Current Drug Therapy - Volume 12, Issue 2, 2017

Background: Ezetimibe is an inhibitor of the intestinal absorption of cholesterol. There are different cholesterol transporters in small intestine and one of the most important is Niemann-Pick C1L1 protein (NPC1L1), who is the therapeutic target of ezetimibe. When we talk about cholesterol gallstones disease, we deal with a public health problem, whose pharmacological treatment is limited. Ursodeoxycholic acid is used to dissolve cholesterol stones, and statins are other drugs with possible applications in the treatment of this disease. Objective: Our main purpose is to discuss how is that the authors have reported on the effects of ezetimibe in cholesterol gallstones disease and to make a proposal on different mechanisms of action that can contribute to the future treatment of this disease. Results: When gallstones generate symptoms, medical treatment indicates gallbladder removal. In different scientific studies, ezetimibe has been studied as a drug for preventing and treating cholesterol gallstones; however, is not the same dissolve cholesterol gallstones (treatment) than inhibit their formation (prevention). In the twenty-first century, there seems to be a broad interest in studying the intestinal absorption of cholesterol and associate it with the treatment of gallstones. It is an interesting research pathway in the research of treatment and prevention of gallstones. Conclusion: Ezetimibe is a drug that needs more clinical studies to be considered as an agent for the treatment and prevention of cholesterol gallstones.

Background: Swine influenza is a seasonal health threat due to global outbreak of H1N1 pandemic in 2009 leading to death of millions of people because of antigenic drift of the dangerous influenza A viral strains. Scarcity of specific chemotherapeutics emphasizes the priority of drug design and discovery of new anti-influenza leads having less toxicity and resistant to the dynamic viral strains. Objective: The present review is an update in the current trends in drug design from the stand point of ligand and structure based screening of potent swine influenza inhibitors. Method: In quest of different drug targets, ligand and structure based chemometric screening tools are the major platform for the design of potent chemotherapeutics having greater affinity towards various targets including polymerase basic protein 1 (PB1), PB1-F2, PB2, polymerase acidic protein (PA), surface glycoproteins hemagglutinin and neuraminidase, nucleocapsid protein (NP), nuclear matrix proteins including M1, Ion pore protein - M2 as well as two nonstructural proteins NS1 and NS2, respectively. Results: Ligand based screening deals with QSAR and pharmacophore modeling whereas structure based virtual screening deal with crystallography and molecular docking. Conclusion: The study in this direction can increase the search of hit rates and decrease in cost of drug design and development prior to experiment by producing potent chemotherapeutics against swine influenza.

Background: The resistant to current therapy against tuberculosis is tremendously increasing, novel potential anti-tubercular compounds should be developed at the urge. The presently reported analogues act by binding to the kat-G gene present in Mycobacterium tuberculosis which converts them into active form, thereby inhibiting inhA mediated mycolic acid synthesis. Objective: To establish structure activity relationship, identify key features and find out the binding orientation of the compounds to the katG gene present in Mycobacterium tuberculosis for the treatment of tuberculosis. Methods: In the present work, 2D Quantitative Structure Activity Relationships, 3D Quantitative Structure Activity Relationships, pharmacophore mapping and docking studies of isoniazid derivatives have been carried out with V-life Molecular Design Suite 4.2, Schrodinger and GOLD (Genetic Optimization for Ligand Docking) program. The model was developed by PLS (Partial Least Square) and kNN (k-nearest neighbour) as variable selection method. Results: The best 2D Quantitative Structure Activity Relationships model was developed with r2 = 0.9688 and q2 = 0.8082 and correlated the effect of descriptors on the biological activity. The best 3D Quantitative Structure Activity Relationships model showed a crossvalidated correlation coefficient (q2) of 0.7332 and a predicted r2 for the external test (pred_r2) of 0.9032. The pharmacophore analysis represented that the features such as hydrogen bond acceptor, hydrogen bond donor and aromatic ring were essential for the anti-tubercular activity. When docked, the isoniazid derivatives showed good binding affinity to the receptor even in resistant cases (mutant type) and showed favourable fitness scores in-silico as compared to isoniazid. Conclusion: The whole studies served as a basis for the development of better potential therapeutic compounds for anti-tubercular activity.

Objective: The aim of present study is to develop and explore efficiency of 5.0G EDA PAMAM dendrimers as long-duration drug release carriers for the treatment of tuberculosis. Method: Rifampicin (RIF) was selected as a major drug for incorporation into PAMAM dendrimers based on its anti-tubercular activity and hydrophobic nature. Further polyethylene glycol (PEGylated) PAMAM dendrimers were evaluated for their hemolytic toxicity and in vivo anti-tubercular studies. The 5.0G PAMAM dendrimers are prepared by using initiator core ethylene diamine and methyl acrylate. Furthermore, the PEGylation was done by polyethylene glycol 2000 using epichlorhydrin as a cross linking agent. Result: The Rifampicin loaded PEGylated 5.0G PAMAM dendrimers were characterized by FTIR, NMR, DSC and SEM analysis. The in vivo study report ensures the suitability of PEGylated dendrimer in connection to prolonged delivery of Rifampicin. Moreover, PEGylated system has shown a reduced hemolytic toxicity. Conclusion: The observed results concluded that the PEGylated method was less time consuming, inexpensive, and reproducible, and it also reduces toxicity.

Background: Ceftriaxone belongs to the third-generation β-lactam antibiotics and it is useful for the treatment of a number of infectious diseases caused by both aerobic and anaerobic Gram-positive and Gram-negative bacteria. Phenylalanine is an essential aromatic amino acid of human being, from which dopamine and norepinephrine neurotransmitters are being synthesized. In the present study, we examined their combined efficacy against different types of pathogenic bacterial strains. Objective: The aim of the study was designed to investigate the effects of ceftriaxone combination with phenylalanine on antimicrobial activity Method: Gram positive-bacteria and Gram negative- including Klebsiella pneumoniae, – ATCC 25923, Proteus vulgaris, Escherichia coli, Serratia marcrescens, Staphylococcus epidermis, Alpha haemolyticus streptococcus, Enterococcus faecium, Pseudomonas aeruginosa, Listeria monocytogenes ATCC 7644, Enterococcus durans, Salmonella kentucky, Enterobacter aerogenes ATCC 13048 and Candida albicans ATCC 26555 were exposed to ceftriaxone and phenylalanine based on disk-diffusion method, and Minimum inhibition concentration (MIC) was determined with ceftriaxone. Results: 0.3 mol/L ceftriaxone and 0.3 mol/L phenylalanine solutions were mixed and observed greater zone of inhibition than ceftriaxone or phenylalanine alone against above mentioned bacterial strains. These results might open up a new avenue for using phenylalanine in combination with ceftriaxone to lower MIC level for better antibacterial effect, to reduce side effects of antibiotics, and to reduce emerging threats of antibiotic resistance bacteria. Conclusion: In this study, combined use of phenylalanine and ceftriaxone has revealed increased antimicrobial sensitivity against some selected both Gram positive and Gram negative bacteria in vitro.

Background: The damage of synapses and neurons leads to the cognitive impairment and this is the root cause of progression of Alzheimer's disease. The nematode Caenorhabditis elegans is widely used as an in vivo model to study the synaptic transmission because of the relatively modest worm nervous system, which is like mammals. Objective: The aim of this work is to assess the effectiveness of resveratrol-loaded nanostructured lipid carrier for the management of Alzheimer's disease. Method: Resveratrol loaded nanostructured lipid carrier (RES-NLC) was prepared by modified solvent emulsification-diffusion technique, using compritol 888ATO (solid lipid), sesame oil (liquid lipid) and tween 80 (surfactant). Results: Formulations were characterized via particle size (155.08±3.28 nm), polydispersity index (PDI) (0.121), and zeta potential (-16.58). The entrapment efficiency was found to be 79.65±2.52% and cumulative percentage drug release was 63.54% up to 8 hours. Anticholinesterase inhibition competence was performed through Aldicarb assay. It was found that surge in the dose of RES-NLC caused an increased worm paralysis, which was credited to the accumulation of acetylcholine in synapses. Quantitative RT-PCR performed showed the effect of formulation on acetylcholinesterase (AChE) AChE 1 and AChE 2 genes. RES-NLC (dose 400 μg/ml) decreased the AChE 1 expression 3.23±0.13 fold whereas AChE 2 expression decreased 3.34±0.14 fold with the same dose. RES-NLC displayed transfer latency and escape latency of 27.50 ± 2.34 and 30.17 ± 2.82. Conclusion: Based on the results, it was concluded that RES-NLC was effective in increasing acetylcholine concentration in synapses and thus in the treatment of Alzheimer's disease.

Background: The anti-anginal agent ivabradine hydrochloride acts by selective and specific inhibition of the cardiac pacemaker current. The oral bioavailability of ivabradine is approximately 40% because of first-pass effect in liver and intestines. Objective: The present study targets QbD abetted formulation and in vivo evaluation of transdermal patch to avoid limitations allied with oral administration. Method: Transdermal patch was prepared using HPMC K15 and ethyl cellulose by solvent evaporation technique. D-optimal mixture design was applied to study the effects of critical process parameters, HPMC K15 and Ethyl cellulose ratio on critical quality attributes, permeation flux, cumulative amount of drug permeated, per cm2 of skin at 12 and 24 h. The optimized batch was evaluated for in vitro dissolution, physicochemical parameters, drug release and pharmacokinetic study, using developed bioanalytical method. Results: Transdermal patch containing HPMC K15 and ethyl cellulose (66.132: 33.868) showed control release and acceptable physicochemical properties. Chromatographic separation of analytes, Ivabradine hydrochloride and Verapamil hydrochloride, internal standard, was achieved on C18 column (250 x 4.6 mm, 5µm) using methanol: 5mM disodium hydrogen phosphate buffer (80:20, %v/v), at 1 ml/min flow rate and 287nm. This proposed bioanalytical method was further applied for pharmacokinetic studies of prepared transdermal patch after single application to Wistar rats. It exhibits higher AUC, mean residence time, and longer t1/2 as compared to marketed formulation. Conclusion: The successful verification of safety and pharmacokinetic profile of IH transdermal patch advocated the suitability of formulation for transdermal use and an efficient alternative of oral administration.