg), which resembled control tissue (MDA=12 nmol/mg). Superoxide dismutase (SOD): aspirin (SOD=12 U/mL), NCX-4016 (SOD=21 U/mL), CVM-01 (20 U/mL), control tissue (23 U/mL). Conclusions: The N-diazeniumdiolate containing aspirin prodrug CVM-01 is as effective as NCX-4016 (an organic nitrate-containing aspirin prodrug) in anti-inflammatory, analgesic, and anti-pyretic assays in vivo, and it showed an equivalent safety profile in stomach. These results underscore the use of diazeniumdiolate-containing NSAIDs (NONO-NSAIDs) in future chemopreventive assays. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A42.

Highthroughputput Screening (HTS) Assays for Cyclooxygenase-2 and 5-Lipoxygenase, the Targets for Inflammatory Disorders

High-throughput screening (HTS) involves testing of compound libraries against validated drug targets using quantitative bioassays to identify 'hit' molecules that modulate the activity of target, which forms the starting point of a drug discovery effort. Eicosanoids formed via cyclooxygenase (COX) and lipoxygenase (LOX) pathways are major players in various inflammatory disorders. As the conventional non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit both the constitutive (COX-1) and the inducible (COX-2) isoforms have gastric and renal side effects and the recently developed COX-2 selective anti-inflammatory drugs (COXIBs) have cardiac side effects, efforts are being made to develop more potent and safer anti- inflammatory drugs. Current assay methods for these enzymes, such as oxygraphic, radioisotopic, spectrophotometric etc. are not compatible for screening of large number of compounds as in drug discovery programs. In the present study, HTS- compatible assays for COX-1, COX-2 and 5-LOX were developed for screening of compound libraries with the view to identify potential anti-inflammatory drug candidates. A spectrophotometric assay involving co-oxidation of tetramethyl-p- phenylene diamine (TMPD) during the reduction of prostaglandin G 2 (PGG 2) to PGH 2 was adopted and standardized for screening of compounds against COX-1 and COX-2. Similarly, the HTS-compatible FOX (ferrous oxidation-xylenol orange) based spectrophotometric assay involving the formation of Fe 3+ /xylenol orange complex showing absorption in the visible range was developed for screening of compounds against 5-LOX.