Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 15, Issue 2, 2016

Background: Green tea has been shown to have beneficial effects against a variety of diseases such as cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases. Through cellular, animal, and human experiments, green tea and its major component, epigallocatechin-3-gallate (EGCG) have been demonstrated to have anti-inflammatory effects. Our previous findings have indicated that green tea and EGCG suppress the gene and/or protein expression of inflammatory cytokines and inflammation-related enzymes. Methods: Using bibliographic databases, particularly PubMed (provided by the http://www.ncbi.nlm.nih.gov/pubmed, US National Library of Medicine, National Institutes of Health, United States), we examined the potential usefulness of green tea/EGCG for the prevention and treatment of inflammatory diseases in human clinical and epidemiological studies. We also reviewed results from cellular and animal experiments and proposed action mechanisms. Results: Most of the results from the human studies indicated the beneficial effects of green tea and tea catechins against inflammatory diseases. The cellular and animal studies also provided evidence for the favorable effects of green tea/EGCG. These results are compatible with our previous findings and can be largely explained by a mechanism wherein green tea/EGCG acts as an antioxidant to scavenge reactive oxygen species, leading to attenuation of nuclear factor-κB activity. Conclusion: Since green tea and EGCG have multiple targets and act in a pleiotropic manner, we may consider their usage to improve the quality of life in patients with inflammatory disease. Green tea and EGCG have beneficial health effects and no severe adverse effects; however, care should be taken to avoid overdosage, which may induce deleterious effects including hepatic injury.

Glucocorticoids are the most widely used drugs for the treatment of hypersensitivity, however these drugs themselves and the excipients contained in commercial corticosteroid formulations are able to induce severe immediate-type hypersensitivity reactions. Reactions involving excipients have been confirmed to be IgE mediated by the demonstration of specific-IgE to excipients such as carboxymethylcellulose and lactose. In case of hypersensitivity reactions to corticosteroid preparations, a complete allergy work-up with skin tests and/or challenge tests should include testing excipients as well as the active ingredients.

Background: Although, a number of formulations have been developed for the treatment of IBD yet the developed formulations are having side effects such as high dose, lack of solubility and permeability problems at the site of action. Very few formulations have been developed for the IBD treatment in the form of nanoparticles. Nanoparticles have shown their potential in the recent findings in the treatment of IBD at cellular level. This research work aims to develop nanosuspension of newly introduced drug Rifaximin currently available in the form of tablet for the treatment of IBD. Rifaximin in the form of tablet is given in high dose concentration so to avoid the large dose and to increase the permeability action of drug a nanosuspension is prepared using a well known polymer Eudragit S 100 which is itself a colon targeted polymer and simultaneously improves the site specific delivery of the drug. Method: We thoroughly reviewed and tested the previous work for the development of nanoparticles in the laboratory for the treatment of IBD. A number of research as well as review articles were followed in order to get quality information. For this all the research as well as review work was collected from the quality journals. A simple yet a high result oriented technique nanoprecipitation was used for the development of nanoparticles. Results: A total of 21 research and review papers were studied deeply. Before developing the final formula a number of trials were carried out and from the trials, the formulation which showed better release profile and presence of nanoparticles was then optimized and a total of five formulations were developed. In each of the five formulations the concentration of the polymer and external phase was varied along with the concentration change in P.F. 68 for getting a superior formulation in terms of release, size and entrapment. The least size nanosuspension was subjected to Transmission Electron Microscopy for confirmation of nanoparticles and to check the morphological characters of the prepared nanoparticles and size of the nanoparticles was in the range of 19nm to 25nm. The prepared formulation was subjected to stability studies and it was freeze dried. Conclusion: The outcome of this research work confirms the formation of nanoparticles and release profile of the prepared nanosuspension proved its site specificity. The release graphs indicated the release of the drug in colon proving its potential in the treatment of IBD and entrapment study indicates the drug entrapment capacity for delivering the required concentration of drug at the site of action. Moreover, the nanoformulation reduces the dose and the side effects due to its specific targeting at the site of inflammation which makes it a better choice over the tablets.

Background: Currently used anti-inflammatory drugs are associated with some severe side effects such as gastric irritation, which may range from simple discomfort to ulcer formation. Therefore, the development of potent anti-inflammatory drugs with fewer side effects is important. Benzimidazole, tetrazole and its various derivatives have been used in the synthesis of numerous heterocyclic compounds. In the past few decades, these compounds received much attention due to their diverse array of biological activities. As these heterocycles are known to possess anti-inflammatory activity individually, we thought it worthwhile to link these heterocycles, synthesize them and evaluate for possible changes in this anti-inflammatory activity. Methods: Novel benzimidazole linked tetrazole compound 2-{[2-(1H-tetrazole-5-yl)ethyl] sulfanyl}-1,3-benzimidazole (3) was synthesized by cyclization of 3-(1,3-benzimidazol-2-ylsulfanyl) propanenitrile in presence of sodium azide. A series of tetrazolobenzimidazole derivatives (3a-h) were synthesized by the reaction of compound (3) with acid chlorides. All the synthesized compounds were subjected to structural elucidation by IR, 1H-NMR spectroscopy, Mass spectrometry and elemental analyses. The newly synthesized compounds were screened for anti-inflammatory activity by carrageenan-induced paw oedema method in albino rats. Results: Compounds (3a, 3c, 3g) which contain acetyl, benzoyl and benzoyl moieties; respectively at N-1of tetrazole exhibited anti-inflammatory activities comparable with standard drug diclofenac. Other compounds exhibited anti-inflammatory activity less than the standard. The differences between control and treatment group were tested using one way ANOVA followed by Dunnett’s test. A probability value less than 0.01 was considered to be statistically significant. The GraphPad Instat 3.0 version was used for statistical analysis. Conclusion: Synthesized compounds having anti-inflammatory activity better than standard were found to be 1-{5-[2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3c) and 1-{5-[5-methoxy-2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3g) and the compounds (3a, 3e, 3f) were found to exhibit anti-inflammatory activity comparable to that of standard. All the compounds were found to cause less gastric ulceration than the standard drug diclofenac.

Background: Designing new anti-inflammatory agents possessing safe therapeutic profiles and devoid of potential undesirable side effects is an active field in medicinal chemistry. Thus, a series of N-(4-substituted phenyl)glycine derivatives was designed and synthesized. The idea behind the design is to utilize the bifunctionality of 4-aminoacetophenone via converting the amino group into glycine derivative as a side arm to mimic the glycine amino acid enhancing the overall physicochemical and biological characteristics. In addition, the opposite acetyl group was used as a center for modification and derivatization. Methods: The starting N-(4-acetylphenyl)glycine was converted into two intermediates: the chalcone analog 2 and the thiosemicarbazone derivative 8. Both 2 and 8 were derivatized and/or cyclized into different heterocyclic target derivatives (3-7 and 9-12). The target compounds were screened for anti-inflammatory activity using carrageenan-induced rat paw edema assay. Results: The results showed that compounds 6, 7, and 3, were the most active among the tested compounds at 50 mg/kg dose level with % inhibition of edema of 51.82, 43.80, and 40.39, respectively. Conclusion: The authors succeeded to introduce a simple and versatile skeleton with a side arm resembling the glycine amino acid; imparting a potential improvement in physicochemical properties. We utilize the other side of the skeleton’s aromatic ring as a center for derivatization. The chalcone analog and its cyclized heterocyclic derivatives were of remarkably higher anti-inflammatory activity than the thiosemicarbazone and its derivatives.

Background: Endothelial nitric oxide synthase (eNOS) is known to be expressed in endothelium and smooth muscle cells of arteries. The aim of this study was to investigate the expression of eNOS in intimal and medial layer of aorta from rats fed with a high salt diet and its modulation by losartan and tempol. Methods: Rats were fed during three weeks with: normal salt diet (NS, 0.4% NaCl); high salt diet (HS, 8% NaCl); NS plus tempol 1 mM (NS-T); HS plus tempol (HS-T); NS plus losartan 40mg.kg-1 (NS-L) and HS plus losartan (HS-L). Systolic blood pressure was recorded by the tail cuff method. Rats were then anaesthetized and the thoracic aorta and small arteries (bronchial branches of aorta) were processed to evaluate the expression of eNOS and aquaporin-1 (AQP-1) by immunohistochemistry. Results: HS group showed increased systolic blood pressure, increased eNOS and AQP-1 immunoexpression in the aorta intimal layer, and decreased eNOS immunoexpression in the aorta medial layer, respect to NS group. Losartan and tempol prevented hypertension and changes in the expression of eNOS and AQP-1 of the intimal layer. However, only tempol increased the expression of eNOS elicited by sodium overload in the medial layer of the aorta and small arteries respect to HS group. Conclusion: A high salt diet decreases eNOS expression in vascular smooth muscle layers of aorta and small arteries, which is reversed by tempol. These results suggest an adverse effect of oxidative stress on vascular eNOS in rats fed a high salt diet independently of hypertension.

Background: The involvement of debilitating side effects of allopathic antiasthmatic drugs provides a strong impetus for the development of new herbal therapeutics. Myrica nagi Thunb. (Syn. Kaiphal) of Myricaceae family is a known drug of the Ayurveda system used for the treatment of several diseases including asthma. Methods: The present study deals with the preparation and phytochemical screening of polar, non-polar and methanolic extracts of Myrica nagi bark followed by the evaluation of their antiasthmatic activity using four different animal experimental models: acetylcholine induced bronchospasm in conscious guinea pigs, acetylcholine induced contraction on isolated guinea pig tracheal chain preparation, compound 48/80 induced mast cell degranulation using rat, and trypsin and egg albumin induced bronchospasm in conscious rat. Results: Polar extract of M. nagi bark (200 mg/kg, p.o.) exerted strong antiasthmatic effects near to Ketotifen (1 mg/kg, p.o) as standard drug. Polar extract of M. nagi bark (200 μg/ml) significantly inhibited Ach induced contraction of isolated guinea pig tracheal chain preparation. Pre-incubation of rat peritoneal mast cells with test drugs (methanolic, non polar and polar extracts) showed dose dependent significant reduction of % mast cell degranulation. Polar extract (200mg/kg) & Methanolic extract (200mg/kg) of M. nagi bark treated animals showed significantly lesser serum bicarbonate level, higher tidal volume, lower level of eosinophils and neutrophils. Conclusion: The results of present investigation suggest that the polar extracts of Myrica nagi bark have better antiasthmatic activity than the non polar and methanolic extract.