Jignasa K. Savjani

Drug Solubility: Importance and Enhancement Techniques

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

Mechanisms of Resistance: Useful Tool to Design Antibacterial Agents for Drug - Resistant Bacteria

Drug-resistant bacteria are now a global health threat. In the last 5 years the WHO, The House of Lords (UK), the Centre for Disease Control (USA) and many more agencies have presented reports on the scale of this problem. Microorganisms multiply very rapidly and have adapted to fill almost every available environmental niche (Rapidly growing species of bacteria under ideal conditions of growth can multiply in about 20 minutes). All members of the chemically related beta-lactam class act at the same phase in cell wall synthesis; as a result, a bacterial cell resistant to one agent is often resistant to all other analogues. The beta-peptide has two promising characteristics that distinguish it from traditional antibiotics. Firstly, bacteria may have trouble developing resistance to the beta-peptide since bacterial defenses may not recognize its unnatural amino acids. Secondly, the magainins that the beta-peptides mimic have been around for millions of years, yet bacteria have not become resistant to them. All classes of antibiotics are subject to resistance by an efflux mechanism mediated by more than one type of pump within the same organism. The bacterial cell may have a membrane pump capable of pumping a class or several classes of antibacterial agents back out of the cell. Other mechanisms of drug resistance include destruction of beta-lactam ring by beta-lactamases, impermeability of the drug into the bacterial cell wall, alteration of targets within the bacterial cells and the by-pass mechanism (bacterial cell may have acquired an alternative mechanism for achieving the essential function).

A review on ROCK-II inhibitors: From molecular modelling to synthesis.

Rho kinase enzyme expressed in different disease conditions and involved in mediating vasoconstriction and vascular remodeling in the pathogenesis. There are two isoforms of Rho kinases, namely ROCK I and ROCK II, responsible for different physiological function due to difference in distribution, but almost similar in structure. The Rho kinase 2 belongs to AGC family and is widely distributed in brain, heart and muscles. It is responsible for contraction of vascular smooth muscles by calcium sensitization. Its defective and unwanted expression can lead to many medical conditions like multiple sclerosis, myocardial ischemia, inflammatory responses, etc. Many Rho kinase 1 and 2 inhibitors have been designed for Rho/Rho kinase pathway by use of molecular modeling studies. Most of the designed compounds have been modeled based on ROCK 1 enzyme. This article is focused on Rho kinase 2 inhibitors as there are many ways to improvise by use of Computer aided drug designing as very less quantum of research work carried out. Herein, the article highlights different stages of designing like docking, SAR and synthesis of ROCK inhibitors and recent advances. It also highlights future prospective to improve the activity.

Recent updates for designing CCR5 antagonists as anti-retroviral agents

The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.

Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents

ABSTRACT Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non‐Steroidal Anti‐inflammatory Drugs (NSAIDs). Cyclooxygenase‐2 (COX‐2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti‐inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID‐4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4‐Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure‐Activity Relationships) software. The study indicated most of the compounds under safe category. In‐vitro pharmacological assessment of heterocyclic compounds was done for COX‐1 and COX‐2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti‐inflammatory activity and ED50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX‐2 enzyme. The pharmacological screening uncovered that compound substituted with p‐bromophenyl indicated maximum potency. Graphical abstract Anti‐inflammatory activity with IC50=2.13 &mgr;M. Figure. No Caption available.

Computer aided docking studies of some antimicrobial agents

Mark S. Kindy Department of Neurosciences, Medical University of South Carolina, and the Ralph H. Johnson VA Medical Center, USA Recently, interest in semiallogeneic vaccines has been increasing, as shown by the publication of successful preclinical and clinical studies by us and others that validate this immunotherapeutic approach to cancer, viral diseases such as the acquired immunodefi ciency syndrome and neurological diseases. Th ese reports indicate that treatment with semiallogeneic vaccines can induce a specifi c immune response against various tumors and against the human immunodefi ciency virus. Experimental studies using inbred mice and their syngeneic tumors initially established that 1) inoculation of semiallogeneic cell hybrids (derived from the fusion of syngeneic tumor cells with an allogeneic cell line) protects the animal host from subsequent lethal challenges with unmodifi ed syngeneic tumor cells; 2) adoptive transfer of immunity required T lymphocytes; and 3) the enhanced immunity was not the result of an allogeneic eff ect per se, because the tumor-associated antigens and alloantigens needed to be on the same cell (the hybrid). Human studies with semiallogeneic cell hybrids have focused on the use of therapeutic vaccines for cancer. Because of the many technical problems associated with obtaining suffi cient amounts of autologous tumor cells for the preparation of patient-specifi c cancer vaccines, and because of evidence that allogeneic eff ects may enhance the antitumor immune response, it seemed reasonable to combine the best of both approaches (autologous and allogeneic), because semiallogeneic hybrids focus allorecognition and major histocompatibility complex self-restricted recognition on the same cell and, therefore, in the same microenvironment. Our studies demonstrate the feasibility of using semiallogenic vaccines to treat a variety of tumors and neurological disease.Daming Zhu Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Disease, National Institutes of Health, USA Malaria is one of most deadly infectious diseases in the world, with an estimated 350-500 million people suff ering from malaria episodes and nearly 1 million deaths per year. Most of these episodes are caused by Plasmodium falciparum and P. vivax parasites. Th e world is in urgent need of a vaccine to combat against malaria. Th e quality control is one of the most important processes in vaccine research and development because it directly relates to the safety and effi cacy of the vaccines. Th is presentation will focus on the quality control evaluation of malaria sub-unit vaccines. Th e biophysical/biochemical/biological methods involved in evaluating vaccine purity, identity, integrity, stability and potency will be discussed. Th ese methods should have general applications for the quality control evaluation of subunit vaccines.Olga Borges University of Coimbra, Portugal Th e development of oral and nasal formulations for under-utilized vaccines in order to simplify their transport, storage and administration in poor countries is considered a challenge [1]. In fact, for eff ective oral immunization, antigens must be protected from the acidic and proteolytic environment of the gastrointestinal tract, effi ciently taken up by cells of the gut associated lymphoid tissue (GALT) and an appropriate immune response must be induced [2]. With this in mind we have been working on the design of chitosan-based particles as adjuvant for mucosal vaccination and recently a new delivery system was evaluated as adjuvant for oral administration of the recombinant hepatitis B antigen (HBsAg) [3]. In this previous work we obtained some promising results, like high titers of anti-HBsAg IgG in serum and antiHBsAg sIgA in mice intestinal washings. However, a high percentage of non-responder mice were observed. Th erefore, the main objective of the group is to develop more sophisticated chitosan-based delivery systems associating to the particles not only the antigens but also an immunopotentiator. Th ree diff erent chitosan-based formulations were developed associating to them aluminum salts, a mast cell activator (c48/80 compound) and CpGODN. An overview of the work done by group on the development of a mucosal hepatitis B vaccine, as well as in vitro results of these new adjuvants will be present during the congress.Yasuyuki Ishi RIKEN Research Center for Allergy and Immunology, Japan Invariant natural killer T (iNKT) cells having Th e invariant T cell antigen receptor (TCR)  chain are a unique population to regulate the immune response between the innate and acquired immunity. iNKT cells interact with glycolipids presented via CD1d molecule on antigen-presenting cells (APCs), resulting in the activation of killing activity and the production of a variety of cytokines. KRN7000, alpha-galacosyl ceramide (-GalCer), among glycolipids functions as the powerful ligand for not only rodent but also primate iNKT cells. As iNKT cells potentially have two bi-directional functions, one is immune activation and the other is immune suppression, it was expected that KRN7000 would be utilized as an adjuvant for various vaccines of cancer, infectious and immune diseases. However, the pharmaceutical development of KRN7000 is not successful because of the bi-directional functions of iNKT cells. In our recent studies, two functions of immune activation and suppression are dissected by the in vivo delivery system of KRN7000. Dendritic cells (DCs), the professional APCs, could be used as delivery cells of KRN7000 for immune activation. Systemic administration of KRN7000-pulsed DCs preferentially enhanced protective immunity against tumors and infection by microbes. In contrast, liposomal formulation of KRN7000 could be delivered to the marginal zone B220positive cells in a spleen, induce regulatory T cells (Treg) and diminish immune responses in model animals of autoimmunity, allergic diseases and graft versus host diseases (GvHD).Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Egypt Th e success of anti-tumor immunity depends on the generation of functionally eff ective T cells. Adoptive cell therapy (ACT) of autologous tumor-reactive T cells aft er chemotherapy a nd followed by vaccination is a promising approach for generation of functional T cells for cancer immunotherapy. Th is ACT modality consists of in vitro stimulation of T cells from a host own peripheral blood or tumor and then infusing them back to the same host blood followed by vaccination regimen such as peptide or peptide-pulsed dendritic cells (DCs). Th e host is irradiated or treated with chemotherapeutic drug such as cyclophosphamide (CTX) prior ACT to induce lymphopenia. Th e cellular and molecular mechanisms underlying the benefi cial eff ects of lymphodepletion in the context of adoptive T cell therapy and vaccination, however, are not well understood. Defi ning these mechanisms would signifi cantly improve the application of lymphodepletion to ACT. Our recent studies have identifi ed expansion of DCs, the central player of immune response, as a potential mechanism. We have utilized the toll-like receptor 3 (TLR3) agonist poly(I:C), a synthetic viral mimic double-stranded RNA, to induce the full activation of DCs expanded in vivo aft er chemotherapy and during vaccination with defi ned tumor antigens, resulting in effi cacious therapeutic anti-tumor responses. Our results reveal that the combination of T cell therapy and vaccination in the presence of a potent adjuvant such as a TLR agonist at precise timing post chemotherapy opens a new avenue for cancer immunotherapy that can be translated into the clinical setting to cure diff erent cancers.