Induced Rat Paw Edema Model Research Articles

Quality by design-based optimization of teriflunomide and quercetin combinational topical transferosomes for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease. Combination therapy is anticipated to surpass monotherapy by targeting multiple pathways involved in RA progression. The present aim is to develop a combination of Teriflunomide (TFD) and Quercetin (QCN) loaded transferosomal gel to enhance permeability and achieve localized delivery to joint tissues. TFD or QCN transferosomes were optimized employing a 3-level, 3-factorial design Box-Behnken design (BBD). The transferosomes exhibited sustained in-vitro drug release. The topical combination gel underwent thorough evaluation of rheology, and also ex-vivo studies showed enhanced permeability through rat skin. The synergistic combination of TFD and QCN effectively suppressed NO, TNF-α and IL-6 levels in in-vitro RAW 264.7 cells. The cytotoxicity in HaCaT cell lines indicates non-toxicity of the gel, further confirmed by skin irritation study conducted in rats. The in-vivo anti-arthritic activity was evaluated in complete freund’s adjuvant induced rat paw edema model illustrates the effectiveness of the combination transferosomal gel compared to other treatment groups. In conclusion, the topical delivery of TFD and QCN combination transferosomal gel demonstrated anti-arthritic activity through localized delivery whichallows for dose reduction, thereby may reduce the systemic drug exposure and mitigate the side effects associated with oral administration of TFD.

Design, synthesis of new 2,4-thiazolidinediones: In-silico, in-vivo anti-diabetic and anti-inflammatory evaluation

In this study, a series of nine novel heterocyclic compounds were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione or rhodanine ring-system. Comprehensive physicochemical and spectral analyses, including FTIR, Mass, 1H NMR and 13C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their potential in various therapeutic domains. In-vivo anti-diabetic activity was assessed diabetes induced wistar rats, anti-inflammatory effects were gauged using the carrageenan and formalin induced rat paw edema model. Additionally, the in-vitro PPAR-γ modulatory activity, glucose uptake by using Saccharomyces cerevisiae and rat hemidiaphragm and cyclooxygenase inhibitory activity along with scavenge free radicals was tested by FRAP and DPPH method. According to the potential binding patterns of the most potent anti-diabetic compounds, namely 7a and 13a with the active sites of target PPAR-γ (PDB ID: 5U5L), was obtained through molecular docking using Schrodinger’s Glide model. Among the tested compounds, the compound 13a demonstrated significant antidiabetic activity with reduction in blood glucose levels (108.5 ± 2.171 mg/dL), comparable to the effect of pioglitazone (101.66 ± 0.95 mg/dL), similarly anti-inflammatory activity at fourth hour paw volume 93.6% and thickness at 3.99 ± 0.076 mm, respectively closer to that of standard drug diclofenac sodium (91.2% and 4.7 ± 0.057 mm) in carrageenan-induced paw edema in rat. The compound 13a displayed promising COX-2 inhibitory activity (IC50 = 7.82 μM) and DPPH antioxidant activity showcasing its multifaceted therapeutic potential. This study not only presents multi-targeting approach and highlights the significant potential compounds as a lead molecule for further therapeutic development.

Formulation and Evaluation of Diclofenac Sodium as a Topical Preparation

The aim of this study was to evaluate and compare the in vitro and in vivo transdermal potential ofw/o microemulsion (M) and gel (G) bases for diclofenac sodium (DS). The effect of dimethylsulfoxide (DMSO) as a penetration enhancer was also examined when it was added to the Mformulation. To study the in vitro potential of these formulations, permeation studies wereperformed with Franz diffusion cells using excised dorsal rat skin. To investigate their in vivoperfoniranc e, a car-rageenan - induced rat paw edema model was used. The commercial formulationof DS (C) was used as a reference formulation. The results of the in vitro permeation studies andthe paw edema tests were analyzed by repeated - measures analysis of variance. The in vitropermeation studies found that M was superior to G and C and that adding DMSO to M increasedpermeation rate. The permeability coefficient (Kp) of DS from M and M + DMSO were higher(Kp :4.9 X 10 -3 +3.6 X l0 -4 cm lhand 5.3 X 10 -3 + l.2X 10 -3 cm / h, respectively) than the($p) of nS from C (Kp: 2.7 xl0-3 +7.3 X 10 -4 cm /h) and G (Kp:4.5 X i0 -3 x+.s X 10 -scm / h). In the paw edema test, M showed the best permeation and effectiveness, and M + DMSOhad nearly the same effect as M. The in vitro and in vivo studies showed that M could be a new,altemative dosage form for effective therapy.

Cubosomes for Enhancing Intestinal Absorption of Fexofenadine Hydrochloride: In situ and in vivo Investigation.

PurposeThe aim of this work was to probe cubosomes for enhanced intestinal absorption and oral bioavailability of poorly absorbable fexofenadine HCl (FEX-HCl).Materials and MethodsTwo cubosomal systems were fabricated utilizing glyceryl mono-oleate, a lyotropic mono lamellar lipid as oil phase and poloxamer407 as stabilizer at weight ratios of 8:2 and 7:3. The morphology of cubosomes was researched using transmission electron microscopy (TEM) and particle size was measured using photon correlation spectroscopy. FEX-HCl release was monitored in vitro. The effect of cubosomal encapsulation on intestinal absorption was assessed using in situ rabbit intestinal perfusion technique. Carrageenan induced rat paw edema model was utilized to monitor in vivo anti-inflammatory effect before and after cubosomal encapsulation.ResultsTEM revealed the existence of spherical and polygonal nanostructures arranged in honeycomb organization. Size measurement reflected nanoparticles with reduced size at higher poloxamer concentration. Release studies revealed liberation of FEX-HCl from cubosomes based on Higuchi kinetics model. The intestinal permeability data indicated incomplete absorption of FEX-HCl from simple aqueous solution with P-glycoprotein efflux contributing to this poor intestinal absorption. Incorporation of FEX-HCl in cubosomes enhanced membrane transport parameters. The intestinal absorption did not correlate with drug release suggesting that drug release is not the rate limiting with possible intact cubosomal transport. Cubosomal encapsulation of FEX-HCl significantly enhanced its in vivo anti-inflammatory efficacy compared to the aqueous FEX-HCl dispersion.ConclusionCubosomes are promising novel carriers for enhancing intestinal absorption of FEX-HCl. Intact FEX-HCl-cubosomal absorption is possible via trans-lymphatic pathway but this requires further investigations.

EVALUATION OF ANTI-INFLAMMATORY (IN VIVO) ACTIVITY OF ARIFLEX LINIMENT IN COMPARISON WITH DICLOFENAC GEL IN CARRAGEENAN INDUCED RAT PAW EDEMA MODEL

Objective: The present study was conducted to evaluate anti-inflammatory activity of Ariflex liniment (conceptualized and developed by Ari Healthcare Pvt. Ltd) in comparison with Diclofenac gel in carrageenan induced rat paw edema model.
 Methods: Wistar rats of either sex weighing 150-180 g were taken and divided into 3 groups with 6 animals in each group i.e. Group 1 (Controlled Group), Group 2 (Diclofenac gel) and Group 3 (Ariflex liniment). The study drugs were topically applied 30 min prior to carrageenan injection. After 30 min 1% w/v of 0.05 ml carrageenan was injected subcutaneously in the paw. The paw was marked with ink at the level of lateral malleolus and immersed in mercury up to the lateral malleolus mark. The paw volume was measured plethysmographically, immediately after injection i.e. on 0 min, and then on 30 min,1h, 2h,3h, 4h and 5hr after injection.
 Results: Diclofenac gel sodium treated group showed significant inhibition (p<0.01) of paw edema at 30 min, 1, 2, 3, 4 and 5th hrs as compared to control group. Ariflex Liniment showed significant inhibition (p<0.05) of paw edema at 30 min, 1, 2, 3, and 4th hrs as compared to the control group. Group treated with Ariflex Liniment did not show any significant decrease in paw edema volume at 5th hrs when compared to the control group.
 Conclusion: Ariflex Liniment possesses anti-inflammatory activity.

Formulation and preclinical evaluation of Anti-inflammatory activity of Triticum aestivum

A wide scope of medical advantages has been credited to wheatgrass, the young grass of the wheat plant Tritium aestivum. Wheat grass is a decent wellspring of mineral supplements. It contains critical measures of iron, phosphorous, magnesium, manganese, copper and zinc. Wheatgrass is a rich supplement of tocopherols with high vitamin E content. Wheatgrass is beneficial in restoring more infections due to its significant function that, it can arrest the development of antagonistic microbes which are responsible for spreading certain diseases. constituents of wheatgrass may be obtained from fresh juice, frozen juice, powder, tablets with compositions differing as per their production methods which otherwise depends on growing conditions of wheatgrass. Anti-inflammatory activity of wheatgrass tablets was assessed by using formalin induced rat paw edema model. The results obtained were compared with aceclofenac, standard drug.
 Keywords: Triticum aestivum, Flaxseed gel, Anti-inflammatory, Aceclofenac, Formalin.

<p><strong>Carbohydrate fraction of <em>Aloe vera </em>ameliorates inflammation through suppression of pro-inflammatory mediators and oxidative stress <em>in vitro</em> and rats with Freund’s adjuvant induced paw edema</strong></p>

Aloe vera (L.) Burm. F (Asphodelaceae) is a traditional medicinal plant having multiple biological activities such as wound healing, anticancer and antidiabetic activity, etc. These properties have been attributed to the constituents present in Aloe vera. One of the major constituents is carbohydrate, which has not been explored much for its antioxidant and anti-inflammatory activity. Here, we evaluated the antioxidant and anti-inflammatory potential of carbohydrate fraction (CF) of Aloe vera extract using in vitro and in vivo model for its therapeutic application in the treatment of inflammation. CF extract was prepared using hot water extraction followed by ethanolic precipitation. The CF extract was tested for free radical scavenging assays, lipopolysaccharide-stimulated RAW264.7 cells in vitro and in vivo by Freund’s adjuvant induced rat paw edema model. The free radical scavenging activity of CF extract significantly increased in a concentration-dependent manner with maximum inhibition observed at the concentration of 2 mg/mL. CF extract (20 and 60 µg/mL) showed their maximum cell viability in RAW264.7 cells by MTT assay. CF extract shows a considerable decrease of inflammatory mediators in both in vitro and as well as in vivo studies. The increase of superoxide dismutase and catalase levels in CF treated adjuvant induced rats decreases ROS/RNS levels and inflammatory mediators. It may be primarily activated by NF-κB and AP-1 indicating its potent antioxidant activity that promotes modulation in cellular redox state. The results suggest that carbohydrate fraction of Aloe vera could be useful for the management of oxidative stress and inflammatory diseases.

Anti-Inflammatory Activity of Human Lens Crystallin Derived Peptide.

Inflammation has become the culmination point for several chronic diseases like skin diseases, asthma, neurological disorders, cancer, and cardiovascular disorders. Mini αA-crystallin peptide, identified from a highly conserved region of human lens protein αA-crystallin, is known to have a chaperone-like function; hence, it has generated interest in exploring the anti-inflammatory potential of the peptide. The objective of the study was to evaluate the anti-inflammatory potential of mini αA chaperones using in vitro, ex-vivo, and in vivo models. The peptide was tested for its phosphodiestarase4 B inhibition, anti-inflammatory and free radical scavenging abilities in HaCaT cells. Carbopol gel formulations with varying concentrations of mini αA-crystallin peptide and diclofenac sodium were prepared and optimized. Skin permeation studies of prepared formulations were carried out on excised abdominal skin of Wistar rat using a vertical type diffusion cell. Carrageenan induced rat paw oedema model was used for determining the anti-inflammatory potential of the peptide in prepared gel formulation with or without diclofenac sodium. The peptide exhibited appreciable free radical scavenging and weak PDE4B inhibition. Gel formulation with 1% Tween-80, 1% carbopol, and 10% ethanol showed better permeation compared to other formulations. The in vitro skin permeation studies revealed good improvement in permeation characteristics of diclofenac and peptide from the gels. The peptide was retained within the skin tissue, which is an ideal requirement for the delivery of an anti-inflammatory topical formulation. In preclinical anti-inflammatory studies, gel formulation containing mini αA-peptide and diclofenac sodium showed a significant decrease in paw volume compared to other combinations tested. The study revealed the additive effect in anti-inflammatory activity by combining mini-αA peptide and diclofenac sodium which effectively reduced the inflammation.

Anti-Inflammatory Activity of Ethnic Vegetables Osonshak <i>(Spilanthes calva)</i> and Chikipung <i>(Rumex vesicarius)</i> in Animal Model

The aqueous leaf extract of ethnic vegetables Osonshak (Spilanthes calva), Chikipung (Rumex vesicarius) and Kochi ampata (Mangifera indica) widely consumed by the ethnic people of Chittagong Hill Tracts was investigated for their anti-inflammatory activity. Carrageenan induced rat paw edema model was employed to test the anti-inflammatory property. The plant extract (500 mg/kg body weight) was given orally to the rats. Diclofenac sodium (50 mg/kg) was used as the positive control. Osonshak and Chikipung showed significant anti-inflammatory activity.

Discovery and Development of a Novel mPGES-1/5-LOX Dual Inhibitor LFA-9 for Prevention and Treatment of Chronic Inflammatory Diseases.

BackgroundNon-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 selective inhibitors, have been explored for prevention and treatment of several inflammatory chronic conditions including arthritis, and cancer. However, the long-term use of these drugs is associated with gastrointestinal, renal, and cardiovascular side effects. Later, COX/5-lipoxygenase (5-LOX) dual inhibitors (eg, licofelone) have been developed but did not enter into the market from the clinical trails due to COX-1/2 inhibition-associated side effects. Hence, targeting microsomal prostaglandin E synthase-1 (mPGES-1) and 5-LOX can be an ideal approach while sparing COX-1/2 activities for development of the next generation of anti-inflammatory drugs with better efficacy and safety.Materials and MethodsIn silico (molecular modelling) studies were used to design a mPGES-1/5-LOX dual inhibitory and COX-1/2 sparing lead molecule licofelone analogue-9 (LFA-9) by modifying the pharmacophore of licofelone. In vitro cell-free enzymatic (mPGES-1, 5-LOX, COX-1/2) assays using fluorometric/colorimetric methods and cell-based assays (LPS-induced PGE2, LTB4, and PGI2 productions from macrophages) using ELISA technique, isothermal calorimetry, and circular dichroism techniques were performed to determine the mPGES-1/5-LOX inhibitory efficacy and selectivity. Anti-inflammatory efficacy of LFA-9 was evaluated using a carrageenan (inflammogen)-induced rat paw edema model. Infiltration/expression of CD68 immune cells and TNF-α in paw tissues were evaluated using confocal microscope and immunoblot analysis. Anti-cancer effect of LFA-9 was evaluated using colon spheroids in vitro.ResultsLFA‐9 inhibited mPGES-1/5-LOX and their products PGE2 and LTB4, spared COX-1/2 and its product PGI2. LFA‐9 bound strongly with human mPGES‐1/5‐LOX enzymes and induced changes in their secondary structure, thereby inhibited their enzymatic activities. LFA-9 inhibited carrageenan-induced inflammation (70.4%) in rats and suppressed CD68 immune cell infiltration (P ≤ 0.0001) and TNF-α expression. LFA-9 suppressed colon tumor stemness (60.2%) in vitro through inhibition of PGE2 (82%) levels.ConclusionOverall study results suggest that LFA-9 is a mPGES-1/5-LOX dual inhibitor and showed anti-inflammatory and colorectal cancer preventive activities, and warranted detailed studies.

Abstract 6364: LFA-9, a dual mPGES-1 and 5-LOX inhibitor, suppresses colon cancer stemness and inflammogen-induced inflammatory response

Abstract Chronic inflammation triggers tumorigenesis of the colorectum; hence several non-steroidal anti-inflammatory drugs (NSAIDs) have been explored for prevention and treatment of inflammatory diseases, including colorectal cancer (CRC). Although traditional NSAIDs and COX-2 inhibitors are effective chemopreventive agents for CRC, unwanted side effects (gastrointestinal and renal) hinder their use. Mechanistic studies suggest that the side effects are in part due to a COX-2 inhibition-associated increase in 5-lipoxygenase (5-LOX) metabolites and reduced PGI2 levels. Hence, agents targeting microsomal prostaglandin synthase-1 (mPGES-1) and 5-LOX inhibitors may prove to be more effective and safer agents for chemoprevention. LFA-9 was designed based on the pharmacophore of licofelone by adding 2-aminoethanoic acid (Glycine) at its carboxylic end to enhance renal clearance and selectivity towards dual mPGES-1 and 5-LOX inhibition. Here we characterized LFA-9 in detail for its mPGES1/5-LOX selectivity over COX-1/2 using in silico molecular modelling, in vitro enzyme activity assays, and ex vivo inhibition studies with human/mouse/rat mPGES-1 and 5-LOX enzymes to facilitate pre-clinical experimentation and clinical translation. In silico, LFA-9 showed strong binding affinity against 5-LOX (binding energies -199.85 and -215.3 Kcal/mol) and mPGES-1 (binding energies -238.27 and -257.76 Kcal/mol), but not against COX-1/2. LFA-9 substantially inhibited mPGES-1 (IC50 0.52 - 1.40 µM) and 5-LOX (IC50 0.89 - 2.75 µM) but not COX-1/2 (IC50>1mM) in cell-free assays. Ex-vivo, LFA-9 inhibited PGE2 (IC50 0.47 - 0.78 µM) and LTB4 (IC50 0.66 - 1.24 µM) production and spared PGI2 (IC50>1 mM) and TXB2 (IC50>1 mM) production in LPS-stimulated human/mouse/rat macrophages and whole blood (cell-based system). Circular dichroism and isothermal calorimetric-based studies demonstrated that LFA-9 strongly binds and induces changes in the secondary structure of human mPGES-1 and 5-LOX enzymes, thereby inhibiting their activities. Since PGE2 from mPGES1 activity promotes colon tumor stemness, LFA-9 was evaluated on colonic cancer organoids (spheroids) derived from PIRC (Polyposis in Rat Colon) rats that replicate human familial adenomatous polyposis. LFA-9 significantly inhibited the growth of colonic spheroids at 25 µM as compared to that of untreated as well as licofelone-treated spheroids. Anti-inflammatory properties of LFA-9 were evaluated in vivo using an inflammogen (carrageenan)-induced rat paw edema model. Dietary LFA-9 inhibited edema formation after carrageenan injection. In summary, LFA-9 showed anti-inflammatory and anti-tumor properties through mPGES1/5-LOX inhibition. Our data supports LFA-9, a novel mPGES-1 and 5-LOX inhibitor, as a safer drug candidate for prevention and therapy of colorectal cancer. (Supported by R01CA 213987, NIH/NCI HHSN261201500024I and VA merit). Citation Format: Nagendra Sastri Yarla, Gopal Pathuri, Hariprasad Gali, Venkateshwar Madka, Janani Panneerselvam, Parthasarathy Chandrakesan, Courtney W. Houchen, Elizabeth R. Glaze, Jennifer Fox, David McCormick, Chinthalapally V. Rao. LFA-9, a dual mPGES-1 and 5-LOX inhibitor, suppresses colon cancer stemness and inflammogen-induced inflammatory response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6364.

Formulation and characterization of lornoxicam-loaded cellulosic-microsponge gel for possible applications in arthritis

Rheumatoid arthritis (RA) is an autoimmune disease associated with severe joint pain. Herein, we report lornoxicam loaded cellulosic microsponge gel formulation with sustained anti-inflammatory effects that are required to manage arthritic pain. The microsponges were formulated using quasi emulsion-solvent diffusion method employing four different surfactant systems, namely polyvinyl alcohol (PVA), Tween80, Gelucire 48/16 and Gelucire 50/13. All the lornoxicam loaded microsponge formulations were extensively characterized with a variety of analytical tools. The optimized microsponge formulation was then converted into gel formulation. The lornoxicam loaded microsponge gel formulation had adequate viscosity and sufficient pharmaceutical properties as confirmed by the texture analysis and the drug release followed Super case II transport. It is noteworthy that we described the preparation of a new cellulosic polymers based microsponge system for delivery of lornoxicam to provide quick as well as lasting (sustained) anti-inflammatory effects in rats using carrageenan induced rat paw edema model. We were able to demonstrate a 72% reduction in inflammation within 4 h using the optimize transdermal gel formulation utilizing Transcutol P as permeation enhancer and with the aid of skin micro-piercing by microneedles, hence, demonstrating the potential of this microsponge gel formulation in arthritis management.

Anti-inflammatory and analgesic activities of <i>Clerodendrum capitatum</i> (Willd) Schum. & Thonn. (Verbenaceae) leaves

Clerodendrum capitatum (Willd) Schumach and Thonn. (Verbenaceae) is a perennial herb, which grows up to 0.5 m to 2 m high. It is widespread over North-East, East, and South Central Africa. It is known as “bambaro or maashayi” by the Hausas of Northern Nigeria. The leaves are used traditionally to treat intercostal pain, headaches and toothaches. The aim of this study is to evaluate the anti-inflammatory and analgesic activities of the aqueous ethanol extract and fractions of C. capitatum. The anti-inflammatory activity was investigated using carrageenan induced rat paw oedema model, while acetic acid induced mice writhing model was used to evaluate the anti-nociceptive property. The oral median lethal dose values were found to be greater than 5,000 mg/kg for the aqueous ethanol extract, ethyl acetate and n-butanol fractions, while that of dichloromethane fraction was less than 2000 mg/kg using OECD method. The acetic acid induced writhing was significantly (P<0.05-0.001) reduced particularly for the EF and NF fractions at 200 mg/kg (93.12% and 98.79%). DF showed percentage inhibition of 87.59% and 81.75% at 50 and 100 mg/kg respectively. The extracts and fractions also caused a significant (P<0.05-0.001) dose dependent reduction of inflammation induced by carrageenan when compared with the negative control with the maximum inhibitory effect of 43.69% observed in Ethyl acetate fraction at 50 mg/kg dose at the 3rd hour. It can be concluded that the leaf extracts of C. capitatum possess anti-inflammatory and analgesic effects in animal models, which may be mediated through the phytochemical constituents present in the extract and fractions of the plant.
 Keywords: Clerodendrum capitatum; Anti-inflammatory; Analgesic; OECD

Development and Characterization of Niosomal Gel System using Lallementia royaleana Benth. mucilage for the treatment of Rheumatoid Arthritis.

Niosomes structural framework comprises of non-ionic surfactant-based microscopic lamellar structures which carries the potential to sustain the effect of drug from its delivery system. In present work, the attempt was made to identify the effect of different ingredients such as effect of Tweens and natural mucilage of Lallemantia royaleana Benth. on the performance of developed niosomal gel formulations in order to prolong the duration of action of drug and to minimize its side effects of topical conventional drug administration. All Ibuprofen loaded niosomes formulationswere prepared by ether injection method; using cetosteryl alcohol with different variants of Tweens and Spans. Various evaluation parameters were performed to confirm niosome formation. Further, the niosomes were incorporated into gel system and evaluated for in-vitro permeability study (ex-vivo) on excised rat skin by membrane diffusion method and in-vivo study by carrageenan induced rat paw edema model. The best selected niosome formulation F9 gave no sedimentation, layer separation and unchanged particle shapes and thus selected for gel preparation using Lallemantia royaleana Benth. mucilage and carbopol in different ratios. Ex-vivo and in-vivo studies indicated high skin retention and penetration rates within the skin for tests niosomal gel formulations (G1 & G2). The present study suggested that developed topical gel formulation provides enhance permeability and longer duration of drug action over conventional gels.

Synthesis and Biological Evaluation of Some Piperazine Derivatives as Anti-Inflammatory Agents

Some 1-((4-methylpiperazin-1yl)methyl)-1H-benzo[d]imidazole & 1-((4-phenylpiperazin-1yl)methyl)-1H-benzo[d]imidazole derivatives were synthesized through reaction of 1-substituted piperazines with different benzimidazole derivatives in methanol yielded the corresponding mannich bases (42-a to 42-i). All the synthesized compounds were elucidated by IR, 1H NMR and MASS spectroscopy. They were tested for anti-inflammatory activity using in-vivo (Carrageenan- induced rat paw edema model) method at a dose of 50mg/kg. result showed that compounds 42-c, 42-d and 42-h were found to be most potent in series.
 Keywords: 1,4-disubstituted Piperazine, Anti-inflammatory, Mannich Base.

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders. The therapeutic action of the Non-Steroidal Anti-inflammatory Agents (NSAIDs) is based primarily on the COX-2 inhibition. With this background we have synthesized some azomethine derivatives of 3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 6(a-o) and were characterized by 1HNMR, 13CNMR and Mass spectral techniques. All the synthesized pyrazole derivatives were tested for in vitro membrane stability property in both COX-1 & COX-2 inhibition studies and in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Among them, compound 6k showed very good activity by in vivo anti-inflammatory activity with 0.8575 mmol/kg as ED50. Similarly compounds 6m, 6o, 6i and 6h exhibited comparable anti-inflammatory activity to standard drugs. Also the active compounds were further screened for ulcerogenic activity and were found be safer with less ulcer index compared to the marketed drugs like aspirin, ibuprofen and celecoxib.

Anti-inflammatory effect of Śirīṣāvaleha prepared by two liquid media on carrageenan induced rat paw oedema model

Background: Steroidal and non-steroidal anti-inflammatory agents have several limitations, due to which people are moving towards use of traditional medicines. Considering this, the current attempt is aimed to evaluate in vivo anti-inflammatory effect of a poly-herbal formulation Śirīṣāvaleha prepared in presence of water and Kanji (sour gruel). Kanji is anticipated to bring extraction of more principles from the raw drugs and may improve therapeutic attributes of the drug. Considering this, Kanji was used as a liquid medium for preparation of Śirīṣāvaleha and was evaluated for anti-inflammatory activity in comparison to Śirīṣāvaleha prepared with water. Materials and Methods: The activity was screened in carrageenan induced rat paw oedema model in albino rats. The raw materials were collected; authenticated and trial formulations were prepared by following standard classical guidelines. Randomly selected animals were divided into four groups of six animals each. The test drugs were administered orally at a dose of 1.8 g/kg for five days. Phenylbutazone was used as standard anti-inflammatory drug for comparison. Results: Results showed the presence of pronounced anti-inflammatory activity in Śirīṣāvaleha prepared with water (SW) followed by Śirīṣāvaleha prepared with Kanji (SK). Conclusion: Study shows that both samples of Śirīṣāvaleha have anti-inflammatory effect.

EVALUATION OF ANTI-ASTHMATIC ACTIVITY OF METHANOLIC EXTRACT OF BERLERIA PRIONITIS LINN. AERIAL PARTS

Objective: The aim of the present study is to evaluate the aerial parts of a plant of Barleria prionitis Linn., for its antiasthmatic activity with the separation of active moieties.Methods: Adult wistar albino rats were used for the anti-inflammatory study. Histamine-induced bronchospasm was conducted on isolated goat trachea.Results: The dried and powdered aerial parts of Berleria prionitis was extracted with continuous soxhlet extraction with Petroleum ether (40-60 ° C), Chloroform, Ethyl acetate, Acetone, Methanol, and Hydroalcoholic solvents. Preliminary phytochemical screening of all extracts was done. Preliminary animal studies by In vitro isolated goat trachea chain preparation of all extracts were done to find out the potent extract. In this study, the methanolic extract of aerial parts of Berleria prionitis was found to be potent comparative to another extract. The results of carrageenan induced rat paw oedema model indicated the dose-dependant anti-inflammatory activity. As compared to standard drug (Indomethacin), methanolic extract showed similar activity which was found to be statistically significant (P<0.0001). The extent of DPPH radical scavenging was determined by calculated the IC50 value of methanolic extract Berleria prionitis (133.5) compared with the Ascorbic acid (114.7) taken as standard. In the present study, the histamine-induced dose-dependent contraction of goat tracheal chain was significantly inhibited (p<0.001) by methanolic extract of aerial parts of Berleria prionitis (200 μg/ml). Thus the present study revealed that the methanolic extract of Berleria prionitis (MEBP) has significant antihistaminic (H1 receptor antagonist) activity.Conclusion: In view the fact that tribal have well experienced the antiasthmatic effects of the roots of Barleria prionitis Linn. The results of our study, for the first time, show that the methanolic extract of aerial parts of Berleria prionitis Linn. possesses antioxidant, anti-inflammatory, Bronchodilator properties and therefore can be used for the antiasthmatic treatment.

Peels of Citrus Fruits: A Potential Source of Anti-inflammatory and Anti-nociceptive Agents

Introduction: The present study was contemplated to evaluate the anti-inflammatory and analgesic potentials in peels of some commercially grown Citrus fruits of South India viz, Lime (Citrus aurantifolia), Orange (Citrus reticulata), Sour Orange (Citrus aurantium), Pomello (Citrus grandis) and Citron (Citrus medica). Methods: The peel of the fruits were separated and subjected to cold extraction using 70% alcohol. The extracts obtained were screened for the presence of phytoconstituents by qualitative phytochemical analysis; the anti-inflammatory activity of extracts at 250 and 500mg/Kg body weight concentrations were assessed by in vivo Carrageenan induced rat paw edema model and in vitro HRBC membrane stabilization assay whereas Tail immersion and Hot plate methods have been used to evaluate their analgesic property. Results: The results revealed that, all extracts treated animals have shown significant decrease in paw edema volume at 3rd and 4th hour of treatment and increase in reaction time in tail immersion and hot plate readings at 120 and 150 min and are comparable to the standards. From the results it was evident that Citron peel extract exhibited significant antiinflammatory and analgesic property in all models. Preliminary phytochemical investigation revealed that extracts were bestowed with presence of flavonoids, terpenoids, steroids, glycosides, alkaloids, carotenoids and phenolic compounds which might be responsible for the antinociceptive and anti-inflammatory activities. Conclusion: From the results it was evident that all citrus fruits have prominent activity in terms of parameters assessed in a dose dependent manner and are more effective in the later phase. The study thus documents that Citrus peels are good sources of anti-inflammatory and anti-nociceptive agents.

Substituted Benzamides from Anti-inflammatory and p38 Kinase Inhibitors to Antitubercular Activity: Design, Synthesis and Screening.

Twenty one amide compounds possessing phenoxy/benzyloxy/pyridinyl groups have been synthesized by benzoylation of respective amines in presence of base with moderate to encouraging yields. Upon confirmation of structure, compounds were subjected for p38 kinase inhibitory, anti-inflammatory, antimicrobial and antitubercular activities. Anti-inflammatory activity was determined using carrageenan induced rat paw edema model while p38 kinase inhibitory activity was studied using ELISA method and serial dilution method was employed to determine MICs. Two compounds 4g and 4n showed over 30% p38 kinase inhibitory activity at 10 µM and best anti-inflammatory activity was found for compounds 4g, 4i, 4n and 4o which exhibited to reduce paw edema over 70%. Compound 4b was observed to be the most potent against gram +ve organisms with MIC value of 1.6 µG/mL and compound 4u displayed potent antibacterial activity against gram negative organisms. Most encouraging antitubercular activity was noticed for compounds 4u, 4r and 4k with 6.25, 12.5 and 12.5 µG/mL Further, in order to know the binding site interactions, a docking simulations of compounds was performed. These preliminary results will certainly show fruitful directions to improve the activities of compounds.