Current Drug Therapy - Volume 12, Issue 1, 2017

Background: Hybrid systems in recent times are drawing considerable attention in the area of drug development as many of such systems are now becoming drug targets in diverse therapeutical applications. In our recent work, we reported a Microwave (MW) irradiated Ugi-4 component reaction (Ugi-4CR) in synthesizing a number of steroid-amino acid conjugates based on seco-steroid hydroxyacids (A, B & D ring cleavage) in an expedited way giving very high yield of hybrid products. Considering the importance of steroid based hybrid molecules coupled with advantages of MW energy in organic synthesis, we report here a very high yield synthesis of another class of important hybrid system based on aminosteroids by the application of MW-irradiated Ugi-4CR in expedited way. Methods: For the first time author synthesized Steroid-amino acid conjugated based on steroidal amines by using microwave irradiated Ugi-4CR. Results: The diverse synthesis of Steroid-amino acid conjugated would undoubtedly find a significant place in organic synthesis as steroid-peptide conjugates are currently gaining considerable importance because of their diverse biological properties. Conclusion: The method may also be helpful in promoting green technology in organic synthesis. The reaction proceeds smoothly requiring very short duration of time giving very high yield of Ugi-4CR coupling products. Further work on the biological evaluation of various steroid-amino acid conjugates synthesized is in progress and the results will be published in due course of time.

Background: Gelatin tannate is bowel selective, safe and effective, and acts locally to form a biofilm. As an adjuvant to oral rehydration solution (ORS), gelatin tannate acts as a mucoprotectant in the management of acute diarrhea in children. Objective: To provide an up-to-date review of the pharmacological profile of gelatin tannate, and its efficacy and safety in the treatment of children with acute gastroenteritis. Methods: A medical literature review was conducted using the PubMed database, analyzing all gelatin tannate preclinical research and clinical reports, and post-marketing surveillance data. Results: In vitro studies have demonstrated that gelatin tannate protects biological membranes against corrosive substances. In vivo, gelatin tannate acts not only as a gut mucoprotectant but also as an anatomical and physiological modulator. Moreover, gelatin tannate is an intestinal barrier enhancer endowed with gut homeostatic recovering properties. Clinical studies have shown that the combination of gelatin tannate and ORS has a fast onset of action and is effective and safe in the relief of acute diarrheal conditions in children. Conclusion: Although ongoing clinical studies will address current clinical gaps with gelatin tannate, the findings highlighted in this overview may have particular implications for the use of gelatin tannate in resource-poor, developing countries to treat cases of pediatric acute gastroenteritis.

Background: The Carrier linked prodrug as per literature is known to be a pharmacologically inactive chemical derivative and could be used to change the physicochemical properties of compounds. Codrugs is a type of carrier linked prodrug, and consist of two usually synergistic drugs or moieties attached to each other. Objective: synthesis of codrug consists of two pharmacologically active compounds coupled together where one drug is the carrier for the other and vice versa. Result: It is a very beneficial area of research and its admittance in human therapy has given successful results clinically as well as therapeutically. Conclusion: The emphasis is carried on Benorylate, the Codrug of aspirin and paracetamol for improved anti-inflammatory and analgesic activity. The article also takes a review of the various applications of Codrugs and the development in this field during the last few decades.

Background: New anticancer drug discovery, development and manufacture entered the bottleneck stage. Many limitations of both technology and animal models slow down the anticancer drug developments Objective: To ease economic burdens for drug developers and general patient populations. Methods: Key factors affecting anticancer drug developments and possible roadmaps for updating drug screening routines worldwide are suggested. Results: Drug development chains must be updated and better drug development paradigms must be established. Conclusions: This world welcomes global participations in anticancer drug developments and utilities.

Background: Trans-2-Enoyl-ACP reductase (InhA) is an established target towards anti-tuberculosis therapy. Objective: Computational studies on imidazo[2,1-b][1,3,4]thiadiazole derivatives as putative InhA inhibitors. Methods: Combined molecular docking and three-dimensional quantitative structureactivity relationship (3D-QSAR) comprising comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on imidazo[2,1-b][1,3,4]thiadiazole derivatives as putative InhA inhibitors. Results: Docking analysis reveals that hydrogen bonding, α-π and hydrophobic interactions are the governing factors for anti-TB activity. Furthermore, their best poses were used as an alignment tool for the development of 3D-QSAR models. The CoMFA model exhibited statistically significant results where Leave One Out (LOO) crossvalidated (q2), non-cross validated (r2) and predicted correlation coefficient (r2 pred) values were found to be 0.812, 0.982 and 0.667 respectively, therefore unveiled the important key structural requirements for InhA inhibition. Conclusion: The active site residues GLN100, PRO156, TYR158, LEU197, ALA198, MET199, and LEU218 were identified as crucial binding residues responsible for interactions between inhibitors and InhA. Further, CoMFA analysis theorized that more potent InhA inhibitor could be developed based on proper substitution pattern around the phenyl ring at R2 and R3 position. Conclusively, this comprehensive study, an integration of molecular docking and CoMFA analysis provided insights and new predictive tools for structure-based design and optimization of InhA inhibitors.

Background: Brain insulin receptor is considered an important regulatory factor for appetite regulation, white fat mass metabolism, and hepatic glucose output. Disruption of neuronal insulin action leads to obesity, metabolic syndrome and neurodegenerative disorders. Objective: The aim of the present study was to find out the effect of exenatide, a GLP-1 analog, on the hypothalamic insulin receptor (IR) gene expression in high fat diet (HFD) obesity rat model. Method: Rats were fed on HFD for 16 weeks and received exenatide (10μg/kg/d, SC) for one month. The body weight difference, fasting blood glucose, fasting insulin levels, HOMA index, lipid profile, oxidative stress markers and serum TNF-α were measured. Additionally, hypothalamic IR gene expression was analyzed using real time polymerase chain reaction. Results: HFD rats showed significant body weight gain, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and increase in the oxidative stress and TNFα together with down-regulation of IR gene expression in the hypothalamus. Exenatide significantly reduced the body weight, fasting blood glucose and insulin levels, insulin resistance, dyslipidemia, the oxidative stress and TNF-α serum level. Also, exenatide caused significant up-regulation of hypothalamic IR gene expression. Conclusion: In conclusion, exenatide may exert hypothalamic insulin-sensitizing effect along with its antiinflammatory and antioxidant effects in HFD obese rats.

Background: Methemoglobinemia is a rare cause of cyanosis in pediatric patients and may arise as a result of a genetic defect in red blood cell metabolism or hemoglobin structure, or it may be acquired following exposure to various oxidant drugs or toxins. It is characterized by increased quantities of hemoglobin in which the iron of heme is oxidized to the ferric (Fe3+) form. Case Report: We describe a case of a premature infant who developed cyanosis after dermal application of 1 gram of a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% ointment before the insertion of a central venous catheter for parenteral nutrition. Eight hours after dermal application, his methemoglobin levels were 24.6% and was given an intravenous methylene blue infusion which promptly cleared his cyanosis and restored tissue oxygenation. The samples were analyzed for methemoglobin reductase enzyme activity. The initial enzyme activity level was 14.8 IU/g. Seven months later, the activity level of methemoglobin reductase was repeated and resulted normal (25.7 IU/g). Conclusion: We conclude that a light inadvertent miscalculation of the dose can lead to serious adverse effect, such as in our case. Because preterm neonates are easily overdosed for low weight routinely use of EMLA should be carefully evaluated.