Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (v.12, #3)

Asthma shows heterogeneity in the cellular sources of inflammation and response to therapy. Although glucocorticoids(GC) are very effective for the treatment of most patients with asthma, an important subgroup of patients failsto show clinical improvement. GC resistance (GC-R) could result from either inherited or acquired variation in GC sensitivity.Diverse cells, such as T helper (Th)1 cells, Th2 cells, and Th17 cells, and innate immunity associated pathways areinvolved in GC-R asthma. The GC receptor (GR) plays a central role in GC sensitivity. Recent molecular biological studieshave revealed the involvement of protein kinase signaling to GR, GR phosphorylation, interactions of GR with excessiveactivation of transcription factors, and impaired histone deacetylase (HDAC). Long-acting β(2)-adrenoceptor agonists(LABAs) may improve the clinical efficacy of GCs by enhancing GR function. Inhibitors of kinase pathways, such as p38mitogen-activated protein kinase (MAPK) inhibitors and phosphoinositide-3-kinase (PI3K)δ inhibitors, are candidates fornew therapeutic agents for GC-R asthma.

T Cell Targeted Strategies for Improved Efficacy and Safety of Specific Immunotherapy for Allergic Disease by Jennifer M. Rolland, Sara Prickett, Leanne M. Gardner, Robyn E. O (201-222).
Allergic diseases including asthma, rhinitis and eczema are known to be a major health and economic burdenworldwide. Specific immunotherapy (SIT) is potentially curative but restricted in use, e.g. for asthmatics, due to risk ofserious adverse events. Safer, effective SIT preparations require elucidation of mechanisms and immunoregulatory factors.Allergen-specific T cells play a pivotal role. For allergic individuals, allergen-stimulated T cells largely secrete IL-4,IL-5 and IL-13 (Th2-type cytokines), whereas non-allergics show predominant IFN-γ secretion (Th1-type). Clinically successfulSIT is accompanied by altered allergen-specific T cell response, with decreased Th2/Th1 ratio, enhanced IL-10 secretionand regulatory T cell induction. Contributing factors include allergen concentration and form, adjuvant and antigenpresenting cell type. In conventional SIT, high dose unfractionated allergen extracts are injected incrementally via thesubcutaneous route. To avoid adverse IgE-mediated events but retain efficacy, hypoallergenic T cell-reactive allergen derivativescan be used. These include peptides containing dominant T cell epitopes of allergens, chemically-modified allergens,and recombinant whole or mutant allergens. Such approaches have been evaluated successfully in animal modelsand early phase clinical trials. Adjuvants and carriers including bacterial and viral components, liposomes and DNA vaccinesalso promote repolarisation of T cell response and regulatory T cell induction. However caution is needed as excessiveIFN- γ secretion may invoke pathogenic inflammation. Sublingual administration has fewer adverse events and isgaining popularity for respiratory allergens, and other routes including intranasal and oral are under evaluation. T cell targetedstrategies will facilitate wider clinical application of SIT and reliable laboratory assays for monitoring treatment.

Nail biting is a common behavioral problem. While there are established behavioral interventions for management,they are of modest efficacy, and there is minimal evidence for effective pharmacotherapy. This study investigatedthe role of N-acetylcysteine (NAC) a potent glutathione and glutamate modulator for the treatment of pathological nailbiting in children and adolescents. This pilot randomized, double-blind, placebo-controlled clinical trial of NAC(800mg/day) or placebo enrolled 42 children and adolescents with chronic nail biting. Nail length was the objective outcome.Evaluations were carried out three times; before treatment, one month after enrollment in the study, and twomonths after enrollment. The duration (chronicity) of nail biting in the NAC and placebo groups was 3.63(2.45) and5.09(3.74) years (P=0.14). The mean nail length gradually increased in both the NAC and placebo groups during this trial.There was a statistically significant difference between the two groups regarding increased nail length after the first monthof trial [(5.21(5.75) and 1.18(3.02) millimeters], however no difference after two months was observed. Two patients inthe NAC group discontinued medication due to adverse events. One patient experienced headache, agitation, and socialwithdrawal, and another patient expressed severe aggression after taking medication and was withdrawn from the study.This study supports the hypothesis that NAC decreases nail biting behavior in children and adolescents over the shortterm. NAC is relatively well tolerated and severe adverse effects are rare. However, there was a high rate of dropout. Furtherstudies with longer durations that build on these preliminary data are recommended. This study is registered at theIranian Registry of Clinical Trials (Irct registration number: IRCT201103023930N3).

Retrospectively, we have measured the antioxidant activity and a variety of antioxidant compounds under versatileextraction conditions of sweet cherry (Prunus avium) extracts. Further in this study, in order to understand the biochemicalconstituents and antioxidant activities of a variety of extracts of black sour cherries (P. cerasus), a related species,antioxidant compounds, including L-ascorbic acid (vitamin C), phenols, flavonoids, and anthocyanins, and the totalantioxidant activity were simultaneously measured under varying extraction conditions (mild heating and brief microwaveexposure) for: i) whole juice extracts (WJE), ii) methanol-extracted juice (MEJ), iii) ddH2O-extracted pomace (dPOM),and iv) methanol-extracted pomace (mPOM). The antioxidant activity for WJE was substantially increased with mild andprolonged exposure to either heating or microwave, such that the % inhibition against 2,2-diphenyl-1-bspicrylhydrazyl(DPPH) followed a positive correlation (heating, 5 ? 20 min.; microwave, 1 ? 2 min.), insignificant with MEJ and dPOM,whereas with mPOM there was sharp downregulation. L-Ascorbic acid content was not affected with mild to prolongedheating or microwave exposure (WEJ and mPOM), except a mild increase with MEJ and dPOM. Similarly, total phenolsassessed showed no significant variations, as compared with control extracts, except a mild decrease with exposure formPOM. In a manner similar to L-ascorbic acid, total flavonoid content was increased under varying conditions for WEJand MEJ, and slightly decreased for dPOM and mPOM. On the other hand, anthocyanins showed differential variationswith exposure (up- and downregulation). Assessment of extraction means as compared with WJE revealed sharp increasein the antioxidant activity for MEJ, dPOM and mPOM, significant increase in L-ascorbic acid, total phenol, and flavonoidcontents for MEJ, dPOM and mPOM, and mild decrease in anthocyanin contents for MEJ, dPOM, and mPOM. These resultssubstantiate the measurable antioxidant activities and contents of P. cerasus extracts under versatile conditions ofmild exposure, an effect bearing significant fluctuation with biochemical properties. Since many of those molecules areknown to have immuno-biochemical constituencies, antioxidant compounds in sour cherries may have putative antiinflammatorypotential and applications in medicinal chemistry, corroborating the observation of regulating and attenuatingthe growth of microorganisms of medical importance in vitro.

Development and Evaluation of Transdermal Organogels Containing Nicorandil by J.R. Madan, Banode Sagar, Dinesh K. Chellappan, Kamal Dua (246-252).
The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, becauseit has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects.The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusionacross the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancerto 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulationswere evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitrostudies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulationusing HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all otherformulations.

Development and Anti-microbial Potential of Topical Formulations Containing Cocos nucifera Linn. by Ravi Sheshala, Ling Teck Ying, Ling Shiau Hui, Ankur Barua, Kamal Dua (253-264).
In order to achieve better treatment for local wounds and bacterial infections, topical formulations containingCocos nucifera Linn. were developed. These formulations were evaluated for their physicochemical properties and antimicrobialefficacy against various strains of microorganisms. Semisolid formulations containing 5% w/w of Cocos nuciferaLinn. were prepared by employing different dermatological bases and were evaluated for their physical appearance, pH,rheological properties, FTIR-spectroscopic analysis, thermodynamic stability and stability studies. The antimicrobial activityof each prepared formulation was determined using disk-diffusion method against various strains of microorganisms.All the prepared formulations were found to be stable and exhibited suitable physicochemical characteristics includingpH, viscosity and spreadability which are necessary for an ideal topical preparation, in addition to strong antimicrobialactivity. Carbopol gel base was found to be the most suitable dermatological base for Cocos nucifera Linn. in comparsionto other bases. Cocos nucifera Linn. formulations showed great potential for wounds and local bacterial infections.Moreover, carbopol gel base with its aesthetic appeal was found to be a suitable dermatological base for Cocos nuciferaLinn. semisolid formulation as it had demonstrated significant physicochemical properties and greater diffusion when assessedusing disk- diffusion method.

Protein Kinase C Modulates Aurora-kinase Inhibition Induced by CCT129202 in HMC-1560,816 Cell Line by Araceli Tobio, Amparo Alfonso, Andrea Fernandez-Araujo, Eva Alonso, Luis M. Botana (265-276).
The human mast cell line HMC-1560,816 carries activating mutations in the proto-oncogene of c-kit that causeautophosphorylation and permanent c-kit receptor activation. The compound CCT129202 is a new and selective inhibitorof Aurora kinase A and B that decreases the viability of a variety of human tumor cell lines. The effect of Aurora kinaseinhibition was assessed in the HMC-1560,816 line in order to find a suitable tool for mastocytosis treatment. CCT129202treatment induces a significant decrease in cell viability in HMC-1560,816 cells after 48 hours of treatment. Moreover,caspase-3 and caspase-8 activation was induced after incubation of HMC-1560,816 cells in the presence of CCT129202. Ithas been demonstrated that Protein Kinase C (PKC) plays a crucial role in mast cell activation as well as cell migration,adhesion and apoptotic cell death. Co-treatment of Ca2+-independent PKCs (δ ε and θ) inhibitor GF109203X withCCT129202, reduces caspase-3 activation which controls cell levels. In contrast, Go6976, an inhibitor of Ca2+-dependentPKCs, increases caspase-3 activation. Oppositely, GF109203X does not modify CCT129202-induced apoptosis throughthe caspase-8 pathway whereas Go6976 treatment abolishes the increase on caspase-8 activity due to CCT129202. Thisimplies that Ca2+-independent PKC isoforms seems to be related with CCT129202-induced apoptosis through the caspase-3 pathway, whereas Ca2+-dependent PKC isoforms are related with the CCT129202 effect on the caspase-8 pathway. Interestingly,CCT129202 cytotoxic effect remains even though Ca2+-dependent PKCs are inhibited, which shows that theAurora kinase inhibitor effect is acting through the caspase-3 pathway. On the other hand, Ca2+-independent PKCs inhibitiondoes not affect the final apoptotic CCT129202 effect because this seems to be mediated by the caspase-8 pathway.Moreover, CCT129202 does not affect PKCδ and Ca2+-dependent PKC translocation, which indicates that PKC translocationpivots on its activation. This demonstrates that Aurora kinase inhibition is not related to this process. Finally, whenPKC is silenced in HMC-1560,816 cells, the effect of CCT129202 on the caspase-3 pathway disappears, which indicates thatthe CCT129202 effect is clearly PKC-dependent.