ArticleLiterature Review

How do NSAIDs cause ulcer disease?

March 2000
Best Practice & Research Clinical Gastroenterology 14(1):147-59

DOI:10.1053/bega.1999.0065

Source
PubMed

Authors:

University of Calgary

Gastroduodenal ulceration and bleeding are the major limitations to the use of non-steroidal anti-inflammatory drugs (NSAIDs). The development of safer NSAIDs or of effective therapies for the prevention of the adverse effects of existing NSAIDs requires a better understanding of the pathogenesis of NSAID-induced ulcer disease. NSAIDs can cause damage to the gastroduodenal mucosa via several mechanisms, including the topical irritant effect of these drugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood flow and interference with the repair of superficial injury. The presence of acid in the lumen of the stomach also contributes to the pathogenesis of NSAID-induced ulcers and bleeding, by impairing the restitution process, interfering with haemostasis and inactivating several growth factors that are important in mucosal defence and repair. In recent years, a fuller understanding of the pathogenesis of NSAID-induced ulcer disease has facilitated some new, very promising approaches to the development of stomach-sparing NSAIDs.

Gardenia jasminoides fruit extract alleviates non-steroidal anti-inflammatory drug–induced gastropathy in rats

Article

Full-text available

Nov 2024

Background NSAID-induced gastropathy is a health burden that requires effective intervention. Among various prevention options, Gardenia jasminoides fruit extract (GJE) has demonstrated gastroprotective effects through anti-inflammatory pathways with a wide safety margin. However, the detailed molecular mechanisms of GJE regarding mucoprotective and anti-inflammatory effects remained to be explored. Therefore, we investigated the effects of GJE on NSAID-induced gastric injury in rats, focusing on the expression of the protective factors: prostaglandin E2 (PGE2) and mucin 5AC (MUC5AC), and the aggravating factors: inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB). Methods Twenty-four male Sprague–Dawley rats were assigned to three experimental groups (n = 8/group): the control group, the NSAIDs group receiving indomethacin to induce gastric ulcers, and the NSAIDs with GJE pretreatment (NSAIDs + GJE) group. After a two-day experimental period, the stomachs were collected for histopathological examination, immunohistochemical staining, and protein expression analysis in gastric tissue lysates. Results The NSAIDs group exhibited severe neutrophil infiltration with ulcers upon gastric histopathological examination. Pretreatment with GJE attenuated NSAID-induced gastropathy, as evidenced by reduced neutrophil infiltration and decreased ulceration. Immunohistochemical staining and Western blotting demonstrated reduced expressions of PGE2 and MUC5AC, while the expressions of iNOS and NF-κB were increased following NSAID administration. In comparison to the NSAIDs group, the NSAIDs + GJE group exhibited higher expressions of PGE2 and MUC5AC and lower expressions of iNOS and NF-κB, providing evidence of the gastroprotective effects of GJE. Conclusions Pretreatment with GJE alleviated NSAID-induced gastric ulcers by increasing the expression of PGE2 and MUC5AC and decreasing the expression of iNOS and NF-κB. This study contributes to the understanding of the mechanisms by which GJE attenuates NSAID-induced gastropathy. Further studies are required to validate the effect of GJE in clinical settings.

Application of the heme oxygenase-1/carbon monoxide pathway and the hydrogen sulfide pathway as new approach to prevent postoperative ileus

Thesis

Jan 2022

Jonas Van Dingenen

Synthesis, characterization, docking studies and anti-inflammatory activity of new safe NSAIDs agent based on Ibuprofen phenylalanine derivatives

Article

Aug 2022

Effectiveness and safety of human placenta hydrolysate injection into subacromial space in patients with shoulder impingement syndrome: a single-blind, randomized trial

Article

Full-text available

Jan 2025
BMC MUSCULOSKEL DIS

Background Human placental hydrolysate (hPH) contains anti-inflammatory substances. This study aimed to analyze whether injecting hPH into the subacromial space could reduce pain in patients with shoulder impingement syndrome. Methods This single-blind, randomized controlled study enrolled 50 patients with shoulder impingement syndrome who were randomly assigned to either the hPH or placebo groups. All patients received three ultrasound-guided subacromial space injections of 4 mL hPH or normal saline every week. Outcome measurements included the Visual Analog Scale (VAS) score during daily activity, Shoulder Pain and Disability Index (SPADI), and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) utility index. Patients were followed up for nine weeks after the last injection. Results Significant differences were noted in the VAS (p < 0.001) during daily activity, SPADI total score (p < 0.001), and EQ-5D-5L utility index (p < 0.001) nine weeks after the last injection between the hPH group and placebo group. Significant time effects were observed for all outcome measurements (all p < 0.001) in the hPH group but not in the placebo group. No severe complications, such as local infections or laboratory abnormalities, were reported during this study. Conclusions Subacromial injections showed significant improvement in pain, functional level, and quality of life in patients with shoulder impingement syndrome. Therefore, hPH can be used as an alternative treatment for shoulder impingement syndrome. Trial registration The trial was registered on www.Clinicaltrials.gov (NCT05528705, Registration Date: 06/09/2022).

Ensuring safe and effective pharmacotherapy: The role of “community pharmacology” in attaining “health for all” from the Indian perspective

Article

Full-text available

Dec 2024
JFMPC

A BSTRACT The novel approach of “Community Pharmacology” integrates pharmacological principles with community health to achieve the “Health for all” goal through safe and efficient health care. Pharmacovigilance, medication errors (ME), irrational prescriptions, and antimicrobial resistance in the community could be the key areas. Though life expectancy and other health indicators have improved in India, the disparity between rural and urban quality healthcare access should be addressed. Despite India’s enormous progress in vaccine manufacture, supply, and mass immunization through the Universal Immunization Programme (UIP) and Mission Indradhanush, issues remain in incomplete coverage and vaccine hesitancy. Other key challenges include high health expenditures, shortage of trained healthcare professionals, and lack of patient safety and irrational pharmacotherapy in remote areas. Community Pharmacology offers a multifaceted solution in community healthcare delivery through a well-designed integrated network equipped with skills in practical implications of pharmacology aimed at better medication supply, storage and dispensing, adherence to formularies according to the community needs, preparing Essential Medicine List and implementation of rational prescribing. Antimicrobial stewardship (AMS), adverse drug reaction (ADR) monitoring, and evidence-based usage of different drug formulations or drug delivery systems must be implemented beyond the tertiary level, involving both public and private stakeholders. Integrating Community Pharmacology into public health is crucial for fulfilling the global health initiatives to reach the Sustainable Development Goals (SDGs) as well as attaining India’s ambitious overall development targets.

Risk stratification of residual abscess after surgical treatment for gastroduodenal perforation

Article

Full-text available

Nov 2024

Aims Residual abscess is a major complication after emergency surgery for gastroduodenal (GD) perforation. However, there is little evidence regarding potential risk factors contributing to its development. Establishing a risk stratification strategy would be valuable for the entire management process. Methods This single‐center, retrospective study analyzed 115 consecutive patients who underwent surgery for GD perforation between 2010 and 2023 at a secondary emergency care hospital. Patients were divided into two groups based on the presence or absence of residual abscesses. Potential risk factors for abscess formation were evaluated from various aspects. Results The incidence of residual abscesses was 19.1% (22 of 115). Multivariable analysis revealed that current use of nonsteroidal antiinflammatory drugs (odds ratio [OR] 3.76, p = 0.037), cancer chemotherapy (OR 13.56, p = 0.005), and preoperative renal dysfunction (OR 4.72, p = 0.018) were independent predictors. A potential scoring model could be created using these three parameters, and the number of risk factors correlated with the likelihood of developing a residual abscess (0 vs. 1 vs. ≥2; 6.2% vs. 29.4% vs. 50.0%, p < 0.001). From a bacteriological point of view, the presence of Enterococcus in the ascites culture was closely related to its occurrence with 100% probability. Moreover, regarding early detection of this complication, C‐reactive protein on postoperative d 5 had the highest predictive ability with an area under the curve of 0.818. Conclusion The risk of residual abscess formation after surgical treatment of GD perforation can be assessed utilizing both preoperative and postoperative information.

Upper Gastrointestinal Mucosal Damage and Subsequent Risk of Parkinson Disease

Article

Full-text available

Sep 2024

Importance: The gut-first hypothesis of Parkinson disease (PD) has gained traction, yet potential inciting events triggering Parkinson pathology from gut-related factors remain unclear. While Helicobacter pylori infection is linked to mucosal damage (MD) and PD, it is unknown how upper gastrointestinal MD from any source increases PD risk. Objective: To evaluate any association between upper endoscopy findings of MD and subsequent clinical PD diagnosis. Design, Setting, and Participants: This was a retrospective cohort study of patients with no PD history undergoing upper endoscopy with biopsy between January 2000 and December 2005, with final follow-up assessments completed July 31, 2023. The study was conducted within the Mass General Brigham system, a multicenter network in the greater Boston, Massachusetts, area. Patients with MD were matched 1:3 to patients without MD based on age, sex, and date of initial endoscopy. Exposure: MD, defined as erosions, esophagitis, ulcers, or peptic injury, observed on upper endoscopy or pathology reports. Main Outcomes and Measures: The relative risk of PD given a history of MD, estimated using incident rate ratio (IRR) and multivariate Cox proportional hazard ratios (HRs). Results: Of 9350 patients, participants had a mean (SD) age of 52.3 (20.3) years; 5177 (55.4%) were male; and 269 (2.9%) were Asian, 737 (7.9%) Black, and 6888 (73.7%) White. Most participants underwent endoscopy between the ages of 50 and 64 years (2842 [30.4%]). At baseline, patients with MD were more likely to have a history of H pylori infection, proton-pump inhibitor use, chronic nonsteroidal anti-inflammatory drug use, gastroesophageal reflux disease, smoking, constipation, and dysphagia. The mean (SD) follow-up time was 14.9 (6.9) years for the whole cohort, during which patients with MD were more likely to develop PD (IRR, 4.15; 95% CI, 2.89-5.97; P < .001) than those without MD, even after covariate adjustment (HR, 1.76; 95% CI 1.11-2.51; P = .01). Constipation, dysphagia, older age, and higher Charlson-Deyo Comorbidity Index were also associated with higher PD risk. Conclusions and Relevance: In this cohort study, a history of upper gastrointestinal MD was associated with elevated risk of developing a clinical PD diagnosis. Increased vigilance among patients with MD for future PD risk may be warranted.

Evaluation of pharmacological actions of derivatives of 4-thiazolidiones and 1,3,4- thiadiazoles

Article

Full-text available

Jan 2019

Shail Modi

The pharmacological activities of derivatives of 4-thiazolidinone and 1, 3, 4- thiadiazoles were explored in this study. The derivatives were investigated for various activities such as inflammation, analgesia, and some CNS activities such as CNS depressant, anti-psychotic, and skeletal muscle relaxant activity. In-vitro tests like membrane stabilization and protein denaturation and in-vivo activities such as mice paw edema, cotton pellet granuloma, forced swim test, and locomotor activity were carried out to know the pharmacological activities of the test drugs. It was concluded that the derivatives had anti-inflammatory and analgesic properties without developing ulcers. They also showed muscle relaxant properties and depressant characteristics which could be helpful for sedation. Further investigations were still required to confirm CNS activities.

Rosuvastatin repurposing for prophylaxis against ethanol-induced acute gastric ulceration in rats: a biochemical, histological, and ultrastructural perspective

Article

Full-text available

Jul 2024
InflammoPharmacology

Ethanol (EtOH) consumption is frequently associated with acute and chronic gastrointestinal disorders. Rosuvastatin (RSV), a third-generation statin, has demonstrated certain biological functions beyond its lipid-lowering properties. This study is designed to explore the gastroprotective impact of RSV in a rat model of EtOH-induced gastric ulceration in a dose-dependent manner through the evaluation of oxidant/antioxidant biomarkers, inflammatory myeloperoxidase (MPO) enzyme activity, and prostaglandin E2 (PGE2) levels in gastric tissues, along with histopathological examination of the gastric tissues. Therefore, 40 adult male rats were randomly divided into five equal groups as control, EtOH (gastric ulcer), RSV-low dose plus EtOH and RSV-high dose plus EtOH. The EtOH rat model of gastric ulceration was achieved by intragastric administration of a single dose of EtOH. Seven days before EtOH administration, rats were orally administered either omeprazole (20 mg/kg/day) or RSV (10 mg/kg/day or 20 mg/kg/day). RSV administration enhanced the antioxidant glutathione reduced, countered oxidative malondialdehyde, augmented cytoprotective PGE2, suppressed inflammatory MPO enzyme activity in gastric tissues, decreased ulcer index scoring, increased the percentage of ulcer inhibition, and reversed the associated histological and ultrastructural abnormalities, additionally, RSV treatment resulted in weak positive nuclear staining for the inflammatory nuclear factor kappa B in a dose-dependent manner. It is concluded that RSV demonstrates gastroprotective potential, attributable at least in part, to its antioxidant and anti-inflammatory properties, as well as its ability to promote ulcer protection through the maintenance of mucosal content and PGE2 levels. Thus, RSV therapy emerges as a safe option for patients with gastric ulcers.

Novel gastroulcer protective micro(hydro)gels of sulfated locust bean gum-aluminium complex for immediate release of diclofenac sodium

Article

May 2013

Combined treatment of dexamethasone mouthwash and low‐level laser therapy in the management of aphthous‐like ulcers caused by nonsteroidal anti‐inflammatory drugs: A case report

Article

Full-text available

Mar 2024

Key Clinical Message A case of major aphthous‐like ulcer was described in a 50‐year‐old patient. The patient showed the main signs of aphthous stomatitis painful ulcer, 1–2 cm in diameter, located on the ventral of the tongue, buccal mucosa, and the palate. These ulcers persisted for more than 3 weeks. The patient's self‐administration of a nonsteroidal anti‐inflammatory drug (NSAID) was suggested as the leading cause of aphthous‐like ulcers in this case. ulcers were treated with dexamethasone mouthwash and low‐level laser therapy (LLLT).

Deep learning driven de novo drug design based on gastric proton pump structures

Article

Full-text available

Sep 2023

Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a Ki value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.

Haematococcus - Biochemistry, Biotechnology and Biomedical Applications

Book

Aug 2023

Covers recent topics of algae from bionanopesticides to genetic engineering Presents algal biotechnology, updated food processing techniques and Biochemistry of Haematococcus Offers information on the less explored areas of in silico therapeutic and clinical applications

Anti-Ulcer activities, physicochemical properties, antioxidant activity, and volatile compounds of pomegranate juice fortified with peel powder or seed homogenate in experimental rats

Article

Full-text available

Dec 2023

Natural products are used to develop anti-ulcer drugs with minimal side effects. In the present study pomegranate juice samples fortified with peel powder or seed homogenate were investigated for the treatment of induced peptic ulcer in rats. Forty-two female Albino rats weighing about 150±5 g were divided into two groups. The first group was fed only the basal diet as a negative. The second major group was randomly divided into six groups (six animals each). Group (2) the Positive control group (ve+) received orally (2 ml/kg BW) distilled water/day/rat by epi-gastric tube. Group (2) pretreated orally with 5mg/day (P. juice). Group (3) pretreated orally with (5mg/day) from (1.5 g PPP /100 ml P. Juice). Group (4) pretreated orally with (5mg/day) from (1.5 g PSP /100 ml P. Juice). Group (5) was pretreated orally with (a 5g/ 100 g diet /day) from (PPP). Group (6) received orally (50 mg/kg BW) Antodine® suspended in distilled water. After 7 days, animals were fasted for 24 hrs. Induction of ulcers in The second major group was done on the last day of the experiment.to induce acute gastric mucosal lesion, ibuprofen was treated orally in a dose of 200 mg/kg body weight three times a day at an interval of 8 hrs. Ulcer index, protective index, volume of gastric juice, and pH of gastric juice were evaluated in all groups. In biochemical parameters, Malondialdehyde (MDA), Reduced glutathione (GSH) concentration, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, Total protein, Albumin, and Alkaline phosphatase (ALP) activity were determined. The results indicated that the macroscopic and lipid peroxidation in the stomach had significant anti-ulcer activity of pomegranate juice, pomegranate juice enriched with peel powder and seed homogenate, peel powder, and Antoine. The anti-ulcer activity was comparable to the positive control. The results also indicated that there were no significant differences in values of physicochemical parameters including pH, titratable acidity, and TSS among the control rats group and fortified juice sample groups, especially at the level of (1.5 g/100 mL) either in peel powder or seed homogenate. The fortification treatments caused significant differences in the total phenolic, antioxidant activity and total flavonoid content among studied samples. Nineteen phenolic compounds had identified with significant variation among the studied samples. Seventeen volatile compounds were detected in the aroma profiles of pomegranate juice and selected supplemented pomegranate juice samples. Fortified pomegranate juice with peel powder recorded an increase of fenchone and a-terpineol to 5.39% and 4.21%, respectively compared to fresh pomegranate juice. The pretreatments with pomegranate and its derivatives did not produce significant changes in the tested biochemical parameters and histopathology in Female rats with Ibuprofen-induced gastric ulcer. It was concluded the fortification of pomegranate juice by peel powder or seed homogenate could be considered a promising gastroprotective and anti-ulcerative agent.

Clinical Applications of Haematococcus

Chapter

Aug 2023

Haematococcus is a genus of green microalgae widely distributed in freshwater and seawater and well known for their ability to produce astaxanthin, a powerful antioxidant with diverse applications. Eight species have been assigned to this genus based on a recent genetic classification and among them Haematococcus lacustris (previously named Haematococcus pluvialis) is the most studied. This species is regarded as the most promising microalgae for the production of natural astaxanthin. It is also known for its ability to synthesize other interesting bioactive compounds with a wide range of biological activities. The present work highlights the diverse therapeutic applications of Haematococcus bioactive molecules such as antioxidant, anti-inflammation, antimicrobial, skin protection, treatment and prevention of cancer, treatment of eye and neurodegenerative diseases, and immune stimulation.KeywordsAstaxanthinAntioxidantAnti-inflammationCancer preventionNeurodegenerative diseases

Molecular docking and anti-ulcerative potential of Cucumis (L. Inodorous) on ibuprofen induced gastric ulceration in male wistar animals

Article

Full-text available

Mar 2023

Background: The use of NSAIDs have caused stomach injury by inhibiting endogenous mucosal prostaglandin production. Cucumis melo is reported to possess antiulcer potential. This study investigates the mechanism underlying the antiulcer potentials of Cucumis melo (CUM). Methods: Thirty-five male Wistar rat were randomly assigned to each of seven groups; A(control given water and rat pellets), B(gastric ulcer induced with ibuprofen 400 mg/kg), C (Misoprotol 200 μg/kg), D to G (pretreated with different variation of CUM extract; 25 %, 50 %, 75 % and 100 % at a dose of 1 ml/kg for 3 weeks prior to gastric ulcer induction). Ulcer score, ulcer index and percentage inhibition, total gastric acidity was measured. Antioxidant activities, Malondialdehyde, H+/K+ ATPase, PGE2, TNF-α was done by spectrophotometry. Molecular docking investigation of Cucumis melo compounds against Prostaglandin E2 was carried out. Level of significance was tested at P ≤ 0.05 using Tukey post hoc. Result: Total gastric acidity, ulcer score, ulcer index, MDA, TNF-α significantly decreased after CUM treatment when compared to group B. The percentage inhibition, antioxidant activities, PGE2 concentration was significantly increased in all treatment groups compared to group B. Interactions of selected compounds of CUM with Prostaglandin E2 at various docking pockets showed folic acid has highest binding affinity followed by delta7-avenasterol and codisterol to PGE2 receptor. this study shows that one of the mechanisms by which CUM exhibits its antiulcer potential by enhancing Prostaglandin synthesis and antioxidant capacity. Therefore, Cucumis melo can therefore be explored as novel antiulcer agents.

A Retrospective Assessment of Proton Pump Inhibitors Use in A Tertiary Care Hospital, Chennai, India

Article

Feb 2023

Naproxen sodium nanoparticles are less toxic and gastroprotective agents than the conventional NSAID drug naproxen sodium in Balb/c mice

Article

Aug 2022
TOXICOL APPL PHARM

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is one of the leading causes of gastric ulcers. Excellent therapeutic properties have made the use of NSAIDs widespread. Nano-drug delivery to reduce systemic toxicity through modulating drug pharmacokinetics may be a better choice. Presently, we investigated if naproxen nanoformulation (PVA capped NPRS-MgO NPs) is less toxic to be used as an alternative drug. Groups of mice were assigned to control, NPRS-treated, CNF-treated, UNF-treated, and MgO NPs-treated groups. Analyses included gross examination of gastric mucosa, calculation of ulcer and inhibition indices, determination of tissue levels of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and reduced glutathione (GSH), histological and immunohistochemical assessment of i-NOS, COX-2, and caspase-3 of stomach mucosa, q-PCR for the detection of mRNA expression of IL-1β, IL-6, and TNF-α. Results were compared statistically at P < 0.05. Compared to NPRS-treated mice which developed multiple ulcers, had elevated MDA and ROS levels, and deceased CAT, POD, SOD, and GSH levels, significantly increased expression of IL-1β, IL-6, and TNF-α mRNA, damaged surface epithelium with disrupted glandular architecture and leucocyte infiltration of lamina propria with a marked increase in mucosal COX-2, i-NOS, and caspase-3 expression, oral administration of coated and uncoated naproxen nanoformulations prevented the gross mucosal damage by a restoration of all biochemical, histological, and immunohistochemical alterations to near control levels. The present study demonstrates that naproxen sodium nanoformulation has a gastroprotective action and in the clinical setting can be a better alternative to conventional naproxen.

Acute and sub-chronic toxicity assessment and evaluation of the gastro-protective activity of polyherbal formulation “Mystomate4®” against gastric ulcer in experimental laboratory animal. Clinical Phytoscience. 8(10), (2022)

Article

Full-text available

Feb 2022

Background Ulcer remains a health challenge worldwide with antibiotics and proton pump inhibitors as major management therapy. The study investigated the acute, sub-chronic toxicity and gastrointestinal protective activity of a polyherbal formulation (Mystomate4®) used locally in Nigeria. Methods Oral LD50 and the sub-chronic toxicity test were determined in mice and rats. Mice were grouped into 8 groups of 8 mice each. They were dosed a graded concentration of the formulation (1.28, 2.56; 5.12; 10.24; 20.48; 40.96; 81.92; 163.84 g/kg body weight). The graded dose used was arrived at after an initial pilot study. Thereafter doses were chosen around the dose obtained from the pilot study. Animal were dosed orally and observed for sign of toxicity and number of death recorded after 24 h. The sub-chronic toxicity study was carried out for 3 months in rats at a dose of 2.5 and 5.0 g/kg body weight arrived at by titrating down the LD50 value after which some vital tissues were harvested and assessed for toxicity using relevant biomarkers. Anti-ulcer activity was evaluated in rats using ethanol, indomethacin and pylorus ligation induced ulcer models. Data were analysed with Graph Pad Prism version 5.0 using appropriate statistical method and significant level placed at p ≤ 0.05. Results The acute toxicity study showed an LD50 result of 22,837.21 g/kg. The sub-chronic toxicity study resulted in a significant reduction in body weight due to significant decrease (p ≤ 0.05) in feed consumption. Biochemical analyses of the blood samples showed a significant increase (p ≤ 0.05) in creatinine and albumin level in the 2.5 mg/kg female group. ALT was significantly increased in all the treated rats except in 2 mg/kg female rats. Alkaline phosphatase significantly increased in high dosed male (HM) group while blood urea:creatinine ratio was significantly lowered in all the treated groups. There was a significant increase in serum TGL in all rats while LDL was significantly increased and decreased in HM and high dosed female (HF) respectively. Conclusion Mystomate4® showed significant protection against ethanol and indomethacin-induced ulcer models but did not modify the gastric parameters in pylorus ligation-induced ulcer model. The polyherbal formulation is nontoxic with promising potentials for treating experimental peptic ulcer.

Protective Effect of Prunus Dulcis against Acetylsalicylic Acid Injury on Gastric Parietal Cells An Experimental Study

Article

Full-text available

Jul 2021

Background: Acetylsalicylic acid is in common clinical use but has the side effect of causing gastric mucosal erosions and selective injury to parietal cells. Aim: To explore if prior treatment with Prunus dulcis (almond) had a protective effect against acetylsalicylic acid induced injury. Study design: Experimental study. Methodology: Albino mice weighing 30 to 40 grams were given two drops of almond oil without peel and 300 mg of finely ground whole almond kernel by oral gavage for sixty days followed by 400 mg/kg body weight of acetylsalicylic acid orally. Gastric mucosal damage was observed and recorded as ulcer index. The number of parietal cells/ sq. micrometer and area of parietal cells were observed and recorded under microscope in formalin fixed H and E stained sections. Data analyzed by SPSS 22.0v. Results: Mucosal damage, distortion of gastric glands and damage to parietal cells was pronounced in the positive control animals. The number of surviving parietal cells after acetylsalicylic acid insult in animals given almond oil was significantly higher when compared with positive control animals (p<0.001) and even better in animals receiving whole ground almond kernel. The area of parietal cells was also similarly larger in the treated animals. Conclusion: This study concluded Prunus dulcis offers protection against acute gastric mucosal injury and damage to the gastric parietal cells caused by acetylsalicylic acid in mice. Keywords: Prunus Dulcis, Parietal Cells, Gastric Erosions and Acetylsalicylic Acid.

Drug-drug interactions in atrial fibrillation patients receiving direct oral anticoagulants

Article

Full-text available

Nov 2021

Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0–1, 49.4% in category 2–3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22–55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11–16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.

Gastroprotective effect of n-butanol fractions from Lumnitzera racemosa leaves against indomethacin induced ulcer in Wistar rats

Article

Nov 2021

Phytoconstituents from plants serve as a safe replacement for synthetic molecules in drug production. Lumnitzera racemosa Willd., commonly called white-flowered black mangrove, is used in folk medicine to treat inflammation and other diseases. Here, we evaluated the antiulcer activity of two fractions (LR-B-4-11 and LR-B-4-12) of n-butanol (n-BuOH) fractions of L. racemosa leaves at the doses of 50 and 100 mg/kg, body wt. against indomethacin induced gastric mucosal injury in Wistar rats. The rats were dissected and their stomachs were inspected macroscopically to diagnose hemorrhagic lesions in the gastric and fundic mucosa. Administration of the fractions at doses of 50 and 100 mg/kg body wt., demonstrated a significant reduction in the indomethacin induced gastric erosion when compared to the control. The lower dose of LR-B-4-11 fraction (50 mg/kg) resulted in better inhibition of indomethacin induced gastric ulcer as compared to the control. Histological studies of the fundic and gastric mucosa reported that indomethacin led to mucosal degeneration, ulceration, and migration of numerous inflammatory cells throughout the section. On the other hand, pretreated groups with n-BuOH fractions demonstrated substantial regeneration of the mucosal layer and significant prevention of hemorrhage and edema occurrence.

Development, Characterization and Pharmacological Investigation of Umbelliferone Conjugates of NSAIDs

Article

Full-text available

Jun 2021

The present investigation developed the ester prodrugs of Non-steroidal anti inflammatory drugs (NSAIDs), Mefenamic acid and Flurbiprofen by conjugating with the natural antioxidant, 4-methyl umbelliferone that resulted the formation of Mefenamic acid-umbelliferone ester prodrug and Flurbiprofen-umbelliferone ester prodrug .The principal objective this study is the synthesis of the ester prodrugs of NSAIDs with the enhanced therapeutic activity and minimized side effects. Prodrugs were synthesized by coupling method using N,N’- dicyclohexylcarbodiimide/4-dimethylaminopyrimidine, subjected to physical, chemical characterization, spectral characterization (IR, 1H NMR, 13C NMR and Mass spectra),hydrolysis-kinetic study and pharmacological evaluation such as anti-inflammatory, ulcerogenecity as well as the effect of the NSAIDs in the central nervous system against degenerative mechanisms. The current study revealed that the umbelliferone conjugates of NSAIDs which upon administration would release the parent drug as a result of enzymatic or non-enzymatic hydrolysis in the desired site with enhanced anti inflammatory activity and reduction in the gastro intestinal toxicity. Also the synthesized pordrugs showed enhanced brain targeting efficiency with protective action against the degenerative processes.

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives

Article

Full-text available

Jun 2021
MOLECULES

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

Intravenous Acetaminophen vs Intravenous Diclofenac in the Management of Painful Crisis in Sickle Cell Disease

Article

May 2021
Indian Pediatr

Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors

Article

May 2021
EUR J PHARM SCI

Background Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy. Method α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations. Results Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA. Conclusion Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.

The Protective Effects of Probiotic Bacteria on Indomethacin-Induced Gastric Ulcer in Rats

Preprint

Full-text available

Jan 2021

Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa as a result of its use. For this reason, many experimental studies have been performed to search for new agents in order to treat or prevent gastric ulcers. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria against acute gastric mucosal damage caused by indomethacin. Our research used 40 female Wistar albino rats that were divided into four groups, with 10 in each group: Control group - Physiological saline was administered daily for 10 days. Indo group - Physiological saline was administered daily for 10 days. On day 11, a single 100mg/kg dose of indomethacin was given. Ranitidine + Indo group - A ranitidine dose of 5mg/kg was administered daily for 5 days. On day 11, a single dose of 100mg/kg of indomethacin was given to the same group. Probiotic + Indo group - A dose of 1 ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100mg/kg dose of indomethacin was given to the same group. After application, rats were killed in appropriate conditions, and stomach tissues were obtained. The obtained gastric tissues were used in the biochemical and histopathological analyzes discussed below. As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. However, we found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6, IL-1β, Tnf-α, and COX-2) and inhibits apoptosis (Bax and Bcl-2). This suggests that probiotic bacteria inhibit indomethacin-induced apoptosis. Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant and antiapaptotic properties.

Therapeutic effect of Tarantula cubensis extract on indomethacin induced gastric ulcers in rats

Article

Full-text available

Dec 2020
THAI J VET MED

Non-steroid anti-inflammatory drugs (NSAIDs) have widely been used in patients but side-effects associated with NSAID are also common. Tarantula cubensis extract (TCE) is an antiphlogistic, demarcative, homeopathic and necrotizing drug with wound healing effects in farm animals. However, the therapeutic effects of TCE on gastric ulcers has not been investigated. The aim of this study was to investigate the gastroprotective effects of TCE against indomethacin-induced gastric injury in rats. A total of 28 female, Wistar albino rats were divided into four groups: (i) the control group, (ii) the indomethacin (Indo) group, (iii) the TCE + Indo group, and (iv) the ranitidine + Indo group. We measured total antioxidant capacity, total oxidant capacity and oxidative stress index in the blood serum. We also measured tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, and cyclooxygenase-2 (COX-2) activity level in the stomach tissue of rats. Finally, histopathology of the tissue of all groups was assessed. Immunostaining of 8-hydroxydeoxyguanosine (8-OHdG) and nuclear factor kappa B (NF-kB) was performed in the gastric tissue of all animals studied. Application of the TCE significantly decreased IL-1β and IL-6 levels were markedly lower than ranitidine. Thus, notable Indo-induced alterations in cytokines (IL-1β, IL-6) in rat gastric tissue were alleviated by TCE. Moreover, the gastric mucosal tissues of the TCE treated group exhibited a regular and uninterrupted mucosal layer and epithelial layer. Immunohistochemical results revealed that Indo increased 8-OHdG and NF-kB expression when compared to the control groups and treatment by TCE decreased the expression. The results obtained showed that the group receiving TCE exhibited lower gastric erosion and better efficiency than with ranitidine. These results have demonstrated that TCE provides a therapeutic effect in Indo-induced gastric ulcers in rats. Original Article 560 Makav M. et al. / Thai J Vet Med. 2020. 50(4): 559-566.

Gastroprotective effects of both aqueous and ethanolic extracts of Lemon verbena leaves against indomethacin-induced gastric ulcer in rats

Article

Full-text available

Oct 2020

Objective(s): Regarding Lemon verbena gastroprotective effects, we investigated the protective effects of Lemon verbena extracts on reducing gastric ulcer induced by indomethacin. Materials and Methods: Rats received aqueous and ethanolic extracts of Lemon verbena (50, 100, and 200 mg/kg), zileuton (100 mg/kg), montelukast (10 mg/kg), or 1% Tween 80 in presence or absence of indomethacin (100 mg/kg). Results: Indomethacin produced stomach ulcer and increased neutrophils percentage and MDA level compared with the control group (P<0.001). Co-administration of indomethacin and zileuton, montelukast and ethanolic (200 mg/kg) (P<0.001), aqueous extract (200 mg/kg) (P<0.05) reduced ulcer compared with the indomethacin group (P<0.001). Ethanolic extracts (100 and 200 mg/kg) and aqueous extract (200 mg/kg) reduced the MDA level (P<0.001). Ethanolic (50, 100, and 200 mg/kg) and aqueous extracts (200 mg/kg) significantly decreased neutrophils percentage compared with the indomethacin group (P<0.001). Conclusion: Aqueous and particularly ethanolic extracts of Lemon verbena have protective effects on indomethacin-induced gastric ulcer.

Nicorandil effects on leptin and PG E2 Impact of Different Doses of Nicorandil-Induced Ulceration (Oral , Gastrointestinal Tract, and Anal) in Rats: Roles of Leptin and Prostaglandin E2 ‫

Article

Full-text available

Jan 2016
J PHARM PHARM SCI

Many reports confirm ulcers as an adverse effect of drugs such as nicorandil and aspirin. The exact responsible mechanisms of ulceration have until now not proved. Mucosal ulcers associated with the onset of ulcer are manifested by an increase in proinflammatory cytokine, excessive prostaglandin, and up-regulation of Endothilin-1 level, which directly impacts the release of leptin. These, released locally within mucosal tissues, have played a role in controlling the extent of local inflammatory responses and processes of mucosal repair. This study was designed to find out the correlation of plasma leptin and prostaglandin levels as a possible mechanism of oral ulcer formation as an adverse effect of nicorandil. The effect of nicorandil for inducing ulceration was assessed. The plasma leptin and prostaglandin E2 for the tested groups in relation to the studied parameters (gender, and daily body weight change) were estimated in albino rats. Nicorandil causes mucous membrane damage, inflammation, and ulceration. A significant reduction of plasma leptin level, which was dose-dependent, and a non-significant reduction of serum prostaglandin E2 level. The mechanisms of ulcer induction as an adverse effect of nicorandil can be related to dose-dependant leptin and prostaglandin E2 levels, which affects on repair and healing process. Keywords: Nicorandil, Leptin, Prostaglandin E2, Ulcer.

Epoxy Fatty Acids Are Promising Targets for Treatment of Pain, Cardiovascular Disease and Other Indications Characterized by Mitochondrial Dysfunction, Endoplasmic Stress and Inflammation

Article

Full-text available

Sep 2020
ADV EXP MED BIOL

Bioactive lipid mediators resulting from the metabolism of polyunsaturated fatty acids (PUFA) are controlled by many pathways that regulate the levels of these mediators and maintain homeostasis to prevent disease. PUFA metabolism is driven primarily through three pathways. Two pathways, the cyclooxygenase (COX) and lipoxygenase (LO) enzymatic pathways, form metabolites that are mostly inflammatory, while the third route of metabolism results from the oxidation by the cytochrome P450 enzymes to form hydroxylated PUFA and epoxide metabolites. These epoxygenated fatty acids (EpFA) demonstrate largely anti-inflammatory and beneficial properties, in contrast to the other metabolites formed from the degradation of PUFA. Dysregulation of these systems often leads to chronic disease. Pharmaceutical targets of disease focus on preventing the formation of inflammatory metabolites from the COX and LO pathways, while maintaining the EpFA and increasing their concentration in the body is seen as beneficial to treating and preventing disease. The soluble epoxide hydrolase (sEH) is the major route of metabolism of EpFA. Inhibiting its activity increases concentrations of beneficial EpFA, and often disease states correlate to mutations in the sEH enzyme that increase its activity and decrease the concentrations of EpFA in the body. Recent approaches to increasing EpFA include synthetic mimics that replicate biological activity of EpFA while preventing their metabolism, while other approaches focus on developing small molecule inhibitors to the sEH. Increasing EpFA concentrations in the body has demonstrated multiple beneficial effects in treating many diseases, including inflammatory and painful conditions, cardiovascular disease, neurological and disease of the central nervous system. Demonstration of efficacy in so many disease states can be explained by the fundamental mechanism that EpFA have of maintaining healthy microvasculature and preventing mitochondrial and endoplasmic reticulum stress. While there are no FDA approved methods that target the sEH or other enzymes responsible for metabolizing EpFA, current clinical efforts to test for efficacy by increasing EpFA that include inhibiting the sEH or administration of EpFA mimics that block metabolism are in progress.

Journal of Biologically active Products from nature Anti-ulcer potential of edible mushroom (Pleurotus pulmo- narius) on indomethacin-induced gastric ulcer in male wistar rats

Article

Dec 2024

Pleurotus pulmonarius (Pp), commonly called the Phoenix mushroom, is an edible tropical species with significant interest for its health-promoting properties. Renowned for its nutraceutical potential, Pp exhibits anti-inflammatory, anti-cancer, and prebiotic effects, positioning it as a valuable resource in functional food and therapeutic research. However, its anti-ulcer potential remains largely unexplored, prompting this investigation. The phytochemical profile and antibacterial activities of Pp were assessed using standard procedures. Thirty-five male Wistar rats were randomly assigned to five groups (n=7 per group): normal control (CN), untreated control (CU), pre-treated control with antacid (CP) and two groups treated with Pp supplements at 10% (FS10) and 30% (FS30) concentrations. Following 14 days of treatment, gastric ulcers were induced with indomethacin (40 mg/kg orally) after a 24-hour fast. Four hours post-ulcer induction, rats were anesthetized and stomachs were excised for analyses of ulcer score, nitrite, mucin, H 2 O 2 and H + K⁺-ATPase activity. Stomach tissues were further examined through histopathological analysis. Data were analyzed using descriptive statistics and one-way ANOVA at α=0.05. The study confirmed the presence of all evaluated phytochemicals in Pp. Treatments with FS10 and FS30 resulted in ulcer inhibition rates of 64.5% and 56.58%, respectively. Significant improvements were observed in gastric parameters (total protein, nitric oxide, mucin content, H 2 O 2 levels, malondialdehyde, and H⁺K⁺-ATPase) activities, in the FS10 and FS30 groups compared to the control groups (CN and CU). These findings underscore the antioxidant and gastroprotective properties of Pp, suggesting its potential as a natural therapeutic agent for managing gastric ulcers.

Anti-ulcer potential of edible mushroom (Pleurotus pulmonarius) on indomethacin-induced gastric ulcer in male wistar rats

Article

Full-text available

Nov 2024

Taiwo Michael O.

Pleurotus pulmonarius (Pp), commonly called the Phoenix mushroom, is an edible tropical species with significant interest for its health-promoting properties. Renowned for its nutraceutical potential, Pp exhibits antiinflammatory, anti-cancer, and prebiotic effects, positioning it as a valuable resource in functional food and therapeutic research. However, its antiulcer potential remains largely unexplored, prompting this investigation. The phytochemical profile and antibacterial activities of Pp were assessed using standard procedures. Thirty-five male Wistar rats were randomly assigned to five groups (n=7 per group): normal control (CN), untreated control (CU), pre-treated control with antacid (CP) and two groups treated with Pp supplements at 10% (FS10) and 30% (FS30) concentrations. Following 14 days of treatment, gastric ulcers were induced with indomethacin (40 mg/kg orally) after a 24-hour fast. Four hours post-ulcer induction, rats were anesthetized and stomachs were excised for analyses of ulcer score, nitrite, mucin, H2O2 and H+K⁺-ATPase activity. Stomach tissues were further examined through histopathological analysis. Data were analyzed using descriptive statistics and one-way ANOVA at α=0.05. The study confirmed the presence of all evaluated phytochemicals in Pp. Treatments with FS10 and FS30 resulted in ulcer inhibition rates of 64.5% and 56.58%, respectively. Significant improvements were observed in gastric parameters (total protein, nitric oxide, mucin content, H2O2 levels, malondialdehyde, and H⁺K⁺-ATPase) activities, in the FS10 and FS30 groups compared to the control groups (CN and CU). These findings underscore the antioxidant and gastroprotective properties of Pp, suggesting its potential as a natural therapeutic agent for managing gastric ulcers.

Prevalence, Causes and Outcomes of Acute Gastrointestinal Bleeding in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Article

Jun 2024

Aim The present study aims to investigate the prevalence, causes and outcomes of acute gastrointestinal (GI) bleeding in Rheumatoid arthritis (RA). Methods A systemic search was conducted from electronic databases (PubMed/Medline, Cochrane Library, and Google Scholar) from inception to 14th November 2023. All statistical analyses were conducted in Review Manager 5.4.1. Studies meeting inclusion criteria were selected. A random-effect model was used when heterogeneity was seen to pool the studies, and the result was reported in prevalence and their corresponding 95% confidence interval (CI). Other outcomes were assessed using qualitative analysis. Results A total of eight studies (six observational studies and 2 trials were used to conduct this systematic review and meta-analysis. A total population of 138,041 patients was used. Pooled analysis showed a statistically significant risk of GI bleeding in RA patients receiving NSAIDs (prevalence = 2% (1%, 3%); P < 0.00001; I2 = 98%). Qualitatively, causes and outcomes were discussed. Conclusion Our study showed that 2% RA patients were subjected to GI bleeding, when they used NSAIDs. Other causes of GI bleeding were age-related factors, cardiovascular events, history of GI complications, and peptic ulcers. Outcome varied by the use of specific NSAIDs and the presence of comorbidities. Recent guidelines for the management of RA may mention GI bleeding as a potential complication, but the level of emphasis placed on this issue varies. Some guidelines provide comprehensive recommendations for its prevention and management, while others offer limited guidance.

Treatment of Knee Chondral Defects in Athletes

Article

Jun 2024

Cartilage lesions of the knee are a challenging problem, especially for active individuals and athletes who desire a return to high-load activities. They occur both through chronic repetitive loading of the knee joint or through acute traumatic injury and represent a major cause of pain and time lost from sport. They can arise as isolated lesions or in association with concomitant knee pathology. Management of these defects ultimately requires a sound understanding of their pathophysiologic underpinnings to help guide treatment. Team physicians should maintain a high index of suspicion for underlying cartilage lesions in any patient presenting with a knee effusion, whether painful or not. A thorough workup should include a complete history and physical examination. MRI is the most sensitive and specific imaging modality to assess these lesions and can provide intricate detail not only of the structure and composition of cartilage, but also of the surrounding physiological environment in the joint. Treatment of these lesions consists of both conservative or supportive measures, as well as surgical interventions designed to restore or regenerate healthy cartilage. Because of the poor inherent capacity for healing associated with hyaline cartilage, the vast majority of symptomatic lesions will ultimately require surgery. Surgical treatment options range from simple arthroscopic debridement to large osteochondral reconstructions. Operative decision-making is based on numerous patient- and defect-related factors and requires open lines of communication between the athlete, the surgeon, and the rest of the treatment team. Ultimately, a positive outcome is based on the creation of a durable, resistant repair that allows the athlete to return to pain-free sporting activities.

New Onset of Symptomatic Peptic Ulcer Disease Postpartum Secondary to Nonsteroidal Anti-Inflammatory Drug Use

Article

Full-text available

Jun 2024

The use of nonsteroidal anti-inflammatory drug (NSAID) medications is a risk factor for peptic ulcer disease (PUD). PUD in the postpartum period is rare, despite the common use of NSAIDs. A G1P0 presented 6 days postcesarean section with fatigue, lightheadedness, melenic stools, and a hemoglobin of 5.4 g/dL after using NSAIDs and acetaminophen for postoperative pain control. An esophagogastroduodenoscopy (EGD) was performed for a suspected upper gastrointestinal bleed and found one gastric and one duodenal ulcer. Though typically used for a short course in the postpartum period, NSAIDs remain a predisposing risk factor for PUD postpartum, and patients and providers must be aware of this risk.

Probiotic bacteria protect against indomethacin-induced gastric ulcers through modulation of oxidative stress, inflammation, and apoptosis

Article

Full-text available

May 2024
MOL BIOL REP

Background Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa due to its use. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria (Lactobacillus rhamnosus, Lactobacillus fermentum, and Lactobacillus brevis) against acute gastric mucosal damage caused by indomethacin. Methods Control group - Physiological saline was administered daily for 10 days. Indo group-Physiological saline was administered daily for 10 days. Ranitidine + Indo group 5 mg/kg ranitidine dose was administered daily for 5 days. On day 11, a single dose of 100 mg/kg of indomethacin was given to the same group. Probiotic + Indo group 1 ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100 mg/kg dose of indomethacin was given. After the application, the rats were anesthetized with ketamine xylazine, killed under appropriate conditions, the abdominal cavity was opened and the stomach tissues were removed. The obtained gastric tissues were used in the biochemical and histopathological analyses discussed below. All data were statistically evaluated by one-way ANOVA using SPSS 20.00, followed by Duncan Post hoc test. The data were expressed as mean ± SD. P < 0.05 was considered statistically significant. Results As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. We found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6 and Tnf-α), and inhibits apoptosis (Bax and Bcl-2) (P < 0.05). Conclusion Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant, and antiapoptotic properties.

Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice

Article

May 2024
REGUL TOXICOL PHARM

Tilapia Head Glycolipid Alleviates Indomethacin-Induced Gastric Ulcer via Regulating Oxidative Stress and Inflammation Through COX/PGE2 Signaling Pathway in Adult Rats

Article

May 2024

The aim of this experiment was to investigate the ameliorative effect and molecular mechanism of tilapia head glycolipid (TH-GL) on indomethacin (IDM)-induced gastric ulcer in male Sprague Dawley (SD) rats. The gastric ulcer model was established by oral administration of 30 mg kg−1 IDM after 7 days of TH-GL or omeprazole (OME) administration in rats. Then the macroscopic gastric injury symptoms, gastric mucosa protective factor cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), the levels of oxidative stress, and inflammatory cytokine expression levels in the rats were analyzed. The experimental results showed that multiple ulcers appeared on the gastric surface of the rats in the model group. Compared to the model group, TH-GL significantly alleviated gastric ulcers and reduced the gastric damage index in rats. In addition, TH-GL significantly promoted the expression of constitutive enzyme COX-1 while inhibited the expression of inducible enzyme COX-2, and make PGE2 maintain at normal levels. TH-GL also inhibited oxidative stress and inflammatory responses, increased superoxide dismutase (SOD) activity and glutathione (GSH) content, decreased the level of malondialdehyde (MDA) and the content of pro-inflammatory factor. In conclusion, these results suggested that TH-GL could maintain the expression levels of COX-1 and PGE2 while inhibit the expression of COX-2 in the gastric of rat and then prevent IDM-induced gastric ulcer, which may be related to the regulation of oxidative stress and inflammatory response. Therefore, TH-GL might be a new option for the prevention of gastric diseases induced by IDM.

NSAID use in orthopedic surgery: A review of current evidence and clinical practice guidelines

Article

Jan 2024
J ORTHOP RES

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are a valuable class of medications for orthopedic surgeons and often play a pivotal role in pain control. However, there are many common stipulations resulting in avoidance of its use in the treatment of musculoskeletal disease. This review summarizes the mechanism of action of NSAIDs as well as provides an overview of commonly used NSAIDs and the differences between them. It provides a concise summary on the osseous effects of NSAIDs with regard to bone healing and heterotopic ossification. Most of all, it serves as a guide or reference for orthopedic providers when counseling patients on the risks and benefits of NSAID use, as it addresses the common stipulations encountered: “It irritates my stomach,” “I have a history of bariatric surgery,” “I'm already on a blood thinner,” “I've had a heart attack,” and “I've got kidney problems” and synthesizes both current research and society recommendations regarding safe use and avoidance of NSAIDs.

In Silico Exploration of Therapeutics in Haematococcus pluvialis

Chapter

Aug 2023

Haematococcus, a freshwater chlorophyta belongs to the family of Haematococcaceae and well known for its ability to synthesize large amounts of astaxanthin, a powerful antioxidant used in medicine, aquaculture, and cosmetics. Haematococcus pluvialis were roughly about 83 gb in size with more than 50% GC content and around 18,500 genes. The genomic information coupled with transcriptomic data laid a benchmark to determine the genetic basis for the theoretical and commercial enrichment of astaxanthin. The binding sites of the astaxanthin were predicted from the computational studies and notably specific amino acid substitutions were recorded in several organisms, which are predicted to play a vital role in AST esterification. The biomarker compound identified in Haematococcus pluvialis have been predicted to play in the regulation of vitamin resources. Computational exploration of astaxanthin molecule revealed its medicinal properties via molecular docking analysis. Computational analysis paved a way for the exploration of underlying therapeutic properties in Haematococcus pluvialis.Keywords Haematococcus pluvialis AstaxanthinMolecular dockingTherapeutics

Anti-inflammatory and immunosuppressant drugs

Chapter

Jan 2007

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

Article

May 2022

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

Microencapsulation of Diclofenac Sodium into natural Lycopodium Clavatum spores: In vitro release and gastro-ulcerogenic evaluations

Article

Mar 2022
J DRUG DELIV SCI TEC

This study highlights the protective role developed by encapsulation of Diclofenac Sodium (DIC) into natural Lycopodium Clavatum spores (LCS) to reduce gastric ulcerations associated with DIC administration in stomach of rats. Microencapsulation of DIC into empty LCS extracted from their natural, raw spore species was explored for the first time. LCS were characterized before and after drug loading using light microscopy, SEM, FTIR, TGA and particle size analyses. Different microencapsulation techniques (passive diffusion, vacuum-assisted and a combined passive-vacuum), varying loading duration and drug amounts were evaluated. Gastro-ulcerogenic activity of DIC loaded LCS against plain DIC was evaluated in rats. FTIR and TGA confirmed successful DIC encapsulation within the internal cavities of LCS. SEM, light micrographs and particle size analysis showed that drug loaded spores retained well defined microstructures similar to raw spores, with uniform size distributions of 20–25 μm. Encapsulation efficiency of DIC loaded LCS by vacuum-assisted loading was the highest (50%) compared to other loading techniques. A biphasic release pattern was achieved for drug loaded spores, with an initial fast release up till 2 h followed by a sustain release for 24 h, in phosphate buffer (pH 6.8), while ≥80% of plain DIC was released within 1 h. DIC loaded LCS showed substantial stomach protective action from related gastric ulcerations associated with DIC. Hence, a simple, reproducible approach utilizing Lycopodium Clavatum spores as natural encapsulant for oral delivery was established, with uniform micro-size distribution.

Intravenous Acetaminophen vs Intravenous Diclofenac in the Management of Painful Crisis in Sickle Cell Disease: Authors' Reply

Article

May 2021
Indian Pediatr

Nihar Ranjan Mishra

Effect of Oral Administration of Silymarin on Healing Full-thickness Gastric Wound in Rats

Article

Nov 2020

Anti-Ulcerogenic Effect of Unripe Plantain (Musa paradisiaca) Pulp on Indomethacin-Induced Ulcer in Wistar Rat

Research

Full-text available

Nov 2020

Anti-Ulcerogenic Effect of Unripe Plantain (Musa Paradisiaca) Pulp on Indomethacin-Induced ulcer in Wistar Rat. Tropical Journal of Natural Product Research, 4(10):784-789.

Article

Full-text available

Nov 2020

Musa Paradisiaca has been used in traditional medicine for the treatment of ulcer and our study evaluated the potentials of Musa paradisiaca pulp for the management of ulcer using a standard experimental animal model. The phytochemical, acute toxicity and histological studies of Musa paradisiaca pulp were carried out according to standard methods. The possible anti-ulcer potential investigation was done using 25 rats of 5 rats per group. The animals were administered distilled water 3 mL/kg, extract (100, 200 and 400 mg/kg), cimetidine 100 mg/kg. Ulcer was induced by oral administration of indomethacin (200 mg/kg). No death was recorded in animals that received extract up to 5000 mg/kg body weight. Our data showed that Musa paradisiaca pulp contains flavonoids, tannins, saponins, glycosides, steroids, alkaloids, resins and reducing sugars. The extract showed a significant reduction (p < 0.05) in mean ulcer index (1.50 ± 0.38, 1.63 ± 0.34 and 1.05 ± 0.29) in animals treated with the extract at all doses relative to untreated control (2.18 ± 0.29). A correlation coefficient of 0.728 existed between percentage inhibition and different concentrations of the extract. The Percentage Ulcer Inhibition of Musa paradisiaca pulp varied with doses. The Percentage Ulcer Inhibition of the extract at 400 mg/kg (51.83%) compared favorably with cimetidine (49.54%). The anti-ulcer studies showed considerable ulcer inhibition (31.19%, 25.23% and 51.83%) by Musa paradisiaca pulp which was confirmed by the results of histological studies. It is concluded that Musa paradisiaca pulp possesses anti-ulcerogenic effects which could be attributed to its phytochemical profile. Keywords: Musa paradisiaca, Anti-Ulcerogenic, Indomethacin, Cimetidine, Gastric Ulcer.

Anti-inflammatory and immunosuppressant drugs

Chapter

Jan 2012

Utilization of microalgae Spirulina platensis as a raw material for making capsule shell

Conference Paper

Sep 2020

Research on capsule shells has been developed to replace gelatin capsule because it made from pig skin, so it is not halal for consumption. With this problem, carrageenan is used as a substitute for gelatin, because it has properties as a gelling agent but still has a weakness that is not stable in stomach. The purpose of this study was to use microalgae Spirulina platensis because it contains polyhydroxybutyrate (PHB) which are the kind of polymer to improve performance as a drug delivery agent and prolongs the dissolution of the drugs so that the drug will be released into the intestine. The formulation of the solution that used in this research is variation of Spirulina platensis biomass (1%, 1.5%, 2%, 2.5%, 3%) (w/v). The best formulation was determined by capsule shell performance when characterization tests, such as moisture content test, pH, resistance in water, durability in acid solution test, and flexibility. This parameter follow Departemen Kesehatan RI. The best concentration of S. platensis in this research is 3% (w/v), with characterization that obtained as follows: moisture content is 15.77%, pH is 6.5, dissolve in water in 31 minutes 25 seconds, dissolve in acid environment in 35.23, and flexible when merged between cap and body. This capsule can survive in acid condition at pH 1.2 for 75 minutes and release 61.30% of drugs, the at pH 4.5 release 54.90% of drugs at 120 seconds, and the last at pH 6.8 can release 89.58% of drugs. The concentration of biomass affect to the thickness of capsule shell, disintegration time of capsule, and time for dissolution of the capsule shell. With these parameters, it is expected that the capsule form will have stiff and strong structure and not easily degraded at acid environment, so the drug will be released at intestine.

Aspirin-induced, neutrophil-mediated injury to vascular endothelium

Article

Full-text available

Jun 1995

Previous studies indicate that aspirin can promote neutrophil (PMN) adhesion to endothelial cells and neutrophil-mediated endothelial cell detachment. The objectives of the present study were to determine whether PMN adhesion is a pre-requisite for aspirin-induced, PMN-mediated endothelial cell detachment and whether neutrophil-derived oxidants and/or proteases are responsible for the cell detachment. Human PMNs were added to confluent monolayers of human umbilical vein endothelial cells (HUVEC) and coincubated with or without aspirin at a clinically relevant concentration (300g/ml). Aspirin-activated PMNs induced endothelial cell detachment, but not cell lysis. Endothelial cell detachment was always preceded by retraction of endothelial cells within the monolayer. The aspirin-induced, neutrophilmediated cell detachment was prevented by a monoclonal antibody directed against CD11/CD18 adhesion integrins on PMNs. Elastase inhibitors, but not superoxide dismutase or catalase, prevented both endothelial cell retraction and detachment. If aspirin-activated neutrophils were allowed to migrate across the monolayers, endothelial cell retraction or detachment did not occur. These studies indicate that aspirin-induced, PMN-mediated endothelial cell retraction and detachment requires PMN adhesion to the target cells and is due to neutrophil-derived elastase. Endothelial cell retraction, induced by activated neutrophils, may represent an exaggeration of a normal physiologic event, i.e., neutrophil emigration.

Effects of acid on the basal lamina of the rat stomach and duodenum

Article

Full-text available

Jan 1985
Virchows Arch B Cell Pathol

Rapid restitution of the gastric and intestinal epithelium after acute injury involves emigration of cells from the gastric glands and basal half of the intestinal villi. An intact basal lamina is prerequisite to the restitution process. The present study was performed to determine the effects of acid on the rat gastric and duodenal basal lamina. The basal lamina was denuded in vitro by ultrasonic vibration. The tissue was then immersed in 0.2 M mannitol (control) or in HC1 (5-50 mM) for 10 min. Samples of the tissues were examined by transmission and scanning electron microscopy. Some samples were stained with ruthenium red to demonstrate glycosaminoglycans. The lower concentrations of acid (5 and 10 mM) had little or no effect on the structure of the basal lamina. However, exposure to 20 and 50 mM HCl caused extensive damage to the basal lamina and exposed the underlying connective tissue matrix of the lamina propria. Ruthenium red staining demonstrated differences in size and location of glycosaminoglycans within the basal laminae of stomach and intestine. Exposure to acid at concentrations of 20 or 50 mM caused total loss of ruthenium red staining in both intestinal and gastric basal laminae. Exposure to 10 mM acid resulted in loss of the outermost (luminal) layer of anionic sites from the gastric basal lamina. These studies demonstrate that brief exposure to acid, in concentrations which are necessary for the formation of hemorrhagic erosions in the stomach, caused damage to the basal lamina. This damage may impair epithelial restitution and thus account, in part, for the role of acid in ulcerogenesis.

Achlorhydria does not protect against benign upper gastrointestinal ulcers during NSAID use

Article

Full-text available

Feb 1994

It is widely accepted that the absence of acid-peptic activity excludes the presence of a benign upper gastrointestinal ulcer. We assessed the frequency of a history of benign upper gastrointestinal ulcer disease in patients with and without serological evidence of achlorhydria with reference to the use of nonsteroidal antiinflammatory drugs (NSAIDs). In total 857 patients were interviewed, using a standard questionnaire with emphasis on demographic data, chronic use of NSAID, and history of upper gastrointestinal ulcers. The frequency of achlorhydria was determined by extremely low serum levels of pepsinogen A (PgA

Indomethacin-induced leukocyte adhesion in mesenteric venules: Role of lipoxygenase products

Article

Full-text available

Jun 1992
Am J Physiol

Although the pathogenetic mechanisms underlying indomethacin-induced mucosal injury remain undefined, the results from recent studies suggest that leukocyte adherence in gastric microvessels may be an important component of this injury process. The objective of this study was to determine whether clinically relevant plasma concentrations of indomethacin promote leukocyte-endothelial cell adhesive interactions in postcapillary venules. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 s) and emigrated leukocytes were measured in rat mesenteric venules. Repeat measurements of all parameters were obtained within 20 min after addition of either 2.5 or 25 micrograms/ml indomethacin to the mesenteric superfusate. In some experiments, rats were pretreated with either a leukotriene (LT) synthesis inhibitor (L 663,536), an LTD4 (MK-571) or LTB4 (SC 41930) receptor antagonist, misoprostol, or prostacyclin (PGI2). Indomethacin alone increased the number of adherent leukocytes, reduced both leukocyte rolling velocity and venular shear rate, but did not promote leukocyte emigration. L 663,536 and SC 41930 prevented all of the adhesive and hemodynamic alterations induced by indomethacin; misoprostol and PGI2, but not MK-571, exerted similar beneficial effects. These results indicate that indomethacin promotes leukocyte adherence in postcapillary venules through an LTB4-dependent mechanism.

Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy

Article

Full-text available

Jul 1992

The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model. One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin (20 mg/kg per os). Three hours after indomethacin, the extent of macroscopically visible gastric damage was determined, and gastric LTB4 synthesis was determined. The compounds tested were PF-5901, A-64077, nordihydroguaiaretic acid, and L-698,037. Each compound produced dose-related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin-induced damage. The antioxidant properties of these compounds was assessed using an in vitro assay. There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage. In the second part of the study, the effects of intravenous, administration of LTD4 and LTB4 receptor antagonists on indomethacin-induced gastric epithelial damage (measured by permeability to [51Cr]EDTA) were assessed. The two LTD4 receptor antagonists (MK-571 and ICI-204,219) significantly reduced the permeability changes induced by indomethacin, while the two LTB4 antagonists (SC-41930 and LY-255,283) were without significant effect. Despite the reduction of gastric epithelial injury, blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury. These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs. However, it remains unclear to what extent leukotrienes are involved in the initiation of the injury, as opposed to its amplification.

Role of oxygen-derived free radicals in indomethacin-induced gastric injury

Article

Full-text available

Oct 1991
Am J Physiol

The role of oxygen-derived free radicals in the pathogenesis of acute gastric ulceration induced by indomethacin (Indo) was investigated in rats. Gastric damage was assessed by blood-to-lumen leakage of 51Cr-EDTA, as well as by measuring the extent of macroscopically visible hemorrhagic lesions. The stomach was perfused with isotonic saline for 30 min, followed by Indo (10 mg/ml for 30 min) and HCl (100 mM for 60 min). Rats were given a continuous intravenous infusion of the antioxidant enzymes superoxide dismutase (SOD) or catalase or the iron-chelating agent deferoxamine. Additional rats received an intravenous infusion of the vehicle (control group) or were pretreated with prostaglandin E2 (100 micrograms/kg ip) or allopurinol (50 mg/kg po). Exposure of the stomach to Indo caused a fourfold increase in 51Cr-EDTA leakage compared with that observed in rats receiving only the vehicle for Indo. Subsequent exposure of the stomach to HCl resulted in a further twofold increase in 51Cr-EDTA leakage. Treatment with SOD, catalase, or deferoxamine significantly (P less than 0.05) reduced 51Cr-EDTA leakage during the intragastric perfusion with Indo and during the subsequent exposure to HCl. Pretreatment with PGE2 reduced 51Cr-EDTA leakage during perfusion with HCl only. Pretreatment with allopurinol did not significantly affect 51Cr-EDTA leakage at any time during the experiment. In addition to reducing the leakage of 51Cr-EDTA into the gastric lumen, SOD, catalase, and PGE2 significantly reduced the extent of macroscopically visible mucosal damage (P less than 0.05). These results support the hypothesis that oxygen-derived free radicals, probably derived from neutrophils, contribute to the pathogenesis of Indo-induced ulceration.

Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neurophil-dependent process

Article

Full-text available

Oct 1990
Am J Physiol

The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic by prior treatment with an antibody to rat neutrophils raised in goat were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats pretreated with normal goat serum. The reduction of damage in neutropenic rats was not due to effects of the antineutrophil serum on either gastric acid secretion or the ability of indomethacin or naproxen to inhibit prostaglandin synthesis. Gastric cyclooxygenase activity was inhibited by greater than 95% in both normal and neutropenic rats that received indomethacin or naproxen. Reduction of circulating neutrophil numbers by treating rats with methotrexate also resulted in a significant reduction in the susceptibility to gastric damage induced by indomethacin. Since activation of circulating neutrophils appeared to be important in the development of gastric erosions after administration of indomethacin, and in the significant changes in vascular endothelial integrity (Monastral Blue staining) observed within 15 min of indomethacin administration, we investigated the possibility that leukotrienes (LTs) and platelet-activating factor (PAF) might be involved in the pathogenesis of indomethacin-induced ulceration. Changes in gastric LTB4 synthesis were not observed after indomethacin administration. Pretreatment with either an LTD4 antagonist or a PAF antagonist was without significant effect on the extent of gastric damage induced by indomethacin. These results suggest an important role for neutrophils in the pathogenesis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.

The mucoid cap over superficial gastric damage in the rat. A high-pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin

Article

Full-text available

Sep 1990
GASTROENTEROLOGY

The ability of the "mucoid cap" of mucus, fibrin, and cellular debris that forms over sites of superficial gastric damage to provide a relatively high-pH microenvironment was investigated in the rat. Furthermore, the effects of administration of nonsteroidal antiinflammatory drugs or reduction of mucosal blood flow on this microenvironment were investigated. Superficial mucosal damage induced by a 2-minute exposure to hypertonic saline produces a mucoid cap that has a pH of 4-6 despite the presence in the lumen of a solution of acid with a pH of less than 1. This relatively high-pH microenvironment remained even when the exposure to 0.15-mol/L HCl was continued for as long as 1 hour. Intraperitoneal administration of indomethacin (5 mg/kg) or naproxen (10 mg/kg) resulted, within 10-25 minutes, in complete dissipation of this high-pH microenvironment, with the subsequent development of hemorrhagic erosions. These effects of indomethacin and naproxen occurred subsequent to significant inhibition of gastric prostaglandin synthesis by these agents. Rapid dissipation of the pH gradient could also be produced by brief (30-second) clamping of the arterial blood supply to the chambered mucosa or by systemic administration of a vasoconstrictor (endothelin-1), in both cases resulting in the development of hemorrhagic erosions. These results show that the mucoid cap over sites of superficial damage provides a relatively high-pH microenvironment and that dissipation of this microenvironment by inhibitors of prostaglandin synthesis or by reduction of mucosal blood flow can convert sites of superficial mucosal injury to hemorrhagic erosions. Such inhibitory effects might contribute to the ulcerogenic actions of nonsteroidal antiinflammatory drugs.

Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin

Article

Full-text available

Mar 1989

To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding. Randomised crossover trial. Academic department of therapeutics. Twenty healthy male volunteers aged 19-22. On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6. Loss of blood over 10 minutes into gastric washings. Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin. Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.

Role of mucus in the repair of gastric epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents

Article

Full-text available

Oct 1986
GASTROENTEROLOGY

A role for mucus in providing a microenvironment over sites of gastric damage, which is conducive to reepithelialization, has been proposed. We tested this hypothesis by examining the effects of disruption of such mucus on the recovery of epithelial integrity after damage induced by 50% ethanol. Exposure of an ex vivo chambered gastric mucosa to topically applied 50% ethanol resulted in copious release of mucus, cellular debris, and plasma, which formed a continuous cap over the mucosal surface. Ethanol-induced gastric damage was accompanied by extensive surface epithelial cell damage and a marked decrease in transmucosal potential difference. During the 30 min after ethanol was removed from the chamber, the epithelium became reestablished and the potential difference gradually recovered to 94% of the level before ethanol treatment. However, if the mucolytic agents N-acetylcysteine (5%) or pepsin (0.5%) were added to the bathing solutions, the "mucoid cap" disintegrated and the recovery of potential difference was significantly retarded (recovering to only 51% and 52% of levels before ethanol treatment). Histologic evaluation confirmed that mucosae treated with either agent had significantly less (p less than 0.005) intact epithelium at the end of the experiment. Removal of the mucoid cap with forceps caused a similar inhibition of the repair of the epithelium and the recovery of potential difference. Both mechanical and chemical (N-acetylcysteine) disruption of the mucoid cap resulted in a significant increase in the mucosal leakage of albumin and hemoglobin, supporting previous histologic evidence that the mucoid cap traps blood components over the damaged mucosa. These studies support the hypothesis that mucus released in response to topical application of an irritant plays an important role in the repair of epithelial damage through the process of restitution.

Effect of Chronic Aspirin Ingestion on Epithelial Proliferation in Rat Fundus, Antrum, and Duodenum

Article

May 1982
GASTROENTEROLOGY

Gastric Antisecretory and Antiulcer Properties of PGE2, 15-Methyl PGE2, and 16,16-Dimethyl PGE2

Article

Mar 1976
GASTROENTEROLOGY

Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs

Article

Oct 1993
GASTROENTEROLOGY

Background: We have assessed the extent to which the risk of serious gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) varies with the age and sex of recipients, use of aspirin or alcohol, administration by the oral or rectal route, and dose and choice of drug. Methods: A case-control study was performed with prospective recruitment of cases of gastrointestinal bleeding or ulcer perforation and age- and sex-matched controls. Information on preadmission drug use obtained by structured interview. Results: Six hundred forty-four patients and 1268 controls were recruited. The odds ratio for upper gastrointestinal complications in users compared with nonusers of NANSAIDs increased with age: ≤ 59 years, odds ratio 2.0; 60–79 years, odds ratio 3.0; ≥ 80 years, odds ratio 4.2; and was higher in women (5.4) than in men (1.9). There was a linear dose-response curve that was steeper in women than in men. Combined exposure suggested additive risks: NANSAIDs and aspirin, odds ratio 6.7; NANSAIDs and alcohol, odds ratio 6.0. NANSAIDs by the oral route were associated with an odds ratio of 2.3, compared with 11.4 with rectal administration. Piroxicam was associated with the highest risk, odds ratio 4.8; and ibuprofen the lowest risk, odds ratio 0.7. Conclusions: A number of factors can alter the risk of major gastrointestinal complications with NANSAIDs and need to be considered when individual prescribing decisions are made.

Granulocytes: The culprit in ischemic damage to the intestine

Article

Jan 1987
Am J Physiol

Variability in the risk of major gastrointestinal complications from non-aspirin non-steroidal drugs

Article

Jan 1993
GASTROENTEROLOGY

Gastrointestinal Tract Complications of Nonsteroidal Anti-inflammatory Drug Treatment in Rheumatoid Arthritis

Article

Jul 1996
ARCH INTERN MED

Gurkirpal Singh

Background: Gastrointestinal tract (GI) complications associated with nonsteroidal anti-inflammatory drug (NSAID) use are the most common serious adverse drug reactions in the United States. Nonsteroidal antiinflammatory drugs cause both minor GI side effects such as abdominal pain and vomiting and serious GI events such as ulcers and bleeding. This study evaluates the event rates for all NSAID-induced GI complications in patients with rheumatoid arthritis, describes the time course of these events, and evaluates the role of prophylactic therapy with antacids and H2 receptor antagonists.Methods: We studied 1921 patients with rheumatoid arthritis from 8 ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) centers. Patients were selected for the study if they were treated with NSAIDs and had at least 2.5 years of observation available. Information on GI complications attributed to NSAIDs was obtained from validated patient self-reports collected every 6 months and supplemented by review of hospital records for all hospitalizations.Results: Approximately 15% of the 1921 patients reported an NSAID-induced GI side effect during the 2.5-year observation period. Forty-two patients had a serious GI complication requiring hospitalization; 34 of these 42 patients did not have a preceding GI side effect. Patients who were taking antacids and H2 receptor antagonists did not have a significantly lower risk for serious GI complications than did those not taking such medications. Asymptomatic patients taking these medications had a significantly higher risk for GI complications compared with those who did not take these medications (standardized odds ratio, 2.14; 95% confidence interval, 1.06-4.32).Conclusions: A large majority of patients with serious GI complications do not have preceding mild side effects. Prophylactic treatment with antacids and H2 receptor antagonists is of questionable value and may increase the risk for subsequent serious GI complications.Arch Intern Med. 1996;156:1530-1536

The Relative Gastrointestinal Toxicity of the Nonsteroidal Anti-inflammatory Drugs

Article

Jun 1987
ARCH INTERN MED

Jeffrey Carson

• To assess the relative rate of upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88 044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population. (Arch Intern Med 1987;147:1054-1059)

Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa

Article

Dec 2000

L M Jackson

BACKGROUND AND AIMS Constitutive cyclooxygenase (COX) 1 is believed to mediate prostaglandin dependent gastric protection. However, gastric mucosa contains cells capable of expressing inducible COX-2. We therefore investigated COX-1 and COX-2 expression, localisation, and activity in normal and abnormal human gastric mucosa. METHODS COX-1 and COX-2 distribution was investigated by light and electron microscopic immunohistochemistry and by western blot analysis, and their contribution to prostaglandin (PG)E2 synthesis using selective enzyme inhibitors. RESULTS There was strong parietal cell COX-1 and COX-2 immunoreactivity in all sections and isolated cells, with macrophage and myofibroblast reactivity in some sections. Immunostaining was specifically abolished by antigen absorption. Western blot analysis confirmed COX-1 and 2 expression. COX-1 and COX-2 immunostaining was increased inHelicobacter pylori gastritis, particularly the mid glandular zone and lamina propria inflammatory cells. This was associated with increased ex vivo PGE2 synthesis (62.4 (13.5) pg/mg v 36.3 (15.5) pg/mg in uninflamed mucosa; p=0.017) which was significantly inhibited by COX-1 but not COX-2 inhibition. Increased COX-2 immunostaining in macrophages, endothelial cells, and myofibroblasts (with reduced epithelial expression) was seen at the rim of ulcers. CONCLUSION COX-2, as well as COX-1, is expressed by normal human gastric mucosa and is increased at the rim of ulcers. Although both are increased withH pylori, COX-1 contributes more than COX-2 to gastric PGE2 production.

Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs

Article

Jun 1999
Surv Anesthesiol

Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events

Article

Nov 1991

The Salt Collaborative Group

The efficacy of aspirin in daily doses of 300 mg and more as secondary prophylaxis after cerebrovascular events is well established. Since much lower doses of aspirin can inhibit platelet function, and carry a lower risk of adverse effects, the Swedish Aspirin Low-dose Trial (SALT) was set up to study the efficacy of 75 mg aspirin daily in prevention of stroke and death after transient ischaemic attack (TIA) or minor stroke. 1360 patients entered the study 1-4 months after the qualifying event: 676 were randomly assigned to aspirin treatment and 684 to placebo treatment. The median duration of follow-up was 32 months. Compared with the placebo group, the aspirin group showed a reduction of 18% in the risk of primary outcome events (stroke or death; relative risk 0·82, 95% confidence interval 0·67-0·99; log-rank analysis p=0·02), and reductions of 16-20% in the risks of secondary outcome events (stroke; stroke or two or more TIAs within a week of each other necessitating a change of treatment; or myocardial infarction). Adverse drug effects were reported by 147 aspirin-treated and 123 placebo-treated patients Gastrointestinal side-effects were only slightly more common in the aspirin-treated patients, but that group had a significant excess of bleeding episodes (p=0·04). Thus, we have found that a low dose (75 mg/day) of aspirin significantly reduces the risk of stroke or death in patients with cerebrovascular ischaemic events.

Gastrointestinal-sparing anti-inflammatory drugs: The development of nitric oxide-releasing NSAIDs

Article

Nov 1997
DRUG DEVELOP RES

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications, but their use continues to be limited by significant toxicity, particularly in the gastrointestinal tract and kidney. Better understanding of the pathogenesis of these adverse effects has led to the development of a series of derivatives of standard NSAIDs that are not only less toxic but more efficacious. The coupling of a nitric oxide-releasing moiety to a range of NSAIDs greatly reduces their ability to induce gastrointestinal damage, and greatly increases their tolerability in situations in which there is preexisting gastrointestinal inflammation. There is also evidence that these compounds are much better tolerated by the kidney. On the other hand, the analgesic and anti-thrombotic properties of NO-releasing NSAIDs significantly exceed those of the parent drugs. These compounds appear to represent a significant advance in the treatment of inflammation and pain and for prophylaxis of thrombotic conditions. Drug Dev. Res. 42:144–149, 1997. © 1997 Wiley-Liss, Inc.

Gastroscopic observation of effect of aspirin and certain other substances on stomach

Article

Jan 1938

Douthwaite AH

An important contribution of cyclooxygenase-1 to inflammatory responses in rats and mice: Implications for GI toxicity.

Article

Apr 1998

Effects of very low doses of aspirin (ASA) on gastric, duodenal and rectal prostaglandins (PGs) and mucosal injury (Abstract)

Article

Apr 1995

New insights into prostaglandins and mucosal defence

Article

Jun 2007
ALIMENT PHARM THER

SUMMARYA role for prostaglandins in maintaining mucosal integrity in the gastrointestinal tract is well documented. While traditionally the effects of prostaglandins on mucosal blood flow and epithelial function have been regarded as critical in the mechanism of action of these fatty acids, recent evidence that mucosal ulceration is almost invariably associated with mucosal inflammation has caused a reevaluation of the role of prostaglandins in mucosal defence. This review focuses on the ability of prostaglandins to exert anti-inflammatory, and therefore anti-ulcerogenic, effects in the gastrointestinal tract. These effects of prostaglandins are attributable to their ability to suppress the release of inflammatory mediators and reactive oxygen metabolites from a number of immunocytes, stromal cells and inflammatory cells. There is emerging evidence for cooperative interactions between prostaglandins and nitric oxide in maintaining mucosal integrity. Recent work on the inducible isoform of prostaglandin synthase as it pertains to mucosal defence is also reviewed.

NSAIDs complexed to phosphatidylcholine (PC) have reduced GI toxicity and enhanced bioavailability

Article

Apr 1995

Mitogen-inducible prostaglandin G/H synthase: A new target for nonsteroidal antiinflammatory drugs

Article

Jan 1992
DRUG DEVELOP RES

Prostaglandins have been shown to be involved in many different biological processes, under both normal and pathological conditions. As the key enzyme in the production of prostaglandins and thromboxanes, prostaglandin GIH synthase (PGHS) has been well characterized, including extensive studies as a pharmacological target of the nonsteroidal antiinflammatory drugs (NSAIDs). The gene for this enzyme has been cloned, sequenced, and characterized from sheep, mouse, and human sources. Recently, a new form of this enzyme, a mitogen-inducible PGHS (miPGHS), was identified. Comparisons between these two genes and their protein products have identified significant differences, including structural differences in the proteins and their mRNAs. The genes encoding these two isoenzymes are not coordinately regulated in cultured cells or in tissues. The discovery of this second form of PGHS may change our understanding of how NSAlDs exert their effects. miPGHS is believed to be a new, unique target of NSAIDs which could have a different sensitivity to many of these drugs, compared to the previously identified PGHS. © 1992 Wiley-Liss, Inc.

Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats

Article

Feb 2009
BRIT J PHARMACOL

In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate‐limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non‐steroidal anti‐inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS‐1) and an inducible (PGHS‐2) enzyme. PGHS‐1 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non‐selectively inhibit both PGHS‐1 and PGHS‐2, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS‐2 inhibitors such as L ‐745,337 (5‐methanesulphonamide‐6‐(2,4‐difluorothio‐phenyl)‐1‐indanone) are not ulcerogenic and do not inhibit gastro‐intestinal prostaglandin synthesis. However, minimal information is available on the long‐term effects of PGHS‐2 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS‐1 and PGHS‐2 during gastric ulcer healing and assessed the effects of L ‐745,337 on previously established cryoulcers in the rat gastric stomach. PGHS‐1 and PGHS‐2 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS‐2 immunoreactivity was only negligible in the normal gastric wall, but after gastric ulcerations, it was strongly detected in monocytes, macrophages, fibroblasts and endothelial cells below and between the regenerative glands. PGHS‐1 immunoreactivity detected in normal gastric mucosa, disappeared after gastric ulceration in the mucosa adjacent to the ulcer crater. However, it reappeared in the regenerative glands from day 5 onwards. Thus, PGHS‐1 and PGHS‐2 were located at different sites and their maximal expression followed a different time‐sequence. We assessed the effects of L ‐745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. L ‐745,337, indomethacin and diclofenac dose‐dependently decreased the healing of gastric ulcers. L ‐745,337, indomethacin and diclofenac decreased epithelial cell proliferation in the ulcer margin and microvessel density in the ulcer bed on day 8 and increased the thickness of the granulation tissue below the ulcer crater and the gap between both edges of the muscularis mucosae on day 15. Indomethacin and diclofenac, but not L ‐745,337, decreased synthesis of 6‐keto‐PGF 1α and PGE 2 in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B 2 synthesis in clotting whole blood. Dose‐response curves for the inhibition of chronic gastric ulcer healing by L ‐745,337 (administered twice daily intragastrically) showed an ID 50 value of 1.7 mg (4.3 μmol) kg ⁻¹ . Dose‐response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1 mg (3.1 μmol) kg ⁻¹ and 1.3 (3.3 μmol) mg kg−1 for indomethacin and L ‐745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by L ‐745,337 occurs within a potentially therapeutic dose‐range. In summary, PGHS‐2 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS‐2 by L ‐745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS‐2‐derived prostaglandins seem to have an important role in gastric ulcer healing. British Journal of Pharmacology (1998) 123 , 795–804; doi: 10.1038/sj.bjp.0701672

Diclofenac delays healing of gastroduodenal mucosal lesions

Article

Jan 1991

The effects of the water-soluble and delayed-release formulations of a nonsteroidal antiinflammatory drug, diclofenac, on the healing of gastroduodenal mucosal lesions were compared in a double-blind, double cross-over, placebo-controlled endoscopic study conducted in 14 healthy volunteers. Severe endoscopic lesions (petechiae, erosions, ulcers, and esophageal candidiasis) were found only in the group taking the soluble formulation of diclofenac (P<0.05 vs placebo). The endoscopic healing of biopsies at one week was delayed by both preparations in comparison to placebo (P<0.05 vs placebo). Neither formulation produced significantly more histological inflammation or minor endoscopic lesions (erythema, red striae) than placebo. Both formulations were equally well tolerated and produced no more symptoms than placebo. This study suggests that soluble diclofenac acts topically to delay gastroduodenal healing and produce gastroduodenal injury; it thus provides a model for future studies of the production, perpetuation, and healing of peptic lesions.

Mitochondrial function and modification of NSAID carboxyl moiety

Article

Jan 1996

It is widely believed that the toxic effects of non-steroidal anti-inflammatory drugs are solely due to inhibition of cyclo-oxygenase. However, this view is no longer tenable as it is possible to inhibit cyclooxygenase activities without mucosal injury and cyclo-oxygenase 1-deficient mice do not have gastrointestinal lesions from indomethacin. Alternatively, non-steroidal anti-inflammatory agents may initiate damage by direct mitochondrial toxicity. The current experiments were designed to relate NSAID uncoupling of mitochondrial oxidative phosphorylation to drug pK a and to determine the effect of modification of the NSAID carboxyl group. Effects of non-steroidal anti-inflammatory drugs and modified NSAIDs were tested on isolated coupled rat liver mitochondrial preparations using a Clark-type oxygen electrode. All non-steroidal anti-inflammatory drugs tested uncoupled mitochondrial oxidative phosphorylation to a similar degree, increasing oxygen consumption by 2–3-fold. The uncoupling potency was inversely related to the drug pK a (correlation coefficientr=−0.74;p=0.05). Modification of the carboxyl moiety (dimero-flurbiprofen and nitrobutyl flurbiprofen) abolished uncoupling. The NSAID potency to uncouple oxidative phosphorylation correlated with drug pK a; modification of the NSAID carboxyl moiety may improve their safety profile by reducing the ‘topical’ phase of damage.

The relative gastrointestinal toxiaty of the non-steroidal anti-inflammatory drugs

Article

Jun 1987
ARCH INTERN MED

To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.

The Association of Nonsteroidal Anti-inflammatory Drugs With Upper Gastrointestinal Tract Bleeding

Article

Jan 1987
ARCH INTERN MED

To evaluate the risk of developing upper gastrointestinal (UGI) bleeding from nonsteroidal anti-inflammatory drugs (NSAIDs), a retrospective (historical) cohort study was performed, using a computerized data base including 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. Comparing 47,136 exposed patients to 44,634 unexposed patients, the unadjusted relative risk for developing UGI bleeding 30 days after exposure to a NSAID was 1.5 (95% confidence interval 1.2 to 2.0). Univariate analyses demonstrated associations between UGI bleeding and age, sex, state, alcohol-related diagnoses, preexisting abdominal conditions, and use of anticoagulants. This association between NSAIDs and UGI bleeding was unchanged after adjusting for these potential confounding variables using logistic regression. A linear dose-response relationship and a quadratic duration-response relationship were demonstrated. Non-steroidal anti-inflammatory drugs are associated with UGI bleeding, although the magnitude of the increased risk is reassuringly small.

Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage

Article

Feb 1978
GASTROENTEROLOGY

In a series of in vitro studies, both the soluble (plasmatic) coagulation system and the cellular (platelet-mediated) aspect of coagulation were shown to be extremely sensitive to relatively minor increases in hydrogen ion concentration. All studies became abnormal at pH 6.8. At pH 6.4, assays of the intrinsic and extrinsic coaglution systems, the polymerization of fibrinogen, and assay of the availability of platelet phospholipid (platelet factor 3) were twice prolonged over control values. Platelet aggregation was reduced by more than 50%. At pH 5.4 in vitro, platelet aggregation and plasma coagulation were both virtually abolished. Furthermore, previously formed platelet aggregates disaggregated at a slightly acid pH. Pepsin further enhanced platelet disaggregation. Because gastric acidity is normally two to four orders of magnitude greater than that which abolishes platelet aggregation and plasma clotting in vitro, and pepsin is present in abundance, we call attention to the probable antihemostatic effect of hydrocloric acid and pepsin in the upper gastrointestinal tract. This in vitro study may provide a rationale for meticulous regulation of intragastric pH in an effort to control upper gastrointestinal hemorrhage.

Gastric antisecretory and antiulcer properties of PGE2, 15 methyl PGE2, and 16,16 dimethyl PGE2 Intravenous, oral and intrajejunal administration

Article

Apr 1976
GASTROENTEROLOGY

15-Methyl PGE2 and 16,16-dimethyl PGE2 were found (1) to be 40 and 100 times, respectively, more potent than PGE2 after intravenous administration in inhibiting histamine-stimulated gastric secretion in dogs with a denervated (Heidenhain) gastric pouch, (2) to be active orally and intrajejunally, whereas PGE2 was inactive, and (3) to exert antisecretory activity for longer duration than PGE2. 16,16-Dimethyl PGE2 was about 2.5 times more potent than 15-methyl PGE2. Volume, acid concentration, and output, and pepsin output (but not concentration) were reduced in a dose-dependent manner. In the rat, 16,16-dimethyl PGE2 also inhibited gastric secretion and prevented the formation of ulcers produced by various methods: gastric ulcers (Shay, and steroid induced) and duodenal ulcers (secretogogue induced). In this species, 1l816-dimethyl PGE2 was 2 to 50 times more potent than PGE2, depending on the endpoint, and was active orally. These prostaglandins appear to inhibit gastric acid secretion by acting directly on the parietal cells, and making these unresponsive to most stimulants. Vomiting was a side effect of the prostaglandin analogues in the dog, but almost exclusively when these were given orally. After intravenous or intrajejunal administration at doses inhibiting gastric secretion by 80%, vomiting was seen only once. These results suggest that 15-methyl PGE2 and 16,16-dimethyl PGE2 may be of value in the treatment of peptic ulcer.

Mechanisms underlying gastric mucosal damage induced by indomethacin and bile salts, and the actions of prostaglandins

Article

Aug 1977

Brendan Whittle

1 The mechanisms by which the bile salt, sodium taurocholate, potentiates the formation of gastric mucosal erosions induced by indomethacin has been investigated in the rat. 2 Systemic administration of indomethacin lowered resting mucosal blood flow but had no effect on the acid back‐diffusion across the mucosa. 3 Gastric perfusion of taurocholate in acid solution increased acid back‐diffusion and lowered the potential difference. This was accompanied by an increase in mucosal blood flow, which may represent a protective mechanism in the mucosa. 4 Administration of indomethacin during acid‐taurocholate perfusion reduced this elevated mucosal blood flow without any further change in acid back‐diffusion. 5 The results suggest that although a decrease in mucosal blood flow or an increase in acid back‐diffusion can lead to a low incidence of erosions, a combination of both produces extensive mucosal damage. 6 The (15S)‐methyl analogue of prostaglandin E 2 reduced erosion formation induced by indomethacin and acid‐taurocholate administration. 7 It is suggested that this protective action of the prostaglandin analogue may be linked to changes in gastric mucosal permeability and in mucosal blood flow.

Modulation of leukocyte adhesion in mesenteric venules by aspirin and salicylate

Article

Aug 1992
GASTROENTEROLOGY

Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and number of adherent and emigrated leukocytes were measured in postcapillary venules both before and during superfusion of rat mesentery with either aspirin or sodium salicylate. In some experiments, animals were treated with either a leukotriene (LT)-synthesis inhibitor (L-663,536), an LTD4 antagonist (MK-571), an LTB4 antagonist (SC-41930), misoprostol, or prostaglandin (PG) I2, then the aspirin protocol was repeated. Superfusion of aspirin but not sodium salicylate resulted in increased leukocyte adherence and a reduced leukocyte rolling velocity but did not affect leukocyte emigration. Aspirin-induced leukocyte adhesion was effectively prevented by the LT-synthesis inhibitor and LTB4 antagonist but not by the LTD4 antagonist. Misoprostol and PGI2 also prevented the aspirin-induced adhesion responses. Superfusion of the mesentery with either platelet-activating factor (PAF) or LTB4 enhanced leukocyte adherence and emigration while reducing leukocyte rolling velocity. Sodium salicylate prevented all of the adhesion responses elicited by LTB4. Although salicylate did not affect the PAF-induced leukocyte adherence and rolling responses, it completely prevented the increased leukocyte emigration. These results indicate that aspirin promotes, whereas sodium salicylate inhibits, leukocyte-endothelial cell adhesive interactions at therapeutically relevant concentrations.

Extra-cranial bleeding and other symptoms due to low-dose aspirin and low intensity anticoagulation

Article

Aug 1992

Data from the early stages of the thrombosis prevention trial (TPT) have been used to establish and quantify the risk of extracranial bleeding due to low dose aspirin (75 mg) and low intensity oral anticoagulation with warfarin (international normalised ratio, INR, 1.5) singly or in combination, in men aged between 45 and 69 who are at high risk of ischaemic heart disease (IHD). The design of the trial is factorial, the four treatments being combined low dose aspirin and low intensity anticoagulation (WA), low intensity anticoagulation alone (W), low dose aspirin alone (A) and double placebo treatment (P). The trial is being carried out through the Medical Research Council's General Practice Research Framework, with participating practices throughout the United Kingdom. Results are based on the first 3,667 men entered. The risk of major gastrointestinal bleeding due to active treatment is probably about 1 in 500 man-years of treatment, there currently being no difference between the three active regimes (WA, W, A). Intermediate and minor bleeding episodes occur more frequently with WA than with W or A on their own, the excess being mainly due to minor nose bleeds and bruises. In turn, both W and A on their own cause more such minor episodes than placebo treatment, P. There is no evidence that any of the three active regimens increases the risk of peptic ulceration, nor do they increase reports of indigestion. Aspirin increases reports of constipation and reduces reports of blurred vision. Minor bleeding occurs less frequently in smokers than in non-smokers but is not influenced by age. The antithrombotic regimes used are feasible and acceptable.

Separation of aspirin's impairment of haemostasis from mucosal injury in the human stomach

Article

Nov 1991

1. An increasing body of data suggests that the anti-haemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena. 2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied. 3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7–10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2–16.5, P < 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration. 4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin. 5. We conclude that aspirin can be shown to have both erosive and anti-haemostatic effects in the human stomach. Each can be evaluated separately in our model system. Both are potential therapeutic targets for the prevention of major upper-gastrointestinal bleeding caused by aspirin and probably other non-steroidal antiinflammatory drugs.

A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit

Article

May 1991
GASTROENTEROLOGY

The role of leukocyte adherence in the mechanism of gastropathy induced by nonsteroidal antiinflammatory drugs was investigated using a rabbit model. Gastric damage was induced by intragastric instillation of indomethacin [5 mg/mL] for a period of 30 minutes. Histologically, this treatment resulted in extensive vascular congestion and leukocyte margination within the mucosa. Pretreatment with a monoclonal antibody [IB-4] directed against the common beta subunit of the CD11/CD18 adhesion glycoprotein complex significantly (P less than 0.05) reduced both the vasocongestion and the prevalence of leukocyte margination. Macroscopically, indomethacin treatment resulted in the formation of numerous hemorrhagic lesions in the corpus region of the stomach. Pretreatment with IB-4 reduced the extent of gastric hemorrhagic damage by approximately 85% (P less than 0.001). Damage in the group pretreated with IB-4 did not differ significantly from that in rabbits that did not receive indomethacin. In separate experiments, the dose of IB-4 used was shown to completely suppress the recruitment of granulocytes in response to two different agonists. These results support the hypothesis that leukocyte adherence to the vascular endothelium is an important event in the pathogenesis of ulceration induced by nonsteroidal antiinflammatory drugs. Leukocytes might contribute to ulceration by occluding microvessels, thereby reducing mucosal blood flow, and by releasing various mediators, proteases, and free radicals that can produce tissue necrosis.

Aspirin-induced gastric mucosal damage: Prevention by enteric-coating and relation to prostaglandin synthesis

Article

Aug 1991

1. Gastric damage induced by low-dose aspirin and the protective effect of enteric-coating was assessed in healthy volunteers in a double-blind placebo-controlled cross-over trial using Latin square design. Each was administered placebo, plain aspirin 300 mg daily, plain aspirin 600 mg four times daily, enteric-coated aspirin 300 mg daily, or enteric-coated aspirin 600 mg four times daily for 5 days. Gastric damage was assessed endoscopically, and gastric mucosal bleeding measured. 2. Aspirin 300 mg daily and 600 mg four times daily caused significant increases in gastric injury compared with placebo. Gastric mucosal bleeding was significantly more with the high dose, with a trend towards increased gastric erosions, compared with the low dose. 3. Enteric-coating of aspirin eliminated the injury caused by low dose aspirin and substantially reduced that caused by the higher dose. 4. All dosages and formulations caused similar inhibition of gastric mucosal prostaglandin E2 synthesis. 5. Serum thromboxane levels were suppressed equally with plain and enteric-coated aspirin. 6. In this short-term study in healthy volunteers, gastric toxicity from aspirin was largely topical, independent of inhibition of prostaglandin synthesis, and could be virtually eliminated by the use of an enteric-coated preparation.

Diclofenac delays healing of gastroduodenal mucosal lesions. Double-blind, placebo-controlled endoscopic study in healthy volunteers

Article

Jun 1991

The effects of the water-soluble and delayed-release formulations of a nonsteroidal antiinflammatory drug, diclofenac, on the healing of gastroduodenal mucosal lesions were compared in a double-blind, double cross-over, placebo-controlled endoscopic study conducted in 14 healthy volunteers. Severe endoscopic lesions (petechiae, erosions, ulcers, and esophageal candidiasis) were found only in the group taking the soluble formulation of diclofenac (P less than 0.05 vs placebo). The endoscopic healing of biopsies at one week was delayed by both preparations in comparison to placebo (P less than 0.05 vs placebo). Neither formulation produced significantly more histological inflammation or minor endoscopic lesions (erythema, red striae) than placebo. Both formulations were equally well tolerated and produced no more symptoms than placebo. This study suggests that soluble diclofenac acts topically to delay gastroduodenal healing and produce gastroduodenal injury; it thus provides a model for future studies of the production, perpetuation, and healing of peptic lesions.

NSAID induced ulcers. An emerging epidemic?

Article

Feb 1990

A Review of Gastric Ulcer and Gastroduodenal Injury in Normal Volunteers Receiving Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs

Article

Feb 1989
Scand J Gastroenterol Suppl

F L Lanza

Studies in normal volunteers from our laboratory and by other investigators have demonstrated that non-steroidal anti-inflammatory agents (NSAIDs) can significantly damage the gastroduodenal mucosa. This damage is maximal with plain and buffered aspirin products. The injury produced by non-aspirin NSAIDs in anti-inflammatory doses is less than with aspirin but depends primarily on the dosages used. Pro-drugs and enteric-coated aspirin tend to produce less injury. The incidence of gastric ulcer in 1064 normal volunteers studied in our laboratory over a period of 7 years is reviewed. Seventy-two (6.7%) normal subjects developed a gastric ulcer after 7 days of therapy with anti-inflammatory doses of these drugs. The largest number of ulcers were seen with plain and buffered aspirin, and the lowest number with the lower anti-inflammatory doses of the non-aspirin NSAIDs.

Mechanisms of Action of Antisecretory Drugs: Studies on Isolated Canine Fundic Mucosal Cells

Article

Feb 1986
Scand J Gastroenterol Suppl

A H Soll

Cellular mechanisms underlying the actions of antisecretory agents were studied with dispersed canine fundic cells; aminopyrine accumulation monitored parietal cell (PC) function. Canine PC have pharmacologically typical histamine (H) H2 and muscarinic (M) receptors. PC also have gastrin (G) receptors, which were selectively blocked by gastrin/CCK antagonists. Potentiating interactions occurred between secretagogues, one of the components of the interdependency between regulatory pathways. Prostaglandins (PG) E2 inhibited H-stimulated PC function. Treatment of PC with pertussis toxin (PT), which inactivates the inhibitory GTP-binding protein of adenylate cyclase (Gi), markedly reduced PG inhibition, indicating PG action via Gi. PC function can also be directly inhibited by H+/K+-ATPase inhibitors, such as omeprazole. When canine mucosal cells were studied, stimulatory G and inhibitory M receptors were present on fundic somatostatin (S) cells. Histamine was localized to canine fundic mast cells, which lacked G or M receptors, a conclusion that may not pertain to fundic histamine cells in other species. Nonparietal cell receptors may be important modulators of the regulation of acid secretion.

Rapid barrier restitution in an in vitro model of intestinal epithelial injury

Article

Mar 1989

Mild forms of intestinal epithelial injury commonly occur in many disease states. In order to study how such epithelial "wounds" heal, we have developed a highly reproducible in vitro model of intestinal epithelial injury. Guinea pig ileal mucosal sheets were mounted in Ussing chambers and the mucosal surfaces were exposed to 0.06% Triton-X 100 for 5 minutes. This resulted in denudation of the epithelium at the tips of 86% of villi. As a result of this injury, resistance to passive ion flow decreased significantly (56.5 +/- 1.3 versus 38.4 +/- 2.3 ohm.cm2 for control and injury, respectively, p less than 0.01), as did transepithelial potential difference (-11.9 +/- 0.7 versus -4.3 +/- 0.4 mV for control versus injury respectively, p less than 0.01). In parallel, transepithelial fluxes of the extracellular space markers mannitol and inulin increased 3- to 5-fold immediately after injury. Two hours after injury, villus tips were again confluently covered by columnar absorptive cells, a time course of healing too fast to be accounted for by enhanced cell proliferation. Analysis of the structural events occurring during recovery showed that absorptive cells shouldering the foci of denudation rapidly changed shape after injury: they became flattened and sent cell projections over the denuded basement membrane. By 60 minutes after injury, cells from opposite shoulders of the denudation abutted, thus resealing the defect. Paralleling these structural changes, transepithelial resistance, potential difference, and mannitol and inulin fluxes returned toward control values. These data show that focal epithelial discontinuities in the small intestine may be rapidly resealed. Such reparative processes may substantially limit the deleterious physiologic impact of superficial forms of intestinal injury.

Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies

Article

Oct 1988

The expression of intercellular adhesion molecule-1 (ICAM-1) on primary human fibroblasts, a human fibrosarcoma, chondrosarcoma, and adenocarcinoma cell line in response to IL-1, TNF-alpha, or IFN-gamma was studied using an ELISA with anti-ICAM-1 mAb. The induction of ICAM-1 by these cytokines was neutralized by cytokine-specific antisera as well as some steroids and the glycosylation inhibitor, tunicamycin. Cyclohexamide up-regulated the expression of ICAM-1 on chondrosarcoma cells but had little or no effect on carcinoma cells. These data indicate different mechanisms in the regulation and expression of ICAM-1 on the various cell types and provide some insight into the anti-inflammatory effects of some pharmacologic agents.

Vascular injury in acute gastric mucosal damage - Mediatory role of leukotrienes

Article

Jun 1988

Recent investigations indicate that microvascular injury, leading to increased vascular permeability and capillary stasis, precede the development of chemically induced hemorrhagic mucosal lesions in the stomach. The vascular damage is more amenable to protection by prostaglandins and sulfhydryls than the diffuse surface mucosal cell injury. The vascular and mucosal lesions may be the result of direct toxicity of damaging agents (eg, ethanol, HCl, NaOH) and the release of vasoactive amines and leukotrienes. We review here our recent studies performed in rats indicating that intraarterial infusion of LTC4 or LTD4 in the stomach caused vascular injury as revealed by monastral blue. Infusion of leukotrienes alone caused no hemorrhagic mucosal lesions but aggravated the damage caused by 25, 50, or 100% ethanol and 0.2 N HCl given intragastrically. The ethanol-induced mucosal lesions were slightly diminished by the lipoxygenase inhibitor L-651,392 and markedly decreased by eicosapentaenoic acid, which competes with arachiconic acid as a substrate for 5-lipoxygenase. These results are discussed and correlated with biochemical results from other laboratories demonstrating increased levels of leukotrienes in the gastric mucosa after administration of ethanol and decreased release following pretreatment with prostaglandins or sulfhydryl-related agents. New data thus support a mediatory role for leukotrienes in the pathogenesis of vascular injury and mucosal lesions in the stomach.

How do non-steroidal anti-inflammatory drugs affect gastric mucosal defenses?

Article

Jun 1987

D Fromm

The gastric mucosa possesses a number of mechanisms permitting resistance to damage from its own secreted acid. No single mechanism can account for gastric mucosal defense. Mucosal permeability to acid, active ion transport, blood flow, mucus secretion, epithelial restitution, and prostaglandin synthesis are among the multiple factors involved in gastric mucosal defense. Non-steroidal anti-inflammatory drugs (NSAIDs) cause gross mucosal damage by affecting these defenses. The net effect of NSAIDs is to make the mucosa more susceptible to the damaging effects of acid in the lumen. Acid plays a dual role in this process, by increasing drug absorption (which in turn increases mucosal permeability) and by diffusing from the lumen into the mucosa. If a sufficient amount of acid entering the tissue is unbuffered, necrosis occurs. NSAIDs affect tissue bicarbonate in several ways. These drugs decrease cellular production and secretion of bicarbonate, but increase tissue entry of bicarbonate from blood. NSAIDs also have a dual effect on blood flow. Microvascular stasis occurs at sites of gross mucosal damage, but blood flow increases at visibly normal sites. Mucus is impermeable to pepsin, slows acid diffusion to some degree, traps bicarbonate to create an alkaline interface, and traps cell slough, forming another putative barrier. NSAIDs inhibit mucus secretion and modify its structure. Perhaps related to mucus is the hydrophobic property of the mucosa attributable to an absorbed layer of surfactant. Aspirin reduces surface hydrophobicity, an effect that may increase ion permeability. In addition to secreting mucus, the cells lining the luminal surface also play a key role in maintaining the permeability and active transport properties of the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct medical costs of disease and gastrointestinal side effects during treatment of arthritis

Article

Mar 1988
AM J MED

Bernard S. Bloom

We conducted a study to determine the costs of caring for patients with arthritis. Data were obtained from the Medicaid Management Information System (MMIS) of Washington, DC. A retrospective analysis was undertaken of all direct medical costs related to individual Medicaid recipients who obtained treatment for arthritis. First, all data were adjusted for patient compliance with nonsteroidal anti-inflammatory drugs (NSAIDs). Second, we determined the actual expenditure of treating arthritis. Last, the medical costs of treating adverse gastrointestinal side effects were examined. There was a linear relationship between compliance and pharmaceutical dose schedule per diem. Treatment costs per quarter were

145; 54 percent of the cost was for NSAIDs with the remainder equally divided between physician and hospital costs. Approximately 25 percent of the population experienced NSAID-related gastrointestinal side effects that required further medical care. The per-quarter mean cost of treating these adverse gastrointestinal drug reactions was

66 per person, which added nearly 46 percent to the per-quarter mean cost of treatment. The total cost of treating patients with arthritis therefore averaged $211 per quarter. Nearly one third of overall cost went to provide medical care to the 25 percent of the population who experienced adverse reactions, and slightly more than two thirds went towards treating the disease itself. Overall costs of treating adverse drug reactions were accounted for by pharmaceuticals (about 42 percent), usually the histamine (H2)-receptor antagonist cimetidine, rare but expensive inpatient hospital care (about 38 percent) and physician visits (about 20 percent).

Oxygen free radicals interact with indomethacin to cause gastrointestinal injury

Article

Apr 1986
Agents Actions

In the present study it was shown that, unlikely MK447, a known oxygen free radical compound, PGE2 is much less effective against indomethacin-induced G.I. ulcers than against ethanol damage. It seems likely that factors other than PG deficiency (such as oxygen free radicals), could be involved in the pathogenesis of NSAID-induced G.I. damage. Some compounds that can capture free radicals (aminopyrine, thiourea and its derivative, MK 447) or that inhibit the lipoxygenase pathway (MK 447, salicylazosulfapyridine, BW 755, benoxaprofen) are able to abolish indomethacin-induced G.I. damage. After irradiation with hydroxyl free radicals, indomethacin reacts with them to cause marked G.I. injury, even at a submaximal dose, one poorly ulcerogenic by itself. The above findings suggest that oxygen free radicals are one of the causal factors in the formation of NSAID-induced G.I. side effects. Some of the data in this paper were presented at Fermo, August 31, 1984 (Advanced course on ‘oxygen and sulfur radicals in chemistry and medicine’) and at the 9th Iuphar International Congress of Pharmacology in London, July 30, 1984.

How do NSAIDs cause ulcer disease?

Abstract

No full-text available

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