Current Drug Therapy - Volume 13, Issue 2, 2018

Background: Atopic dermatitis is a common chronic disease with a genetic background known as atopic syndrome characterised by pruritus and cutaneous inflammation. This review provides conventional and modified approaches for the treatment of atopic dermatitis treatment. Objective: The objective of this review is to provide an overview of the current and upcoming therapies along with novel approaches to improve the drug delivery for the treatment of atopic dermatitis. Methods: Common treatments of atopic dermatitis include application of topical corticosteroids, calcineurin inhibitors along with emollients and cutaneous antiseptics. However, severe forms of the disease are resistant to these approaches and need systemic treatments including immunosuppressants such as cyclosporine, systematic glucocorticosteroids and antihistaminic drugs. Results: Phototherapy including UV-B, psoralen plus ultraviolet therapy can also be used as adjuvant therapy in treatment of chronic AD. However, all these therapies have a number of side effects and potential problems, such as limited efficacy, inconvenience, organ toxicity, carcinogenic and broadband immunosuppression. The natural therapy including herbs and natural oils is also being utilized since many years for treatment of dermatitis, although more in vivo, dose and efficacy data needs to be established. Currently biological agents are being studied widely as novel therapeutic options for dermatitis treatment which can lead to less toxic and more targeted approach for the treatment of disease. Conclusion: The present review describes recent advancements and delivery approaches for safe and effective treatment of atopic dermatitis.

Background: Immunosuppressants are a class of drugs that can inhibit the immune response, mainly through the inhibition of IL-2 production, among other mechanisms. The most studied representatives of this class of therapeutic agents are Cyclosporin- A, FK506, and Rapamycin. Due to the structural complexity of these molecules, their chemical synthesis has been difficult and expensive. Objective: To synthesize novel small molecules that are structurally simple and that can be inhibitors of IL-2 production. These molecules are proposed to constitute new hypothetic immunosuppressant agents. Method: These small molecules were obtained through simple, cheap and efficient methods of well-known synthetic transformations. The molecules were synthetized in few steps through a highly convergent route and produced high yields. Results: Among the six compounds synthetized, compounds 4a1 and 4b2 showed interesting inhibitory activity. At higher concentration, compound 4a1 showed significant activity. However, the isomer 4a2 showed considerably less activity than 4a1, perhaps, for the high stereoselectivity ligand-receptor. Furthermore, the evaluation of the effect of novel molecules on the viability of mononuclear cells was carried out. The effect of the molecules proved to be innocuous. Conclusion: The data obtained from the inhibition of IL-2 production and low toxicity in mononuclear cells are promising for the development of future studies on these new hypothetic immunosuppressant agents.

Background: Orodispersible film (ODF) is a novel drug delivery system and most widely used dosage form because of its convenience in terms of self-administration, compactness, and ease in manufacturing. Lutein (Carotenoid) is an antioxidant, belongs to class II (High permeability and Low solubility) under BCS classification. To enhance the solubility, a solid dispersion of Lutein was prepared and then it has been successfully fabricated into ODF to increase its pre-gastric absorption, reduce its first pass effect and avoid further degradation in gastric acid. Objective: The objective of the present research work was to prepare a solid dispersion of Lutein in order to increase its solubility and formulate its ODF to improve its bioavailability. Method: The solid dispersion of Lutein was prepared by a solvent evaporation method using Soluplus as a carrier. The orodispersible films of Lutein were prepared separately using different concentrations of Ethocel E 15 and Aerosil 200 pharma grade by a solvent casting method. Results: The prepared films were evaluated for various parameters such as folding endurance, drug content, disintegration time, in vitro drug release etc. The formulation F3 containing 150 mg of Ethocel E 15 and 20 mg of Aerosil 200 showed rapid disintegration time and in vitro drug release. Conclusion: ODF of Lutein has been successfully formulated. The developed formulation can be used for the treatment of age-related macular degeneration.

Background: The N-methyl-D-aspartate receptors (NMDAR) are extremely important ionotropic glutamate receptors in the central nervous system. These receptors are involved in different pathological conditions, such as Parkinson's, Alzheimer's and Huntington's, and also in neuronal death associated with trauma and stroke. Since the discovery of ifenprodil, many efforts have been made to develop subunit specific NMDAR antagonists with fewer side effects, however without success to deliver a marketed drug. Objective: The aim of this work is to establish a structure-activity relationship analysis of a series of benzimidazole derivatives described in the literature as GluN2B-selective antagonists and evaluate their binding mode. Method: Molecular modeling techniques were carried out, such as docking using Autodock Vina, structure-activity relationship studies using Spartan program, in silico evaluation of the toxicological profile and pharmacokinetic properties as intestinal absoption, blood-brain barrier permeation and oral bioavailability. Results: Our results showed that all compounds presented the structural features observed in ifenprodil- like antagonists and that lipophilicity and number of hydrogen bond donors were the most correlated descriptors with the biological activity. Our docking analysis also revealed a similar binding mode in NMDAR. Furthermore, the benzimidazole derivatives with hydroxyl substituent showed a good safety profile and good bioavailability according to Lipinski's Rule of Five and a modified rule for central nervous system penetration, which could help in future optimizations. Conclusion: In conclusion, our results indicate that benzimidazole derivatives could be useful for the development of subunit selective NMDAR antagonists.

Background: Dipeptidyl peptidase-4 (DPP4), a serine exopeptidase which is found in human, is encoded by the DPP4 gene. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels increase in the presence of DPP-4 inhibitors, which also inhibit the release of glucagon. Accordingly, insulin secretion increases with gastric emptying and blood glucose levels decrease. Objective: The aim of the present work was to screen suitable DPP4 inhibitors which can be used to treat diabetes mellitus type 2. Method: 230 sulfonyl-benzamides have been screened by Discovery Studio Molecular Docking Programme to search the best suitable molecule for type 2 diabetes treatment. To find inhibitors with high stability and flexibility, molecular dynamics (MD) simulation has been done and Lipinski's rule of five protocols has been employed to screen druglikeness. ADMET (absorption, distribution, metabolism, excretion and toxicity) filtration has also been used to value the toxicity. Among them, 106 sulfonyl-benzamide showed better docking score than the approved diabetes mellitus type 2 drug. These sulfonylbenzamides also passed the ADMET and druglikeness filters. Quantitative structure– activity relationship has been studied to observe change in the docking properties with the change of druglike sulfonyl-benzamide molecules. DFT computation of optimized geometry and derivation of molecular orbitals have been used to correlate the druglikeness. The small difference in the energy between HOMO and LUMO may help to activate the drug in the protein environment quickly. Pharmacophore generation has been done to recognize the inhibitors binding modes in the active site of receptor. Results: 4-chloro-N-[3-[[(1S)-1-(4-methylsulfonylphenyl)ethyl]amino]-3-oxopropyl]benzamide (MSPB) showed the best theoretical efficiency as DPP-4 inhibitor. Conclusion: Structure based drug design approach for the treatment of type-2 diabetes revealed its influence on the development of new DPP-4 sulfonyl-benzamide inhibitors.

Background: Mounting evidence over the past decade suggests that the number of phytochemicals were identified and designed on the basis of computer modeling (In slico method) to understand the interactions among the anti-cancer targeting proteins. Objectives: The aim of the present research was to find the anti-cancer targeting efficiency of phloretin by molecular docking. Methods: Based on the experimental evidence, a phytochemical of phloretin and epidermal growth factor receptor (EGFR), B cell lymphoma 2 (Bcl-2), nuclear factor-ΚB (NFkB), c-Kit receptor protein-tyrosine kinase, Farnesyl transferase, platelet-derived growth factors (PDGFs) and vascular endothelial growth factor receptor 2 (VEGFR2) proteins were utilized to perform induced fit docking by using Glide 6.5 (Schrodinger 2014-2). Multiple numbers of the poses were generated and evaluated for understanding the binding conformations and common interacting residues between ligands and proteins. Results: The docking results revealed that phloretin exhibited significant binding interaction pattern when compare to the known cancer target native inhibitor. Conclusion: Phloretin revealed good docking score and glide energy. Further studies are needed to explore its pharmacophoere properties and inhibitory potential in experimental models.

Background: Neuroleptic malignant syndrome (NMS) is an idiosyncratic reaction with systemic manifestations like fever, rigidity, altered sensorium and autonomic disturbances. The syndrome is often seen within days to weeks in patients being treated with antipsychotics. Though reported with the use of atypical antipsychotics, it is relatively uncommon to occur if patient is on a stable dose of antipsychotic for a long time. Objective: Here we report a case of delayed NMS with risperidone use at the lowest recommended dose. Method: Review of probable etiology including drug review was performed in a 60 year hypertensive female presenting with progressive limitation of movements and rigidity in upper and lower limbs along with bilateral hand tremors, fever, poor speech, difficulty in swallowing, agitated behavior, urinary incontinence and altered mental status. Results: NMS occurred in the patient of schizophrenia on the lowest possible therapeutic dose of risperidone of 0.5 mg/day, after 14 years of therapy. The case highlights the possible drug interaction between risperidone and cholinergic drugs resulting in the catastrophe. (Videos before and after therapy are part of submission). Conclusion: Physicians should be vigilant of the risk of NMS with atypical antipsychotics like risperidone particularly when administered along with cholinergic drugs. NMS can occur even after long term use of a stable dose of antipsychotic. Cholinergic drugs like donepezil, citicoline and piracetam should be used with caution in patients who are already on antipsychotics and if needed should be added one by one.