Somesh Sharma - Academia.edu (original) (raw)

Papers by Somesh Sharma

Research paper thumbnail of A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes

Nutrition & Metabolism, Jun 5, 2015

A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytok... more A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytokines and growth factors play a major role in disease progression. The methanolic extracts of Sphaeranthus indicus as well as its active ingredient, 7-hydroxy frullanoide (7-HF), are shown to suppress LPS-induced cytokine production from mononuclear cells, and inhibit the expression of VCAM1, ICAM1 and E-selectin by TNF-α-stimulated HUVECs in a concentration-dependent manner. We tested the hypothesis that the inhibition of cytokines and adhesion molecules should attenuate the progression of atherosclerosis, independent of changes in the lipid profile. Studies were carried out in two animal models: a high fat-fed LDLr-/mouse and a high fat-fed hyperlipidemic hamster. Methanolic extract of S. indicus was dosed to hyperlipidemic LDLr-/at 100 and 300 mg (equivalent to 20 and 60 mg 7-HF)/kg body weight/ day for 8 weeks, and plasma lipids as well as aortic lesion area were quantitated. Hyperlipidemic hamsters were treated with one dose of 200 mg/kg/day. S. indicus extract treatment did not alter the lipid profile in both animal models, but reduced aortic lesion area in LDLr-/mice and hyperlipidemic hamsters by 22 % and 45 %, respectively. Fenofibrate, included as a reference agent, decreased aortic lesions by 26 % in LDLr-/mice and 84 % in hyperlipidemic hamsters, respectively, which was driven by massive reductions in proatherogenic lipoproteins. The lipid-independent anti-atherosclerotic activity of S. indicus was associated with the reductions in the circulating levels of MCP-1, TNF-α, and IL-6 via phosphorylation and degradation of IkB-α that prevents translocation of NF-kB in the nucleus to induce proinflammatory cytokines. Our findings demonstrate that anti-inflammatory agents that lower pro-inflammatory proteins inhibit the progression of atherosclerosis. The methanolic extract of S. inducus, currently being used to treat psoriasis, offer promise to benefit individuals who have high circulating pro-inflammatory cytokines, and predisposed to coronary artery disease.

Research paper thumbnail of Binding of Aminoacyl-tRNA to Bacterial Ribosomes

Research paper thumbnail of Protective immunity in toxoplasmosis: correlation between antibody response, brain cyst formation, T-cell activation, and survival in normal and B-cell-deficient mice bearing the H-2k haplotype

Infection and Immunity, Apr 1, 1987

Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-spe... more Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-specific T-cell activation, and the number of brain cysts were compared in immunocompetent CBA/J (H-2^), C3H/He (H-2^), and BWcell-deficient CBA/N (H-2k) mice. Almost all of the C3H/He mice (94%) survived in comparison to CBA/J (71%) and CBA/N (53%) mice following infection with 20 cysts of Me 49, an avirulent strain of T. gondii. The mortality in susceptible mice was reduced by treatment of the animals with sulfadiazine during the acute stage of infection. Decreased mortality in CBA/J and C3H/He mice as well as in B-cell-deficient mice was paralleled by formation of fewer brain cysts. The Toxoplasma-specific T-cell proliferation was markedly enhanced in all three strains at day 15 postinfection but not at day 45 postinfection when compared to animals not treated with the drug. In contrast, Toxoplasma-specific IgM and IgG levels were lower in CBA/J and CBA/N mice treated with sulfadiazine than in untreated mice of these strains. Although CBA/N mice developed almost no humoral response either with or without drug treatment, they produced fewer brain cysts than normal CBA/J mice. The results indicate a major role of cell-mediated immunity in protection against an acute Toxoplasma infection.

Research paper thumbnail of Oxygen-independent killing by alveolar macrophages

Journal of Experimental Medicine, May 1, 1986

Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Th... more Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Their clinical importance is emphasized by the high incidence of life-threatening pneumonia (7, 8) in patients with abnormal macrophage function (6) or impaired ceU-mediated immunity (6-9). However, the mechanisms by which alveolar macrophages kill microorganisms are poorly understood. We recently examined the mechanism by which human alveolar macrophages kill the intracellular parasite, Toxoplasma gondii (10). We chose this organism because it causes pneumonia in immunosuppressed patients (11-14) but not in healthy individuals (11), and because macrophages play an important part in the host's resistance to this organism (5, 15-17). Our studies showed that killing of T. gondii by human alveolar macrophages occurred without involvement of toxic metabolites of oxygen (Catterall, J. R., and J. S. Remington, manuscript in preparation). This suggested that previous studies of intracellular killing by normal macrophages might have limitations as models for the human alveolar macrophage, since most of them (18-20, and reviewed in 21), including all those that employed T. gondii (18-23), have emphasized the overriding importance of oxidative killing mechanisms. Nonoxidative antimicrobial activity has been shown in subcellular macrophage fragments (21, 24) and in oxidatively deficient cells (19, 21-23, 25), but in none of the previously described models using normal intact macrophages has the killing of intracellular parasites been reported as nonoxidative. To facilitate the study of nonoxidative killing by alveolar macrophages, we have sought a laboratory animal model relevant to the human alveolar macrophage. Since rats more closely resemble human subjects in their resistance to T. gondii than many other animals (26, 27), we have examined the interaction between T. gondii and rat alveolar macrophages in vitro. The studies reported here indicate that rat alveolar macrophages, like those from human subjects, also kill T. gondii, and by nonoxidative mechanisms. They suggest that nonoxidative antimicrobial mechanisms may be important in alveolar macrophages, and they provide a convenient model for the study of such mechanisms. This investigation received financial support from grant AI-04717 from the National Institutes of Health. J. R. Catterall is the recipient of a Medical Research Council (United Kingdom) Traveling Fellowship and a Francis S. North Foundation Fellowship.

Research paper thumbnail of Generation of alloreactive cytotoxic T lymphocytes: production of T cell and macrophage helper factors in addition to IL 1 and IL 2 by peritoneal cells from mice immunized to Listeria monocytogenes

Journal of Immunology, Dec 1, 1981

Protein phosphorylation mediated by IL-2/IL-2 receptor beta-chain interaction.

Research paper thumbnail of Toxoplasma antigen isolated by affinity chromatography with monoclonal antibody protects mice against lethal infection with Toxoplasma gondii

Journal of Immunology, Dec 1, 1984

Bone marrow macrophages process exogenous Toxoplasma gondii polypeptides for recognition by paras... more Bone marrow macrophages process exogenous Toxoplasma gondii polypeptides for recognition by parasite-speci c cytolytic T lymphocytes.

Research paper thumbnail of Comparison of effects of anti-angiogenic agents in the zebrafish efficacy–toxicity model for translational anti-angiogenic drug discovery

Drug Design Development and Therapy, Aug 1, 2014

Background: Anti-angiogenic therapy in certain cancers has been associated with improved control ... more Background: Anti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy-toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery. Methods: The embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window. Results: In alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy-toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds. Conclusion: The zebrafish efficacy-toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.

Research paper thumbnail of In vivo recombinant interleukin 2 administration enhances survival against a lethal challenge with Toxoplasma gondii

Journal of Immunology, Dec 1, 1985

Human monoclonal anti-T cell antibody from a patient with juvenile rheumatoid arthritis.

Research paper thumbnail of Stimulation of T cells by antigenic peptide complexed with isolated chains of major histocompatibility complex class II molecules

Proceedings of the National Academy of Sciences of the United States of America, Feb 15, 1993

Major histocompatibility complex (MHC) class II molecules are heterodimeric glycoproteins with on... more Major histocompatibility complex (MHC) class II molecules are heterodimeric glycoproteins with one a and one ,B polypeptide chain of similar molecular size. In this report, we describe the binding of an acetylated N-terminal peptide of myelin basic protein, [AIa4JMBP-(1-14), to purified individual a and 13 chains of murine I-Ak molecules. Purified complexes of isolated single chains and antigenic peptide bind to cloned T cells restricted by I-Ak and [Ala4JMBP-(1-14)

Research paper thumbnail of Evaluation of antibacterial activity of silver nanoparticles synthesized by a novel strain of marine Pseudomonas sp

Nano Biomedicine and Engineering, 2012

Use of silver nanoparticles to manage pathogenic microorganisms is a modern trend in nanomedicine... more Use of silver nanoparticles to manage pathogenic microorganisms is a modern trend in nanomedicine. Thus our study focused on utilizing the nanoparticle synthesizing properties of marine bacteria. Molecular identification of the selected bacterial strain was done by 16SrDNA sequencing based method, which showed it as a novel Pseudomonas strain. The biosynthesis of silver nanoparticles was obtained by treating the bacteria with 1 mM AgNO 3 and the isolate was found to have the ability to form silver nanoparticles intracellularly within 24 hours at room temperature. The silver nanoparticles synthesized by the novel isolate were characterized by UV-Vis spectroscopy and scanning electron microscope. The UV-Vis absorption analysis showed a peak at 430 nm corresponding to the surface plasmon resonance of silver nanoparticles. Also these silver nanoparticles were evaluated for their antibacterial efficacy against Salmonella typhi, Vibrio cholerae, Bacillus subtilis and Staphylococcus aureus.

Research paper thumbnail of Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice

Infection and Immunity, Feb 1, 1981

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muram... more Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide afforded any resistance to infection with the obligate intracellular protozoan Toxoplasma gondii. Marked resistance to lethal challenge infection was observed in CBA but not C57BL/6 mice pretreated with muramyl dipeptide. In CBA mice, a single muramyl dipeptide treatment administered 14, 7, or 4 days before Toxoplasma challenge did not afford protection, whereas mice treated at-1 day were highly resistant. Additional studies carried out to investigate the mechanisms underlying the enhanced resistance to Toxoplasma in muramyl dipeptide-treated mice failed to reveal either enhanced cytolytic antibodies to the parasite or evidence that peritoneal macrophages from treated mice were activated as determined in vitro by their microbicidal capacity for Toxoplasma or cytotoxic capacity for tumor target cells.

Research paper thumbnail of Safety and Efficacy of Tinefcon (Sphaeranthus indicus) Cream in Treatment of Plaque Psoriasis - A Phase II B, Double Blind, Randomized, and Placebo Controlled Study

Journal of Dermatology and Venereology, 2016

Background: Sphaeranthus indicus is acknowledged for its immunomodulatory and anti-inflammatory a... more Background: Sphaeranthus indicus is acknowledged for its immunomodulatory and anti-inflammatory activities, and possess anti-TNF (tumour necrosis factors) activity. Objective: To evaluate the safety and efficacy of Tinefcon (Sphaeranthus indicus) cream in treatment of plaque psoriasis. Method: This was a phase-IIB, double-blind, randomized, and placebo controlled clinical trial. Total 86 patients diagnosed with stable plaque psoriasis were randomized (2:1 ratio) into two groups and studied for a period of 90 days. Medications were randomly assigned into 58 subjects from Tinefcon cream group and 28 subjects from placebo group. The efficacy parameters studied were mean percent change in local psoriasis severity index (LPSI) of a target lesion, dermatology quality of life index (DQLI), visual analogue scale (VAS), physicians' global assessment (PHGA), and patient's global assessment (PTGA). The cosmetic acceptance and safety profile of Tinefcon cream was also evaluated. Results...

Research paper thumbnail of Efficacy and Safety of Two Doses of Sphaeranthus i ndicus Extract in the Management of Plaque Psoriasis: A Randomized, Double Blind, Placebo Controlled Phase II Trial

Journal of Dermatology and Venereology, 2016

Background: Sphaeranthus indicus (S. indicus) is traditionally used in treatment of various disea... more Background: Sphaeranthus indicus (S. indicus) is traditionally used in treatment of various diseases; in vitro study showed that it inhibited release of inflammatory cytokines. Objectives: To evaluate the efficacy and safety of 12 weeks course of oral tablet of S. indicus extract (Tinefcon® ) in plaque psoriasis patients. Methods: A total of 74 patients with moderate to severe plaque psoriasis were randomized in (1:1:1) ratio to three arms placebo, S. indicus extract 1.4 g/day (low dose) and 2.8 g/day (high dose). Treatment was given for 12 weeks. Patients were evaluated for Psoriasis Area Severity Index score (PASI), Physician’s Global Assessment (PGA) along with histopathological analysis, gene expression profile and safety. Results: At week 12, 65% patients achieved PASI-50 and 40% patients achieved PASI-75 in high dose group also in same group PASI 90 was achieved by 15% patients. PASI-50 and PASI-75 response was achieved in 31% and 23% of patients respectively, in low dose grou...

Research paper thumbnail of Efficacy and safety of Glycebal (PDM011011) capsules as adjuvant therapy in subjects with type 2 diabetes mellitus: an open label, randomized, active controlled, phase II trial

Clinical Diabetology, Sep 7, 2016

Background. Momordica charantia is a medicinal plant used traditionally for treatment of various ... more Background. Momordica charantia is a medicinal plant used traditionally for treatment of various diseases including diabetes. Objective. To evaluate the efficacy and safety of PDM011011 capsules (1.2 g/day) as an adjuvant thera py in subjects with type 2 diabetes mellitus (T2DM). Methods. Each PDM011011 capsule contained 400 mg dry fruit juice powder of Momordica charantia. Ninety three T2DM patients receiving at least one oral hy poglycemic treatment were screened. The eligible 85 subjects were randomized into 3:1 ratio in drug treatment (PDM011011 capsules) and placebo arm. Sixtyfour patients received three 400 mg PDM011011 capsules (1.2 g/day) while 21 patients received three placebo capsules per day for 90 days respectively. The primary efficacy endpoints were mean change in FPG, PPG level and HbA 1c % from baseline to day 30, 60 and 90 after interventions. Results. PDM011011capsule (1.2 g/day) showed sig nificant reduction in FPG level by 14.59% after 90 days treatment, while patients receiving placebo capsules exhibited a marginal increase of 2.12%. The reduction in FPG level was statistically significant (p = 0.013) as compared with the placebo group. It also reduced PPG level by 22.21% as compared to the 3.71% reduction (p = 0.002) in placebo group. The encouraging reduc tion in HbA 1c % in the drug group was 0.78 as compared to the placebo group with only 0.20 (p = 0.066). PDM011011 capsule showed no adverse events, seri ous adverse events and death in the study population. Conclusion. PDM011011capsule (1.2 g/day) showed good efficacy and safety; and it can be prescribed as an adjuvant therapy in subjects with T2DM.

Research paper thumbnail of 7-HYDROXYFRULLANOLIDE, a Sesquiterpene Lactone, Inhibits Pro-Inflammatory Cytokine Production from Immune Cells and is Orally Efficacious in Animal Models of Inflammation

European Journal of Pharmacology, Oct 1, 2010

A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased ... more A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6). In this study, we investigated the anti-inflammatory potential of 7-hydroxyfrullanolide (7HF). 7HF is an orally bioavailable, small molecule sesquiterpene lactone isolated from the fruit of Sphaeranthus indicus. 7HF significantly and dose-dependently diminished induced and spontaneous production of TNF-alpha and IL-6 from freshly isolated human mononuclear cells, synovial tissue cells isolated from patients with active rheumatoid arthritis and BALB/c mice. Oral administration of 7HF significantly protected C57BL/6J mice against endotoxin-mediated lethality. In the dextran sulfate sodium (DSS) model of murine colitis, oral administration of 7HF prevented DSS-induced weight loss, attenuated rectal bleeding, improved disease activity index and diminished shortening of the colon of C57BL/6J mice. Histological analyses of colonic tissues revealed that 7HF attenuated DSS-induced colonic edema, leukocyte infiltration in the colonic mucosa and afforded significant protection against DSS-induced crypt damage. 7HF was also significantly efficacious in attenuating carrageenan-induced paw edema in Wistar rats after oral administration. In the collagen-induced arthritis in DBA/1J mice, 7HF significantly reduced disease associated increases in articular index and paw thickness, protected against bone erosion and joint space narrowing and prominently diminished joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide evidence that 7HF-mediated inhibition of pro-inflammatory cytokines functionally results in marked protection in experimental models of acute and chronic inflammation.

Research paper thumbnail of In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Molecular Cancer Therapeutics, 2007

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractiv... more Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC50 below 250 nmol/L. In this report, we have described the properties of one of the best compound, P276-00 of the flavone's series. P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E. The specificity toward 14 other related and unrelated kinases was also determined. P276-00 was found to be more selective with IC50s <100 nmol/L for C...

Research paper thumbnail of P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models

Molecular Cancer Therapeutics, 2007

P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as ... more P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as a novel antineoplastic agent. In this study, we have selected a panel of human tumor cell lines and xenografts to allow determination of selectivity and efficacy of P276-00. When tested against a panel of 16 cisplatin-sensitive and cisplatin-resistant cell lines, the antiproliferative potential of P276-00 was found to be ∼30-fold higher than cisplatin. Studies to show tumor sensitivity using clonogenic assay in 22 human xenografts indicated that P276-00 was ∼26-fold more potent than cisplatin, and further, it was also found to be active against cisplatin-resistant tumors of central nervous system, melanoma, prostate, and renal cancers. Further, we studied the effects of P276-00 on cell cycle progression by flow cytometry using asynchronous and synchronous population of tumor and normal cells. Asynchronous population of human prostate carcinoma (PC-3) and human promyelocytic leukemia (HL-...

Research paper thumbnail of Efficacy and Safety of PDM011011 Capsules as Compared to Metformin in Subjects with Type-2 Diabetes Mellitus: An Open-Label, Randomized, Active-Controlled, Multicentric, Phase III Study

Journal of Diabetes Mellitus, 2016

Context: Bitter melon (Momoradica charantia) is one of the well-known plants used for lowering bl... more Context: Bitter melon (Momoradica charantia) is one of the well-known plants used for lowering blood glucose since antiquity. Aims: To compare the efficacy and safety of PDM011011 capsule (1200 mg/day) with Metformin (1000 mg/day) in a 15 weeks study using mean change in fasting plasma glucose (FPG) and Hb1Ac% in subjects with type 2 diabetes mellitus (T2DM). Settings and

Research paper thumbnail of Efficacy and Safety of Tinefcon<sup>&reg</sup> Tablets in Subjects with Plaque Psoriasis: An Open Label, Non-Comparative, Multicenter, Phase IV Trial

Journal of Cosmetics, Dermatological Sciences and Applications, 2016

Importance: This post-marketing surveillance study was conducted to evaluate real-world informati... more Importance: This post-marketing surveillance study was conducted to evaluate real-world information about the efficacy and safety of oral Tinefcon ® tablets (Sphaeranthus indicus based) in plaque psoriasis patients. Materials and Methods: Patients aged at least 18 years and older with clinical diagnosis of plaque psoriasis, were enrolled in this open label, non-comparative, multicenter trial. All eligible subjects received four 700 mg Tinefcon ® tablets/day for 12 weeks. The primary outcome measure was percent change in Psoriasis Area Severity Index (PASI) score from baseline to week 12. The secondary outcome measures were Physician Global Assessment (PGA), Nail Psoriasis Severity Index (NAPSI), Psoriatic Arthritis Evaluation and Gene Expression Profiling and Immunohistochemistry. Results: After completion of Tinefcon ® treatment at 12 weeks, more than half of subjects (52%) achieved PASI 50 response; PASI 75 response was attained in 68 (23%) subjects and PASI 90 response in 22 (7%) subjects. Five subjects with severe psoriasis achieved PASI 90 without receiving any concomitant medication. Reduction in severity as assessed by PGA was observed in more than half of patients with moderate disease. Histopathological evaluation revealed that epidermal thickness was considerably reduced in 66% of subjects. The expression of inflammatory marker S100A9 protein was meaningfully reduced in 60% patients with non-significant reduction of Keratin 10 protein expression. Gene expression analysis showed increase down regulation of SERPINB4; PI3 and KRT16 genes after a 12-week treatment period in subjects with higher PASI scores. Conclusion: Oral Tinefcon ® tablets showed good efficacy and had a favorable safety profile in plaque psoriasis patients.

Research paper thumbnail of Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat

Inflammopharmacology, 2010

The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(... more The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(2,6dichlorophenylamino)phenyl)acetate)], a novel NO (nitric oxide) donor prodrug of diclofenac for its ability to release NO and diclofenac, and whether P2026 provides advantage of improved activity/gastric tolerability over diclofenac. Oral bioavailability of P2026 was estimated from plasma concentration of diclofenac and nitrate/nitrite (NOx). Antiinflammatory activity was evaluated in three different models of inflammation: acute (carrageenan-induced paw oedema), chronic (adjuvant-induced arthritis), and systemic (lipopolysaccharide-induced endotoxic shock). Gastric tolerability was evaluated from compound's propensity to cause gastric ulcers. P2026 exhibited dose-dependent diclofenac and NOx release. Similar to diclofenac, P2026 showed potent anti-inflammatory activity in acute and chronic model, whereas it improved activity in systemic model. Both diclofenac and P2026 inhibited gastric prostaglandin, but only diclofenac produced dose-dependent haemorrhagic ulcers. Thus, the results suggest that coupling of NO and diclofenac contribute to improved gastric tolerability while retaining the anti-inflammatory properties of diclofenac.

Research paper thumbnail of A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes

Nutrition & Metabolism, Jun 5, 2015

A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytok... more A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytokines and growth factors play a major role in disease progression. The methanolic extracts of Sphaeranthus indicus as well as its active ingredient, 7-hydroxy frullanoide (7-HF), are shown to suppress LPS-induced cytokine production from mononuclear cells, and inhibit the expression of VCAM1, ICAM1 and E-selectin by TNF-α-stimulated HUVECs in a concentration-dependent manner. We tested the hypothesis that the inhibition of cytokines and adhesion molecules should attenuate the progression of atherosclerosis, independent of changes in the lipid profile. Studies were carried out in two animal models: a high fat-fed LDLr-/mouse and a high fat-fed hyperlipidemic hamster. Methanolic extract of S. indicus was dosed to hyperlipidemic LDLr-/at 100 and 300 mg (equivalent to 20 and 60 mg 7-HF)/kg body weight/ day for 8 weeks, and plasma lipids as well as aortic lesion area were quantitated. Hyperlipidemic hamsters were treated with one dose of 200 mg/kg/day. S. indicus extract treatment did not alter the lipid profile in both animal models, but reduced aortic lesion area in LDLr-/mice and hyperlipidemic hamsters by 22 % and 45 %, respectively. Fenofibrate, included as a reference agent, decreased aortic lesions by 26 % in LDLr-/mice and 84 % in hyperlipidemic hamsters, respectively, which was driven by massive reductions in proatherogenic lipoproteins. The lipid-independent anti-atherosclerotic activity of S. indicus was associated with the reductions in the circulating levels of MCP-1, TNF-α, and IL-6 via phosphorylation and degradation of IkB-α that prevents translocation of NF-kB in the nucleus to induce proinflammatory cytokines. Our findings demonstrate that anti-inflammatory agents that lower pro-inflammatory proteins inhibit the progression of atherosclerosis. The methanolic extract of S. inducus, currently being used to treat psoriasis, offer promise to benefit individuals who have high circulating pro-inflammatory cytokines, and predisposed to coronary artery disease.

Research paper thumbnail of Binding of Aminoacyl-tRNA to Bacterial Ribosomes

Research paper thumbnail of Protective immunity in toxoplasmosis: correlation between antibody response, brain cyst formation, T-cell activation, and survival in normal and B-cell-deficient mice bearing the H-2k haplotype

Infection and Immunity, Apr 1, 1987

Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-spe... more Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-specific T-cell activation, and the number of brain cysts were compared in immunocompetent CBA/J (H-2^), C3H/He (H-2^), and BWcell-deficient CBA/N (H-2k) mice. Almost all of the C3H/He mice (94%) survived in comparison to CBA/J (71%) and CBA/N (53%) mice following infection with 20 cysts of Me 49, an avirulent strain of T. gondii. The mortality in susceptible mice was reduced by treatment of the animals with sulfadiazine during the acute stage of infection. Decreased mortality in CBA/J and C3H/He mice as well as in B-cell-deficient mice was paralleled by formation of fewer brain cysts. The Toxoplasma-specific T-cell proliferation was markedly enhanced in all three strains at day 15 postinfection but not at day 45 postinfection when compared to animals not treated with the drug. In contrast, Toxoplasma-specific IgM and IgG levels were lower in CBA/J and CBA/N mice treated with sulfadiazine than in untreated mice of these strains. Although CBA/N mice developed almost no humoral response either with or without drug treatment, they produced fewer brain cysts than normal CBA/J mice. The results indicate a major role of cell-mediated immunity in protection against an acute Toxoplasma infection.

Research paper thumbnail of Oxygen-independent killing by alveolar macrophages

Journal of Experimental Medicine, May 1, 1986

Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Th... more Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Their clinical importance is emphasized by the high incidence of life-threatening pneumonia (7, 8) in patients with abnormal macrophage function (6) or impaired ceU-mediated immunity (6-9). However, the mechanisms by which alveolar macrophages kill microorganisms are poorly understood. We recently examined the mechanism by which human alveolar macrophages kill the intracellular parasite, Toxoplasma gondii (10). We chose this organism because it causes pneumonia in immunosuppressed patients (11-14) but not in healthy individuals (11), and because macrophages play an important part in the host's resistance to this organism (5, 15-17). Our studies showed that killing of T. gondii by human alveolar macrophages occurred without involvement of toxic metabolites of oxygen (Catterall, J. R., and J. S. Remington, manuscript in preparation). This suggested that previous studies of intracellular killing by normal macrophages might have limitations as models for the human alveolar macrophage, since most of them (18-20, and reviewed in 21), including all those that employed T. gondii (18-23), have emphasized the overriding importance of oxidative killing mechanisms. Nonoxidative antimicrobial activity has been shown in subcellular macrophage fragments (21, 24) and in oxidatively deficient cells (19, 21-23, 25), but in none of the previously described models using normal intact macrophages has the killing of intracellular parasites been reported as nonoxidative. To facilitate the study of nonoxidative killing by alveolar macrophages, we have sought a laboratory animal model relevant to the human alveolar macrophage. Since rats more closely resemble human subjects in their resistance to T. gondii than many other animals (26, 27), we have examined the interaction between T. gondii and rat alveolar macrophages in vitro. The studies reported here indicate that rat alveolar macrophages, like those from human subjects, also kill T. gondii, and by nonoxidative mechanisms. They suggest that nonoxidative antimicrobial mechanisms may be important in alveolar macrophages, and they provide a convenient model for the study of such mechanisms. This investigation received financial support from grant AI-04717 from the National Institutes of Health. J. R. Catterall is the recipient of a Medical Research Council (United Kingdom) Traveling Fellowship and a Francis S. North Foundation Fellowship.

Research paper thumbnail of Generation of alloreactive cytotoxic T lymphocytes: production of T cell and macrophage helper factors in addition to IL 1 and IL 2 by peritoneal cells from mice immunized to Listeria monocytogenes

Journal of Immunology, Dec 1, 1981

Protein phosphorylation mediated by IL-2/IL-2 receptor beta-chain interaction.

Research paper thumbnail of Toxoplasma antigen isolated by affinity chromatography with monoclonal antibody protects mice against lethal infection with Toxoplasma gondii

Journal of Immunology, Dec 1, 1984

Bone marrow macrophages process exogenous Toxoplasma gondii polypeptides for recognition by paras... more Bone marrow macrophages process exogenous Toxoplasma gondii polypeptides for recognition by parasite-speci c cytolytic T lymphocytes.

Research paper thumbnail of Comparison of effects of anti-angiogenic agents in the zebrafish efficacy&ndash;toxicity model for translational anti-angiogenic drug discovery

Drug Design Development and Therapy, Aug 1, 2014

Background: Anti-angiogenic therapy in certain cancers has been associated with improved control ... more Background: Anti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy-toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery. Methods: The embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window. Results: In alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy-toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds. Conclusion: The zebrafish efficacy-toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.

Research paper thumbnail of In vivo recombinant interleukin 2 administration enhances survival against a lethal challenge with Toxoplasma gondii

Journal of Immunology, Dec 1, 1985

Human monoclonal anti-T cell antibody from a patient with juvenile rheumatoid arthritis.

Research paper thumbnail of Stimulation of T cells by antigenic peptide complexed with isolated chains of major histocompatibility complex class II molecules

Proceedings of the National Academy of Sciences of the United States of America, Feb 15, 1993

Major histocompatibility complex (MHC) class II molecules are heterodimeric glycoproteins with on... more Major histocompatibility complex (MHC) class II molecules are heterodimeric glycoproteins with one a and one ,B polypeptide chain of similar molecular size. In this report, we describe the binding of an acetylated N-terminal peptide of myelin basic protein, [AIa4JMBP-(1-14), to purified individual a and 13 chains of murine I-Ak molecules. Purified complexes of isolated single chains and antigenic peptide bind to cloned T cells restricted by I-Ak and [Ala4JMBP-(1-14)

Research paper thumbnail of Evaluation of antibacterial activity of silver nanoparticles synthesized by a novel strain of marine Pseudomonas sp

Nano Biomedicine and Engineering, 2012

Use of silver nanoparticles to manage pathogenic microorganisms is a modern trend in nanomedicine... more Use of silver nanoparticles to manage pathogenic microorganisms is a modern trend in nanomedicine. Thus our study focused on utilizing the nanoparticle synthesizing properties of marine bacteria. Molecular identification of the selected bacterial strain was done by 16SrDNA sequencing based method, which showed it as a novel Pseudomonas strain. The biosynthesis of silver nanoparticles was obtained by treating the bacteria with 1 mM AgNO 3 and the isolate was found to have the ability to form silver nanoparticles intracellularly within 24 hours at room temperature. The silver nanoparticles synthesized by the novel isolate were characterized by UV-Vis spectroscopy and scanning electron microscope. The UV-Vis absorption analysis showed a peak at 430 nm corresponding to the surface plasmon resonance of silver nanoparticles. Also these silver nanoparticles were evaluated for their antibacterial efficacy against Salmonella typhi, Vibrio cholerae, Bacillus subtilis and Staphylococcus aureus.

Research paper thumbnail of Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice

Infection and Immunity, Feb 1, 1981

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muram... more Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide afforded any resistance to infection with the obligate intracellular protozoan Toxoplasma gondii. Marked resistance to lethal challenge infection was observed in CBA but not C57BL/6 mice pretreated with muramyl dipeptide. In CBA mice, a single muramyl dipeptide treatment administered 14, 7, or 4 days before Toxoplasma challenge did not afford protection, whereas mice treated at-1 day were highly resistant. Additional studies carried out to investigate the mechanisms underlying the enhanced resistance to Toxoplasma in muramyl dipeptide-treated mice failed to reveal either enhanced cytolytic antibodies to the parasite or evidence that peritoneal macrophages from treated mice were activated as determined in vitro by their microbicidal capacity for Toxoplasma or cytotoxic capacity for tumor target cells.

Research paper thumbnail of Safety and Efficacy of Tinefcon (Sphaeranthus indicus) Cream in Treatment of Plaque Psoriasis - A Phase II B, Double Blind, Randomized, and Placebo Controlled Study

Journal of Dermatology and Venereology, 2016

Background: Sphaeranthus indicus is acknowledged for its immunomodulatory and anti-inflammatory a... more Background: Sphaeranthus indicus is acknowledged for its immunomodulatory and anti-inflammatory activities, and possess anti-TNF (tumour necrosis factors) activity. Objective: To evaluate the safety and efficacy of Tinefcon (Sphaeranthus indicus) cream in treatment of plaque psoriasis. Method: This was a phase-IIB, double-blind, randomized, and placebo controlled clinical trial. Total 86 patients diagnosed with stable plaque psoriasis were randomized (2:1 ratio) into two groups and studied for a period of 90 days. Medications were randomly assigned into 58 subjects from Tinefcon cream group and 28 subjects from placebo group. The efficacy parameters studied were mean percent change in local psoriasis severity index (LPSI) of a target lesion, dermatology quality of life index (DQLI), visual analogue scale (VAS), physicians' global assessment (PHGA), and patient's global assessment (PTGA). The cosmetic acceptance and safety profile of Tinefcon cream was also evaluated. Results...

Research paper thumbnail of Efficacy and Safety of Two Doses of Sphaeranthus i ndicus Extract in the Management of Plaque Psoriasis: A Randomized, Double Blind, Placebo Controlled Phase II Trial

Journal of Dermatology and Venereology, 2016

Background: Sphaeranthus indicus (S. indicus) is traditionally used in treatment of various disea... more Background: Sphaeranthus indicus (S. indicus) is traditionally used in treatment of various diseases; in vitro study showed that it inhibited release of inflammatory cytokines. Objectives: To evaluate the efficacy and safety of 12 weeks course of oral tablet of S. indicus extract (Tinefcon® ) in plaque psoriasis patients. Methods: A total of 74 patients with moderate to severe plaque psoriasis were randomized in (1:1:1) ratio to three arms placebo, S. indicus extract 1.4 g/day (low dose) and 2.8 g/day (high dose). Treatment was given for 12 weeks. Patients were evaluated for Psoriasis Area Severity Index score (PASI), Physician’s Global Assessment (PGA) along with histopathological analysis, gene expression profile and safety. Results: At week 12, 65% patients achieved PASI-50 and 40% patients achieved PASI-75 in high dose group also in same group PASI 90 was achieved by 15% patients. PASI-50 and PASI-75 response was achieved in 31% and 23% of patients respectively, in low dose grou...

Research paper thumbnail of Efficacy and safety of Glycebal (PDM011011) capsules as adjuvant therapy in subjects with type 2 diabetes mellitus: an open label, randomized, active controlled, phase II trial

Clinical Diabetology, Sep 7, 2016

Background. Momordica charantia is a medicinal plant used traditionally for treatment of various ... more Background. Momordica charantia is a medicinal plant used traditionally for treatment of various diseases including diabetes. Objective. To evaluate the efficacy and safety of PDM011011 capsules (1.2 g/day) as an adjuvant thera py in subjects with type 2 diabetes mellitus (T2DM). Methods. Each PDM011011 capsule contained 400 mg dry fruit juice powder of Momordica charantia. Ninety three T2DM patients receiving at least one oral hy poglycemic treatment were screened. The eligible 85 subjects were randomized into 3:1 ratio in drug treatment (PDM011011 capsules) and placebo arm. Sixtyfour patients received three 400 mg PDM011011 capsules (1.2 g/day) while 21 patients received three placebo capsules per day for 90 days respectively. The primary efficacy endpoints were mean change in FPG, PPG level and HbA 1c % from baseline to day 30, 60 and 90 after interventions. Results. PDM011011capsule (1.2 g/day) showed sig nificant reduction in FPG level by 14.59% after 90 days treatment, while patients receiving placebo capsules exhibited a marginal increase of 2.12%. The reduction in FPG level was statistically significant (p = 0.013) as compared with the placebo group. It also reduced PPG level by 22.21% as compared to the 3.71% reduction (p = 0.002) in placebo group. The encouraging reduc tion in HbA 1c % in the drug group was 0.78 as compared to the placebo group with only 0.20 (p = 0.066). PDM011011 capsule showed no adverse events, seri ous adverse events and death in the study population. Conclusion. PDM011011capsule (1.2 g/day) showed good efficacy and safety; and it can be prescribed as an adjuvant therapy in subjects with T2DM.

Research paper thumbnail of 7-HYDROXYFRULLANOLIDE, a Sesquiterpene Lactone, Inhibits Pro-Inflammatory Cytokine Production from Immune Cells and is Orally Efficacious in Animal Models of Inflammation

European Journal of Pharmacology, Oct 1, 2010

A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased ... more A promising therapeutic approach to reduce pathological inflammation is to inhibit the increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6). In this study, we investigated the anti-inflammatory potential of 7-hydroxyfrullanolide (7HF). 7HF is an orally bioavailable, small molecule sesquiterpene lactone isolated from the fruit of Sphaeranthus indicus. 7HF significantly and dose-dependently diminished induced and spontaneous production of TNF-alpha and IL-6 from freshly isolated human mononuclear cells, synovial tissue cells isolated from patients with active rheumatoid arthritis and BALB/c mice. Oral administration of 7HF significantly protected C57BL/6J mice against endotoxin-mediated lethality. In the dextran sulfate sodium (DSS) model of murine colitis, oral administration of 7HF prevented DSS-induced weight loss, attenuated rectal bleeding, improved disease activity index and diminished shortening of the colon of C57BL/6J mice. Histological analyses of colonic tissues revealed that 7HF attenuated DSS-induced colonic edema, leukocyte infiltration in the colonic mucosa and afforded significant protection against DSS-induced crypt damage. 7HF was also significantly efficacious in attenuating carrageenan-induced paw edema in Wistar rats after oral administration. In the collagen-induced arthritis in DBA/1J mice, 7HF significantly reduced disease associated increases in articular index and paw thickness, protected against bone erosion and joint space narrowing and prominently diminished joint destruction, hyperproliferative pannus formation and infiltration of inflammatory cells. Collectively, these results provide evidence that 7HF-mediated inhibition of pro-inflammatory cytokines functionally results in marked protection in experimental models of acute and chronic inflammation.

Research paper thumbnail of In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Molecular Cancer Therapeutics, 2007

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractiv... more Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC50 below 250 nmol/L. In this report, we have described the properties of one of the best compound, P276-00 of the flavone's series. P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E. The specificity toward 14 other related and unrelated kinases was also determined. P276-00 was found to be more selective with IC50s <100 nmol/L for C...

Research paper thumbnail of P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models

Molecular Cancer Therapeutics, 2007

P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as ... more P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as a novel antineoplastic agent. In this study, we have selected a panel of human tumor cell lines and xenografts to allow determination of selectivity and efficacy of P276-00. When tested against a panel of 16 cisplatin-sensitive and cisplatin-resistant cell lines, the antiproliferative potential of P276-00 was found to be ∼30-fold higher than cisplatin. Studies to show tumor sensitivity using clonogenic assay in 22 human xenografts indicated that P276-00 was ∼26-fold more potent than cisplatin, and further, it was also found to be active against cisplatin-resistant tumors of central nervous system, melanoma, prostate, and renal cancers. Further, we studied the effects of P276-00 on cell cycle progression by flow cytometry using asynchronous and synchronous population of tumor and normal cells. Asynchronous population of human prostate carcinoma (PC-3) and human promyelocytic leukemia (HL-...

Research paper thumbnail of Efficacy and Safety of PDM011011 Capsules as Compared to Metformin in Subjects with Type-2 Diabetes Mellitus: An Open-Label, Randomized, Active-Controlled, Multicentric, Phase III Study

Journal of Diabetes Mellitus, 2016

Context: Bitter melon (Momoradica charantia) is one of the well-known plants used for lowering bl... more Context: Bitter melon (Momoradica charantia) is one of the well-known plants used for lowering blood glucose since antiquity. Aims: To compare the efficacy and safety of PDM011011 capsule (1200 mg/day) with Metformin (1000 mg/day) in a 15 weeks study using mean change in fasting plasma glucose (FPG) and Hb1Ac% in subjects with type 2 diabetes mellitus (T2DM). Settings and

Research paper thumbnail of Efficacy and Safety of Tinefcon<sup>&reg</sup> Tablets in Subjects with Plaque Psoriasis: An Open Label, Non-Comparative, Multicenter, Phase IV Trial

Journal of Cosmetics, Dermatological Sciences and Applications, 2016

Importance: This post-marketing surveillance study was conducted to evaluate real-world informati... more Importance: This post-marketing surveillance study was conducted to evaluate real-world information about the efficacy and safety of oral Tinefcon ® tablets (Sphaeranthus indicus based) in plaque psoriasis patients. Materials and Methods: Patients aged at least 18 years and older with clinical diagnosis of plaque psoriasis, were enrolled in this open label, non-comparative, multicenter trial. All eligible subjects received four 700 mg Tinefcon ® tablets/day for 12 weeks. The primary outcome measure was percent change in Psoriasis Area Severity Index (PASI) score from baseline to week 12. The secondary outcome measures were Physician Global Assessment (PGA), Nail Psoriasis Severity Index (NAPSI), Psoriatic Arthritis Evaluation and Gene Expression Profiling and Immunohistochemistry. Results: After completion of Tinefcon ® treatment at 12 weeks, more than half of subjects (52%) achieved PASI 50 response; PASI 75 response was attained in 68 (23%) subjects and PASI 90 response in 22 (7%) subjects. Five subjects with severe psoriasis achieved PASI 90 without receiving any concomitant medication. Reduction in severity as assessed by PGA was observed in more than half of patients with moderate disease. Histopathological evaluation revealed that epidermal thickness was considerably reduced in 66% of subjects. The expression of inflammatory marker S100A9 protein was meaningfully reduced in 60% patients with non-significant reduction of Keratin 10 protein expression. Gene expression analysis showed increase down regulation of SERPINB4; PI3 and KRT16 genes after a 12-week treatment period in subjects with higher PASI scores. Conclusion: Oral Tinefcon ® tablets showed good efficacy and had a favorable safety profile in plaque psoriasis patients.

Research paper thumbnail of Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat

Inflammopharmacology, 2010

The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(... more The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(2,6dichlorophenylamino)phenyl)acetate)], a novel NO (nitric oxide) donor prodrug of diclofenac for its ability to release NO and diclofenac, and whether P2026 provides advantage of improved activity/gastric tolerability over diclofenac. Oral bioavailability of P2026 was estimated from plasma concentration of diclofenac and nitrate/nitrite (NOx). Antiinflammatory activity was evaluated in three different models of inflammation: acute (carrageenan-induced paw oedema), chronic (adjuvant-induced arthritis), and systemic (lipopolysaccharide-induced endotoxic shock). Gastric tolerability was evaluated from compound's propensity to cause gastric ulcers. P2026 exhibited dose-dependent diclofenac and NOx release. Similar to diclofenac, P2026 showed potent anti-inflammatory activity in acute and chronic model, whereas it improved activity in systemic model. Both diclofenac and P2026 inhibited gastric prostaglandin, but only diclofenac produced dose-dependent haemorrhagic ulcers. Thus, the results suggest that coupling of NO and diclofenac contribute to improved gastric tolerability while retaining the anti-inflammatory properties of diclofenac.