Current Drug Discovery Technologies - Volume 9, Issue 1, 2012

Psoriasis is a common chronic inflammatory condition of the skin that may have a significant impact on the quality of life of the patient. Effecting approximately 2% of the population, the onset of the disease is commonly before 35 years of age. With no cure and a significant proportion of patients finding their treatment unsatisfactory, there remains a clinical unmet need to discover and evaluate new therapies for the disease. The disease is a complex multi-factorial disease with a genetic component which can be brought on by variety of biochemical, viral and physical stimuli thus adding to the complexity of target identification for drug discovery. Psoriasis is largely regarded as a T-cell mediated autoimmune condition, based on evidence derived from animal models of psoriasis and a developing understanding of T-cell infiltration into the dermis and epidermis of the psoriatic plaque. Subsequence activation of the infiltrate by memory T-effector cells requires T-cell activation by antigen presenting cells, such as macrophages, B and dendritic cells. Clinical studies and treatment of patients with drugs such as cyclosporine and other experimental drugs which target the induction or maintenance of T cell activation support the notion of psoriasis as a T-cell driven disease. Although the biochemical processes underlying the onset and propagation of disease are incompletely understood, significant advances in our understanding of the science underpinning the disease have been made over the last 10 years. The paper by Rahman et al., explores the role of biochemical markers in psoriasis some of which are common to many autoimmune and inflammatory conditions. This may present us with the opportunity to derive a panel or ‘finger-print’ of biomarkers, which if restricted to, for example the skin, may prove valuable to drug discovery as either a source of potential new targets or as a route to monitoring patient response through therapy. To date measurement of the inflammatory biomarkers such as high-sensitivity C-reactive protein and erythrocyte sedimentation rate are commonly measured as in other related diseases such as psoriatic arthritis and rheumatoid arthritis. New research and a greater understanding of biochemial processes such as the role of intra-cellular signalling as discussed by Rahman et al. which is aimed at developing biomarkers specific to the mechanism or process under attenutation in the patient has and will continue to guide new efforts to compact this lifelong condition.

In the present scenario, most of the developed and new discovered drugs are posing real challenge to the formulation scientists due to their poor aqueous solubility which in turn is responsible for poor bioavailability. One of the approach to overcome above problem is the packaging of the drug in to particulate carrier system. Among various carriers, lipid emerged as very attractive candidate because of its unique property of enhancing the bioavailability of poorly water soluble drugs. Solid lipid, one of the physical forms of lipid, is used to formulate nanoparticles, popularly known as Solid lipid nanoparticles (SLNs), as an alternative carrier system to emulsions, liposomes and polymeric micro- and nano-particles. SLNs combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews numerous production techniques for SLNs along with their advantages and disadvantages. Special attention is paid to the characterization of the SLNs by using various analytical tools. It also emphasizes on physical state of lipid (supercooled melts, different lipid modifications).

Development of amphiphilic drug-lipid complexes is a potential approach for improving therapeutic efficacy of the drugs by increasing solubility, release profile and oral bioavailability. Quercetin (3, 3', 4', 5, 7-pentahydroxyflavone), a polyphenolic flavonoid, shows several biological effects like anti-inflammatory, anti-cancer, antiproliferative, antimutagenic and apoptosis induction but its use is limited due to its low aqueous solubility. To overcome this limitation, a value added phospholipid complex of quercetin was developed to improve its aqueous solubility for better absorption through the gastrointestinal tract and this might result in improved bioavailability. The quercetin-phospholipid complex thus prepared was evaluated for various physico-chemical parameters like infra red spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM) and solubility study. The In vitro antioxidant activity was also studied. The phospholipid complex of quercetin was found to be fluffy and porous with rough surface in SEM. FTIR, DSC and XRPD data confirmed the formation of phospholipid complex. The water solubility of quercetin was improved by 12 folds (from 3.44 μg/ ml to 36.81 μg/ ml) in the prepared complex. There was no statistical difference between the quercetin complex and quercetin in the In vitro anti-oxidant activity, indicating that the process of complexation did not adversely affect the bioactivity of the active ingredient.

In the present investigation, a computational based structural analysis was performed on a series of 2-piperidin- 4-yl-acetamide derivatives to investigate the physicochemical features of the molecules responsible for the hERG blocking and melanin concentrating hormone receptor-1 (MCH R1) antagonistic activities. The QSAR models derived from MLR analysis were validated by various validation methods and they provided significant statistical results such as Q2, F, ttest, R, predicated residual error values, etc. These significant models were constructed with different type of physicochemical descriptors which showed that the hydrophobic properties on the vdW surface of the molecules are favorable for both the activities (MCH R1 antagonistic and hERG blocking activities) and the presence of polar/electronegative groups in the molecules is detrimental for those activities. The presence of flexible aromatic rings in the molecules has favorable hERG blocking activity. The MCH R1 antagonistic activity also depends upon the vdW volume, shape and flexibility of the molecules. In addition, the presented results will guide for the optimized design of novel bioactive molecules with less/free of hERG blocking activities to avoid unwanted potential cardiotoxic side effects related with the use of these possible antiarrhythmic and anti-obesity agents in humans.

This study examined the antibacterial properties of nineteen benzoxazole, isoniazid, ethionamide and salicylanilide derivatives against Staphylococcus aureus (S. aureus). It was found that three salicylanilide-derived compounds demonstrated antistaphylococcal activity: 5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (5-Cl-4'-CF3- SAL), 4-chloro-2-(3-chlorophenylcarbamyoyl)phenyl)-2-(benzyloxycarbonylamino)propanoate (AIM31) and 4-chloro-2- (4-(trifluoromethyl)phenylcarbamoyl)phenyl acetate (AIM33). Investigation of the chemical structures of these three compounds and comparison with a non-inhibitory salicylanilide compound (i.e. 5,3'-diCl-SAL) illustrated that different combinations of chemical groups at defined positions on the salicylanilide core structure had a marked influence on antistaphylococcal activity. The most effective compound was AIM33 which inhibited staphylococcal growth and displayed an initial MIC value of 3.12 μg ml-1 and subsequent investigation revealed that an MIC as low as of 0.5 μg ml-1 was achievable. In this case, the dual presence of a trifluoromethyl group and an acetylated phenolic hydroxyl to the salicylanilide core structure led to greatly enhanced activity.

Psoriasis is a common chronic autoimmune skin disorder with T-cell mediated multifunctional complex pathogenesis along with genetic predisposition. Conventionally, many therapies are available for the management of psoriasis, but they have limited efficacy due to higher side effects. Over the last decade, one of the major efforts in psoriasis research has been made for the development of drug molecules by understanding the potential biomolecules/biomarkers associated with psoriasis. This approach aims to provide selective immunologically directed intervention with fewer side effects than conventional therapies. The present review aims to give an exhaustive account on various biomarkers including oxidative stress, peptide, biochemical and gene markers responsible for keratocyte hyper proliferation, inflammatory responses and abnormal differentiation in psoriasis. Effective targeting of these over expressed biomarkers can serve as the novel tool for anti-psoriatic drug development. In addition, this review also gives insights into several novel biomarkers targeted drugs under pre-clinical and clinical investigation or have been registered by FDA for psoriasis management.

Conventionally, rodents, mostly mice and rats, have been utilized as animal models for studying drug metabolism and toxicity of new medicines. However, there have been two major problems inherent to these models. One is that there are species differences in major enzymes responsible for drug metabolisms and detoxification such as cytochrome P450 between rodents and humans, and the other is that human hepatitis viruses do not infect rodent livers, which hampers studies for anti-hepatitis virus drugs using these models. As an approach to overcome these intrinsic shortages, we devised a method to generate mice whose livers are mostly (>80%) repopulated with healthy human hepatocytes 7 years ago. Since then, these mice called simply chimeric mice or liver-humanized mice have been widely utilized among researchers in the areas for new drug developments, which, as a result, have proved that the chimeric mouse is a practical solution to solve the above two issues. The hitherto accumulated studies demonstrating the similarities of the chimeric mouse liver to the human crude liver are summarized and reviewed in the present article. In addition, there have been also studies that show us the presence of dissimilarities between them, such as human hepatocytes' manifestation of hyperplasia in mouse liver and their steatotic alterations when the mice are maintained for >50 days post-transplantation. These dissimilarities between them are also reviewed in details, considering that the information of the similarities and the dissimilarities is quite useful to researchers who utilize chimeric mice as a drug discovery tool for correctly evaluating the obtained results.

Genome-wide RNA splicing (with gene expression) can be used to discover variations that drive specific diseases and / or change the susceptibility in individuals to drug responses including tissue specific toxicities. Evidence linking causative SNPs to individual splicing differences between individuals is emerging and this may lead to a better understanding of susceptibilities related to rare drug-induced toxicities. The development of more sensitive genomics tools is expected to further the study of variations in molecular phenotype from alternative splicing of pre-mRNA. This report highlights a genomics platform developed to measure splicing changes that occur in response to drug exposures, and therefore is applicable for the study of drug-induced toxicity. The platform is applicable for humans, all toxicology species, and specialized model systems. For efficiency, multiple samples can be combined into a single sequencing run and individual sequences can be separated via informatics. Biobanked specimens from clinical trials, toxicology studies, from commercial sources, and/or from public ‘omics’ data resources such as in NCBI are the only sample or non-sample data requirements.