Ulcerogenic Activity Research Articles

Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid

ObjectiveTo improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). MethodsThe in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. ResultsWhen the PSs were resuspended in water, MefeGAL’s, MA’s and their mixture’s apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. ConclusionsThese preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

Effect of Quercetin With Oral Hypoglycemics in Streptozotocin‐Induced Diabetes, and Its Effect on Ulcerogenic Activity

AbstractA diabetic‐induced ulcer is a complication of diabetes in which the formation of an ulcer increases and also causes a delay in ulcer healing. Diabetes adds a bonus to various factors like starvation and stress, imbalanced acid‐pepsin secretions, impaired mucosal resistance, acid‐back diffusion, and neuronal dysfunction. Feeding a high‐fat diet for 15 days after induction of STZ in rats develops diabetes mellitus simultaneously with growth, resulting in an acceleration of ulcers for any of the above reasons. The OGTT investigation included both normal and diabetic rats, and the researchers establish a consistently low dosage of conventional oral hypoglycemic agents for the treatment. Clinical studies in the literature highlight that effectively treating patients with diabetes complications has been demonstrated through glycemic control. Hence, effective palliative hypoglycemic agents are employed. Long‐term usage has revealed that they exert a drastic negative effect. Hence, herbal drug combinations with these standard drugs have proved to be effective in minimizing the side effects. QE, which has hypoglycemic, dyslipidemia, and antioxidant properties, has been effective when administered with Glipizide (5 mg kg−1). The monotherapy of this Glipizide and QE has not shown a beneficial effect in protecting the stomach from ulcers. The combination (G + QE) showed effective control of glucose without any hypoglycemia. QE as a single adjunct with Glipizide has proven promising in preventing and treating diabetic ulcers.

Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and positively influences pain sensitivity and work capacity.

The aim of the study was to investigate the effects of rat housing conditions-standard conditions, social isolation, environmental enrichment-and the subsequent reversal of these conditions on the vulnerability of the gastric mucosa to ulcerogenic stimuli, somatic pain sensitivity, and treadmill work capacity. Rats, aged 30days, were placed in standard conditions (SC), social isolation (Is), and environmental enrichment (EE) for 4weeks. Then half of each group underwent a reversal of housing conditions: SC rats were moved to Is, Is rats were placed in EE, EE rats were moved to Is, for 2weeks. The other half served as a control with no change in their initial housing. Two weeks after the reversal, vulnerability of the gastric mucosa to ulcerogenic action of indomethacin (IM, 35mg/kg, sc), somatic pain sensitivity (hot plate test), and work capacity (measured by the running distance on a treadmill) were assessed in control and reversed groups. Social isolation induced a proulcerogenic effect, increasing IM-induced gastric erosions, which was effectively reversed when rats were transferred to an environmental enrichment. Conversely, transferring rats from an environmental enrichment to social isolation exacerbated ulcerogenic action of IM. Somatic pain sensitivity and treadmill work capacity were also influenced by housing conditions, with environmental enrichment showing positive effects. The present findings show that social isolation of rats induces a proulcerogenic effect. Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and increases resilience to pain stimuli and treadmill work capacity.

Study of the anti-inflammatory, analgesic, ulcerogenic and anti-ulcerogenic activity of N-isopropenylimidazole zinc complex derivative

Introduction: Although nonsteroidal anti-inflammatory drugs (NSAIDs) have a clear therapeutic benefit, they can also have serious side effects. The most serious of these is the ulcerogenic effect, which can result in a decline in the quality of life or even death. This calls for the search for and creation of novel compounds with potent anti-inflammatory properties that do not have adverse effects on the digestive system. The aim of the study was to investigate the anti-inflammatory, analgesic, ulcerogenic and anti-ulcerogenic activities of N-isopropenylimidazole zinc complex derivative. Materials and Methods: Experiments in rats and mice were used to determine the median lethal dose LD50 for N-isopropenylimidazole zinc complex derivative (laboratory name Pilim-1). Experimental models of acute exudative inflammation and chronic proliferative inflammation were used. In the first case, the inflammation was induced by sub-plantar injection of carrageenan and a complete Freund’s adjuvant into the hind paw of rats. In the second case, the inflammation was induced by the implantation of a sterile cotton pellet (“cotton pellet–induced granuloma”) under the skin of rats. Acute and tonic pain, visceral, and somatic deep pain were simulated using the formalin test in rats and the acetic acid-induced writhing test in mice, respectively. The ulcerogenic and anti-ulcerogenic effects of Pilim-1 were studied in rat experiments. Pilim-1 and the reference drugs diclofenac, indomethacin and famotidine were administered intragastrically. Results and Discussion: Pilim-1 showed marked anti-inflammatory and analgesic effects, demonstrated less toxicity than diclofenac and indomethacin, while its activity is comparable to diclofenac and superior to indomethacin. Its therapeutic index is higher than that of indomethacin and diclofenac and, in contrast, it essentially has no ulcerogenic effect and exhibits stronger anti-ulcerogenic activity than famotidine. It appears that the anti-inflammatory, analgesic, and gastroprotective properties of Pilim-1 are largely due to its antioxidant and antihypoxic properties, its inhibitory effects on cyclooxygenase and 5-lipoxygenase, and the presence of imidazole and zinc in its structure, both of which have a wide range of biological activity. Conclusion: Pilim-1 can be recommended for further preclinical studies due to its relatively low (practically absent) ulcerative activity, strong anti-inflammatory, analgesic, and anti-ulcerative effects, greater therapeutic index, and less acute toxicity in comparison with diclofenac and indomethacin.

Efficient microwave synthesis of flurbiprofen derivatives and their enhancement of efficacy in chronic inflammatory pain models and gastro-protective potential in post-operative model

Present research was designed to synthesize and characterize the flurbiprofen derivatives and to evaluate their analgesic, anti-inflammatory and gastro-protective activities in post-operative and chronic inflammatory pain models. Flurbiprofen derivatives were produced by using three-step processes involving esterification, hydrazide production, and schiff base, each of which modified a different carboxyl group. All the newly synthesized flurbiprofen derivatives (NS5-NS8) were characterized by 1H NMR,13C NMR,19F NMR and HR-ESI-MS, and the post-operative, inflammatory pain and ulcerogenic activities were determined in well-established in-vivo animal models. To evaluate post-operative and inflammatory pain, various doses of compounds [1, 3, 10, and 30 mg/kg (bwt)] were used, while their ulcerogenic potential was assessed at doses of 100 and 150 mg/kg (bwt). The incisional damage linked pain was significantly (p < 0.001) reduced by derivatives at different doses in both the acute and repeated tests with decreased response of phologistic agent-induced inflammation. The stomach histology and biochemical features demonstrate that the synthesized derivatives have no potential to cause ulcerogenicity as compared to aspirin and flurbiprofen. Furthermore, docking shows that the hydrazide moiety of these compounds is crucial in interacting within COX-2 binding site. Therefore, the synthesized compounds exhibit strong analgesic and anti-inflammatory effects and a low risk of causing ulcers. These attributes render them potentially valuable therapeutic agents for the treatment of pathological disorders associated with inflammation and pain. Communicated by Ramaswamy H. Sarma

Comparative Analysis of the Effects of Insulin and Metformin on the Ulcerogenic Action of Indomethacin in Rats with Streptozotocin-Induced Diabetes

Comparative Analysis of the Effects of Insulin and Metformin on the Ulcerogenic Action of Indomethacin in Rats with Streptozotocin-Induced Diabetes

Caffeic acid phenethyl ester attenuates indomethacin-induced gastric ulcer in rats.

Gastric ulcer is one of the most frequent gastrointestinal ailments worldwide. Indomethacin, one of the most potent NSAIDs, suffers undesirable ulcerogenic activity. Caffeic acid phenethyl ester (CAPE) has known health benefits. The current study examined the potential of CAPE to combat indomethacin-induced gastric ulcers in rats. Animals were randomized into 5 groups: control, Indomethacin (50 mg/kg) mg/kg), Indomethacin + CAPE (5 mg/kg/day), Indomethacin + CAPE (10 mg/kg), and Indomethacin + Omeprazole (30 mg/kg). CAPE prevented the rise in ulcer index, attenuated histopathological changes and preserved gastric mucin concentration. CAPE efficiently significantly prevented accumulation of malondialdehude (MDA) and prevented exhaustion of the enzymatic activities of catalase (CAT) and superoxide dismutase (SOD). Further, CAPE prevented the rise in the expression of tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nuclear factor kapp-B (NFκB). This was associated with down-regulation of Bax and up-regulation of Bcl-2 mRNA. Finally, CAPE prevented induced indomethacin-induced decrease in heat shock protein 70 (HSP70) in gastric tissues. In conclusion, CAPE possesses the ability to prevent indomethacin-induced gastric ulcer in rats. This involves, at least partially, antioxidation, anti-inflammation, anti-apoptosis and enhancement of HSP70 expression.

Influences of Curcuma Longa (turmeric) supplemented diet on the expression of defensive and destructive factors in indomethacin-induced ulcerated Wistar rats.

Turmeric (Curcuma longa) L. has been recognized as a plant with high medicinal value and it has been used in the prevention and treatment of many diseases. Different studies have shown that turmeric has both therapeutic and preventive effects on peptic ulcer. However, there are controversial reports about the anti-ulcerogenic potential of turmeric. Some studies also suggested that turmeric could be ulcerogenic when consumed in large quantity with no mention of the concentration at which this could take place. This study examined the influences of different concentration of turmeric rhizome powder supplemented diet on the gene expressions of both anti-ulcer and ulcer biomarkers in indomethacin-induced ulcerated rats. The study was conducted through prophylactic treatment of test groups with turmeric at different percentage (1%, 2%, 5%, and 10%) for 28 days. Thirty-five rats were randomly divided into seven groups namely A, B, C, D (1%, 2%, 5%, and 10% groups respectively), E (standard drug group (STD)), F (ulcerogenic group) and G (normal control group (CTL)). At the end of 28 days, rats were fasted overnight and ulcer was induced in all the groups except group G by oral administration of 60mg/kg b.w (body weight) of indomethacin. The expression of defensive (Cyclo-oxygenase-1, MUCIN, and Hyme-oxygenase-1) and destructive factors (Pepsin) were then analyzed. Results showed that consumption of TRPSD at 1-5% increased the gene expression of protective factors when compared with animals in group F. Furthermore, Prophylactic treatment of test groups with TRPSD at 1%-5% significantly suppressed the gene expression of pepsin in comparison with animals in group F. However, TRPSD consumption at 10% down-regulated the gene expression of those protective factors. Similarly, at 10%, pepsin gene expression was not suppressed when compared with animals in group F. Conclusively, TRPSD could be gastro protective at 1%-5%. However, these potentials were abrogated in animals in group D indicating the ulcerogenic potential of turmeric at this concentration (10%) and its capability to enhance ulcerogenic action of indomethacin. Turmeric rhizome powder (TRP) have anti-ulcerogenic potential and gastro-protective effect when consumed in appropriate concentration. Consumption of TRP at 10% concentration could enhance ulcerogenic action of indomethacin (NSAIDs) thus predisposing to ulcer. Effects of turmeric rhizome powder supplemented diet (TRPSD) on the mRNA expression of protective agents (cyclo-oxygenase-1 (COX-1), mucin, and inducible heme-oxygenase (HO-1)) and destructive factor (pepsin), in indomethacin-induced ulcerated Wistar rats were explored in this paper. These were determined by prophylactic treatment of test groups with turmeric at different levels (1%, 2%, 5%, and 10%) for 28 days. Thirty-five rats were randomly divided into seven groups namely A, B, C, D (1%, 2%, 5%, and 10% groups respectively), E (standard drug group (STD)), F (ulcerogenic group) and G (normal control group (CTL)). The rats were fasted overnight and ulcer was induced in all the groups except group G by oral administration of 60mg/kg b.w (body weight) of indomethacin. The expression of defensive (Cyclo-oxygenase-1, MUCIN, and Hyme-oxygenase-1) and destructive factors (Pepsin) were then analyzed. Results showed that consumption of TRPSD at 1%-5% increased the gene expression of protective factors when compared with animals in group F. Furthermore, Prophylactic treatment of test groups with TRPSD at 1%-5% significantly suppressed the gene expression of pepsin in comparison with animals in group F. However, TRPSD consumption at 10% down-regulated the gene expression of those protective factors. Similarly, at 10%, pepsin gene expression was not suppressed when compared with animals in group F. Conclusively, TRPSD could be gastro protective at 1%-5%. However, these potentials were abrogated in animals in group D indicating the ulcerogenic potential of turmeric at this concentration (10%) and its capability to enhance ulcerogenic action of indomethacin.

4-(5-Amino-pyrazol-1-yl)benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments

In the current medical era, the single target inhibition paradigm of drug discovery has given way to the multi-target design concept. As the most intricate pathological process, inflammation gives rise to a variety of diseases. There are several drawbacks to the single target anti-inflammatory drugs currently available. Herein, we present the design and synthesis of a novel series of 4-(5-amino-pyrazol-1-yl)benzenesulfonamide derivatives (7a-j) with COX-2, 5-LOX and carbonic anhydrase (CA) inhibitory activities as potential multi-target anti-inflammatory agents. The pharmacophoric 4-(pyrazol-1-yl)benzenesulfonamide moiety in Celecoxib was used as the core scaffold and different substituted phenyl and 2-thienyl tails were grafted via a hydrazone linker to enhance inhibitory activity against hCA IX and XII isoforms, yielding target pyrazoles 7a-j. All reported pyrazoles were evaluated for their inhibitory activity against COX-1, COX-2, and 5-LOX. Pyrazoles 7a, 7b, and 7j showed the best inhibitory activities against the COX-2 isozyme (IC50 = 49, 60 and 60 nM, respectively) and against 5-LOX (IC50 = 2.4, 1.9, and 2.5 μM, respectively) with excellent SI indices (COX-1/COX-2) of 212.24, 208.33, and 158.33, respectively. In addition, the inhibitory activities of pyrazoles 7a-j were evaluated against four different hCA isoforms I, II, IX, and XII. Both transmembrane hCA IX and XII isoforms were potently inhibited by pyrazoles 7a-j with KI values in the nanomolar range; 13.0–82.1 nM and 5.8–62.0 nM, respectively. Furthermore, pyrazoles 7a and 7b with the highest COX-2 activity and selectivity indices were evaluated in vivo for their analgesic, anti-inflammatory, and ulcerogenic activities. The serum level of the inflammatory mediators was then measured in order to confirm the anti-inflammatory activities of pyrazoles 7a and 7b.

The mechanochemically prepared compositions of skin care substances with silicates for medicinal and cosmetic applications

Introduction: The active biological substances used in medicinal and cosmetic applications, are mainly organic acids. The local contact effect of the protons located on the surface of their crystallites can irritate the mucous membranes of the stomach and esophagus (medicines), or skin of the face (cosmetics). The irritating effect of protons can be weakened either by grinding crystalline acid powders to nanoscale sizes, or by neutralizing them. Organic acids are polymerized due to hydrogen bonds, which does not allow them to be dispersed to nanometric sizes by traditional methods. It was previously shown that during the mechanical activation of silicates, short-lived hydroxyl groups become available. Objective: The purpose of this work is to study the possibility of neutralization of protons of organic acids during their mechanochemical interaction with silicates. Methods: The IR spectroscopy, X-ray analysis and electron microscopy methods were used for research. Results: It was shown by that organic acid is "grafted" to the silicate surface due to neutralization of organic acid protons by hydroxyl groups of layered silicates, opened during mechanical activation. This makes it possible to form highly dispersed composite structures "organic acid/layered silicate" in dicarboxylic (carboxylic, aromatic, amino) acids - talc (pyrophyllite, kaolinite) systems. Conclusions: Such mechanochemically synthesized composites, in which acid is grafted to an inert carrier, in addition to high dispersion, provide a decrease in the acidity of the resulting product. In the case of mechanochemical interaction of SiO2 with organic acids, the basic centers mainly work on the surface of SiO2 , which is opened during mechanical activation. Organic acids (hydroxo acids, dicarboxylic, carboxylic, aromatic) are distributed in an extremely thin layer on the surface of silicon oxide due to the "SiO2 — adsorption water — acid" bond. This allows to change the pharmacokinetics and avoid ulcerogenic action and reduce the irritating effect of organic acids on the skin.

Synthesis, analgesic, anti-inflammatory, ulcerogenic evaluation, and docking study of (benzoylphenoxy)-N-{5-[2-methylphenyl-6-chlorobenzoxazole]} acetamides as COX/5-LOX inhibitor

The COX and 5-LOX inhibitors with analgesic and anti-inflammatory effectiveness and very less gastrointestinal toxicity have been recognized as constructive and sustainable agents for inflammatory treatment. In this approach, a series of titled compounds (10a-j) were developed, synthesized, and evaluated in terms of in-vitro COX and LOX enzyme inhibition followed by analgesic, anti-inflammatory, and the ulcerogenic activity. The anti-inflammatory evaluation was conducted on those compounds 10a-c, 10e, and 10g-10i that displayed potential analgesic activity and later, validated for the ulcerogenic effect of potent anti-inflammatory compounds. The compound 10b with ortho substitution of methyl and para substitution of chloro groups on the phenyl ring and meta substitution of chloro group on benzoyl ring of benzophenone appended to benzoxazole was observed to have good inhibitory potency. Furthermore, Autodock tools docking software was used to carry out the in silico studies.

SYNTHESIS OF SOME NEWER THIAZOLIDINONYL QUINAZOLINONES AND AZETIDINONYL QUINAZOLINONES AS POTENT ANTI-INFLAMMATORY AGENTS

3-Substitutedphenyl-2-bromomethyl-6-substituted quinazolin-4(3H)-ones (7-10) were treated with hydrazine hydrate to give 3-substitutedphenyl-2-hydrazinomethyl-6-substituted quinazolin-4(3H)-ones (11-14). Compounds 11-14 were condensed with various aldehydes to afford 2-substitutedbenzylidene hydrazinomethyl-3-substitutedphenyl-6-substituted quinazolin-4(3H)-ones (15-22). Cycloaddition of compounds 15-22 with thioglycolic acid and triethylamine / chloroacetyl chloride yielded 2-[(4’-oxo-2’ -substitutedphenyl-thiazolidin-3’-yl)-aminomethyl]-3-substitutedphenyl-6-substituted quinazolin-4(3H)- ones (23-30) and 2-[(4’-oxo-3’-chloro-2’-substitutedphenylazetidin-1’-yl)-aminomethyl]-3- substitutedphenyl-6-substituted quinazolin-4(3H)-ones (31-38), respectively. The structures of these compounds have been elucidated by elemental (C, H, N) and spectral (IR, 1H-NMR) analysis. All the above mentioned compounds were evaluated for their anti-inflammatory activity, ulcerogenic activity and acute toxicity study. Compound 27 was found to be most potent amongst all the newly synthesized compounds. This compound also exhibits less ulcerogenic activity and ALD50 is &gt;2000 mg kg-1 p.o.

Experimental study of the antiulcer effect of cryopreserved placenta extract on a model of acetylsalicylic acid-induced ulcerogenesis

Abstract Introduction. The gastrotoxicity of nonsteroidal anti-inflammatory drugs is a leading side effect that significantly limits their clinical use, among other types of their toxicity (nephrotoxicity, hepatotoxicity, cardiotoxicity, etc.). Cryopreserved placenta extract has drawn our attention as a potential modifier of the ulcerogenic action of nonsteroidal anti-inflammatory drugs. Aim. To characterize the cytoprotective properties of cryopreserved placenta extract by the condition of the mucous membrane of the proximal (esophagus and stomach) and distal (small and large intestine) parts of the gastrointestinal (GI) tract on the model of ASA-induced ulcerogenesis. Material and methods. The study was performed using 28 male rats weighing 200-220 g. Subchronic ASA-induced ulcerogenesis of the digestive tract was reproduced by intragastrically administration to rats of ASA in a dose of 150 mg/kg. The effect of the studied drugs on the condition of the mucous membrane of the digestive tract was assessed macroscopically by the following criteria: edema, redness and hemorrhage on the surface of the mucous membrane. The ulcer index for each group of animals was calculated. Results and discussion. Five doses of ASA 150 mg/kg cause damage to the esophagus, stomach, small and large intestines in all of the rats. The use of the proton pump inhibitor esomeprazole has pronounced gastrocytoprotective properties, but does not affect the ulcerogenic effect in the small intestine, and in the colon, it enhances it. This is indicated by ulcerative lesions of the colon in 57.1% of all rats administered ASA and esomeprazole, as well as in the folding of the gastric mucosa. In contrast, mild hyperemia of the gastric mucosa was seen in 28.6% of all rats and moderate hemorrhage in 57.1% of all rats due to the combined use of ASA and cryoextract placenta. Conclusions. The use of cryopreserved placenta extract is statistically significantly (p &lt;0.05) inferior to the antiulcer activity of esomeprazole in the stomach. Thus, the ulcer index on the background of the use of ASA and cryopreserved placenta extract was 0.97, and on the background of the use of ASA and esomeprazole – 0.39. In the distal parts of the GI tract cryoextract placenta showed cytoprotective properties against the background of induced ASA ulcerogenesis, in contrast to esomeprazole.

Novel Thiazolotriazolone Derivatives: Design, Synthesis, In Silico Investigation, Analgesic and Anti‐inflammatory Activity

AbstractA group of new thiazolo[3,2‐b][1,2,4]triazol‐6(5H)‐one fenamate‐like derivatives designed by using hybrid strategy in order to explore analgesic/anti‐inflammatory activity of the hybrid structures. Some of the synthesized analogs showed comparable activities with mefenamic acid in abdominal constriction test and carrageenan induced rat paw edema test. 5‐(4‐nitrobenzylidene)‐2‐(2‐(2‐chlorophenoxy)phenyl)thiazolo[3,2‐b][1,2,4]triazol‐6(5H)‐one (8 e) and 5‐(3,5‐di‐tert‐butyl‐4‐hydroxybenzylidene)‐2‐(2‐(2‐chlorophenoxy)phenyl)thiazolo[3,2‐b][1,2,4]triazol‐6(5H)‐one (8 k) were determined as the most active agents with 53.1 and 49.3 percent of inhibition after 4 hrs of ip administration respectively. Flexible docking investigation indicated that the designed molecules interacted with cyclooxygenase 1 and 2 (COX‐1 and COX‐2) active sites. Moreover, the results suggest that thiazolo[3,2b][1,2,4]triazol‐6(5H)‐one moiety has the same effect as mefenamic acid COOH group over COX‐1,2 with a significant low or no ulcerogenic activity. Furthermore, the energetically favorable conformer Z, revealed as the active structural conformation due to the less steric hindrance. Based on the predicted ADME properties of high potent anti‐inflammatory agents, it is proposed that the applied modifications promote the rational drug design of novel analgesic and anti‐inflammatory candidates.

Synthesis of Novel Benzoxazole Derivatives: Exploration of Their Possible Pharmacological Profiles with Computational Studies

Based on the interaction with PDB protein 1PXX of the cox-2 enzyme, a novel series of substituted thiazolidinones (TZD 5a-s) and azetidinones (AZT 6a-s) was designed and synthesized. Molecules were synthesized from 2-mercapto benzoxazole (1) using both conventional and microwave irradiation methods, and their in-vitro antioxidant activity was evaluated using the DPPH free radical scavenging activity, as well as their in-vivo anti-inflammatory activity using the carrageenin-induced rat paw edema method. The reaction time, yield, and purity of microwave and conventionally produced molecules are compared in this work. The molecule ethyl 2-(benzoxazol-2-ylthio)acetate (2) is obtained by reacting 2-mercapto benzoxazole (1) with ethyl 2-chloroacetate in the presence of potassium carbonate and dry acetone. The molecule 2-(benzoxazol-2-ylthio)acetohydrazide (3) was synthesized by reacting ethyl 2-(benzoxazol-2-ylthio)acetate (2) with hydrazine hydrate in the presence of absolute alcohol. Compound 2-(benzoxazol-2-ylthio)acetohydrazide (3) on reacting with different aromatic and heterocyclic aldehyde derivative forms 2-(benzoxazol-2-ylthio)-N'-substituted acetohydrazide Schiff bases (4a-s). 2-(benzoxazol-2-ylthio)-N-(4-oxo-2-substituted thiazolidin-3-yl)acetamide (5a-s) i.e. thiazolidinones benzoxazole derivatives obtained on reacting Schiff bases (4a-s) with thioglycolic acid in a dioxane medium and anhydrous zinc chloride. The Schiff bases (4a-s) were converted into 2-(Benzo[d]oxazol-2-ylthio)-N-(3-chloro-2-oxo-4-substituted azetidin-1-yl)acetamide (6a-s) after treatment with chloroacetyl chloride in the presence of triethanol amine and dioxane. This study focuses on screening of novel synthesized benzoxazole derivatives for in vitro antioxidant, in vivo anti-inflammatory activity, and the evaluation of ulcerogenic activity. The in vivo activity is correlated with the in silico activity, the 3 D QSAR studies were performed for all the compounds by using computer program i.e. SYBYL-X 2.1.1 software. The best CoMFA and CoMSIA models were obtained for the training set compounds with 0.753 and 0.646 leave-one-out coefficients (q2), 0.714 and 0.619 cross validated correlation coefficients (r2cv), and 0.975 and 0.983 conventional coefficients (r2), respectively. Both models were validated with a test set of eight compounds, giving the CoMFA and CoMSIA models a satisfactory prediction (r2pred) of 0.788 and 0.663, respectively. The findings of the study would provide valuable information for the design of new compounds and would also help in predicting the activity of designed compounds. To identify the lead molecule docking studies are performed on COX-2 enzyme of protein 1PXX, the molecules 5c, 5q, 5j, 6q, and 6 g derivatives obtained good - c-docker interaction energy respectively, and in vivo acute ulcerogenic activity.

Repeated Treadmill Running Attenuates Indomethacin‐caused Gastric Injury in Rats with Streptozotocin‐induced Diabetes

Diabetes is one of the most common chronic diseases leading to disability and death. Physical activity has a beneficial effect on all vital functions of the body under the norm as well as pathology including diabetes. Previously we have shown that treadmill running attenuates the vulnerability of gastric mucosa to ulcerogenic action of indomethacin (IM). The aim of the study was to investigate the effect of treadmill running on the vulnerability of the gastric mucosa to ulcerogenic action of IM in rats with streptozotocin‐induced diabetes. Diabetes was induced by a single injection of streptozotocin (STZ, 70 mg/kg, ip). Two regimens of treadmill running, repeated (Experiment 1) and single (Experiment 2), were used. There were four groups of rats in each experiment: two groups (running and sedentary) treated with STZ and two groups (running and sedentary) treated with vehicle of STZ (control). In Experiment 1 daily repeated treadmill running was initiated 7 days before STZ (or its vehicle) administration and continued daily 7 days after STZ administration. The intensity and duration of treadmill running gradually increased from 10 to 15 cm/s and from 10 to 20 min/day, respectively. In Experiment 2 only single treadmill session (15 cm/s, 15 min) was initiated 7 days after STZ (or its vehicle) administration. In both experiments, IM (35 mg/kg, sc) was administered immediately after completion of treadmill session in preliminary (24 h) fasted rats 7 days after STZ injection. Gastric erosion was examined 4 h after IM administration. Glucose level, body weight, water consumption and plasma corticosterone levels were also measured. Signs of diabetes (an increase of glucose level, loss of body weight, an increase of water consumption and elevation of plasma corticosterone levels) were developed 1 week after STZ administration. IM administration caused the gastric erosion 4 h after the injection. STZ‐induced diabetes aggravated ulcerogenic action of IM: the mean area of gastric erosion was significantly greater in rats with STZ injection compared to that in control animals. Repeated as well as single treadmill running did not significantly affect the signs of diabetes. However, repeated daily treadmill running resulted in a significant decrease of the area of gastric erosion in rats with STZ‐induced diabetes as well as control (non‐diabetic) rats compared to corresponding sedentary groups. A single running, before IM administration, reduced the area of gastric erosion in non‐diabetic rats, but it did not affect the gastric injury in rats with STZ‐induced diabetes. The data suggest that regular physical activity started before STZ‐induced diabetes can protect the gastric mucosa against the ulcerogenic action of IM.

Pharmacological Preconditioning by Corticotropin Releasing Factor (CRF) or ACTH Protects the Gastric Mucosa against Ulcerogenic Action of Indomethacin through Involvement of Glucocorticoids

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used as analgesic and anti‐inflammatory drugs. However, adverse effects, including gastrointestinal, renal, cardiovascular side effects, seriously complicate NSAIDs use. Their gastrointestinal side effects are the most known serious complications in patients taking these drugs. Previously we have shown that preconditioning stress attenuates the ulcerogenic action of indomethacin (IM) on the gastric mucosa. According our findings glucocorticoids, released in response to stressor, are gastroprotective hormones and involved in stress preconditioning protective effects. Corticotropin releasing factor (CRF), a major mediator of stress response, stimulates ACTH release through CRF receptors of subtype 1 and ACTH, in turn, stimulates glucocorticoid production. Here we verify the hypothesis that pharmacological preconditioning by CRF or ACTH can protect the gastric mucosa against ulcerogenic action of IM in rats through mechanism associated with glucocorticoids. For this, preliminary fasted (24 h) rats were administered by CRF (2.5 or 5 µg/ kg, ip) or ACTH (1U/kg, ip) 30 min before IM injection (35 mg/kg, sc). Gastric lesions were examined 4 h after IM administration. Plasma corticosterone levels were measured before and 4 h after IM injection. Since the gastrointestinal injury is accompanied by changes in somatic pain sensitivity, we also measured tail flick latencies (tail flick test) before and 4 h after IM. Both CRF and ACTH by itself caused an elevation of plasma corticosterone levels, which was accompanied by an increase of tail flick latencies (analgesic effect). IM administration resulted in the gastric erosion 4 h later. Pretreatment with CRF or ACTH reduced an area of gastric lesions caused by IM (gastroprotective effect). IM‐induced gastric injury was accompanied by an increase of tail flick latencies, which was prevented by CRF (normalization of somatic pain sensitivity). To estimate the role of glucocorticoids in CRF‐induced gastroprotection an inhibitor of corticosterone synthesis metyrapone (30 mg/kg) or CRF receptor type 1 antagonist NBI 27914 (10 mg/kg) or glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was administered before CRF. Both metyrapone and NBI 27914 injected before CRF administration caused an inhibition of CRF‐induced corticosterone response and prevented protective effect of CRF on the gastric mucosa against the IM‐induced injury. The gastroprotective effect of CRF was also eliminated by the pretreatment with RU‐38486. Thus, CRF as well as ACTH can protect the gastric mucosa against ulcerogenic action of IM. Gastroprotective action of CRF accompanied by normalization of somatic pain sensitivity is provided by mechanism associated with glucocorticoids.

Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti-Inflammatory Drugs.

Carbohydrates are one of the most abundant and important classes of biomolecules. The variety in their structures makes them valuable carriers that can improve the pharmaceutical phase, pharmacokinetics and pharmacodynamics of well-known drugs. D-galactose is a simple, naturally occurring monosaccharide sugar that has been extensively studied for use as a carrier and has proven to be valuable in this role. With the aim of validating the galactose-prodrug approach, we have investigated the galactosylated prodrugs ibuprofen, ketoprofen, flurbiprofen and indomethacin, which we have named IbuGAL, OkyGAL, FluGAL and IndoGAL, respectively. Their physicochemical profiles in terms of lipophilicity, solubility and chemical stability have been evaluated at different physiological pH values, as have human serum stability and serum protein binding. Ex vivo intestinal permeation experiments were performed to provide preliminary insights into the oral bioavailability of the galactosylated prodrugs. Finally, their anti-inflammatory, analgesic and ulcerogenic activities were investigated in vivo in mice after oral treatment. The present results, taken together with those of previous studies, undoubtedly validate the galactosylated prodrug strategy as a problem-solving technique that can overcome the disadvantages of NSAIDs.

Amphiphilic Poly-N-vinylpyrrolidone Nanoparticles as Carriers for Nonsteroidal, Anti-Inflammatory Drugs: Pharmacokinetic, Anti-Inflammatory, and Ulcerogenic Activity Study.

Nanoparticles are increasingly utilized as drug delivery agents. Previously, we have developed a drug delivery system based on amphiphilic derivatives of poly-N-vinylpyrrolidone (PVP-OD4000) with excellent biocompatibility. In the current study, we assessed the pharmacokinetics, anti-inflammatory profile, and ulcerogenic potential of indomethacin (IMC)-loaded PVP-OD4000 nanoparticles compared to the free drug. Wistar male rats were utilized for a pharmacokinetics study and an anti-inflammatory study. Loaded IMC exhibited a slower elimination rate (p < 0.05) and a higher blood plasma concentration at 8 and 24 h after intraperitoneal injection compared with free IMC. In addition, decreased uptake of loaded IMC in the liver and kidney compared to free IMC (p < 0.05) was detected. Furthermore, PVP-OD4000 nanoparticles loaded with IMC showed an enhanced anti-inflammatory effect compared to free IMC (p < 0.05) in carrageenan-induced and complete Freund’s adjuvant-induced–(CFA) sub-chronic and chronic paw edema treatment (p < 0.01; p < 0.01). Notably, upon oral administration of loaded IMC, animals had a significantly lower ulcer score and Paul’s Index (3.9) compared to the free drug (p < 0.05). The obtained results suggest that IMC loaded to PVP nanoparticles exhibit superior anti-inflammatory activity in vivo and a safe gastrointestinal profile and pose a therapeutic alternative for the currently available NSAIDs’ administration.

Molecular Docking and Molecular Dynamic Studies, Synthesis, Characterisation of Thiazolidine-4-One Derivatives

Background: Antibacterial, antifungal, anticancer, antitubercular, anti-HIV, analgesic, anti-inflammatory, and ulcerogenic activities have all been documented for thiazolidine derivatives. Molecular docking has become a crucial step in the drug discovery process, with the goal of predicting the binding mechanism and affinity of the protein-ligand complex. AutoDock is a popular non-commercial docking tool that successfully docks ligands to their target proteins (accurate and computationally fast). The Discovery Studio Visualizer is a free viewer that may be used to open data produced by other Discovery Studio tools.&#x0D; Aim: The main aim of this study is:&#x0D; &#x0D; To study the molecular docking and molecular dynamic studies of the different thiazolidine derivatives.&#x0D; To synthesise the compound based on the results produced in the molecular dynamics and molecular studies.&#x0D; To Characterise the synthesised compounds using FTIR, 1H NMR, 13C NMR and Mass Spectral studies.&#x0D; &#x0D; Procedure: In two phases, a new series of Thiazolidine-4-one derivatives was created. The production of Schiff base is the first step, followed by the condensation of Schiff base with Chloro acetyl chloride and subsequent cyclisation steps. FTIR, 1H-NMR, 13C-NMR, and Mass Spectroscopy were used to characterise the chemical structures of the produced compounds.&#x0D; 1BVR protein that was taken from the protein database website&#x0D; The structures were drawn using Chem draw Ultra 8.0 and Biovia draw 2018. Using the Smiles Online Translator, it was stored in Mol format and then converted to PDB format. The Cygwin toolings were used to log all of the files.&#x0D; Conclusion: The conformation was computed using a ranking system. This indicates whether the molecule has strong ligand binding energy, hydrogen bonding, and hydrophobic interaction with the receptor. According to the findings, thiazolidine-4-one derivatives have antitubercular efficacy when used in conjunction with the Enoyl-acyl carrier protein (enoyl-ACP) reductase enzyme.&#x0D; For the docking analysis it indicates if the compound has strong ligand binding energy, hydrogen bonding, and hydrophobic binding with the receptor shows good activity. Using Auto dock 4.2 it was found out that among the above 20 compounds (including the control compound), C2, C5, C6, C8, C11. C13, C15 and C17 directly bind with the functional domain (Casein kinase II phosphorylation site) of the amino acid (252 to 255). The above compounds bind at the 252nd position of the Chain C, where Alanine is present (The target protein, 1BVR () contains ABCDEF chains).