Guidance on the proper conduct and interpretation of new studies on pharmaceutical excipients and food additives [additives] will be reviewed. Since carrageenan (CGN) is used for both applications, this paper will use examples of published CGN studies. Good research on additives requires an understanding of their physical/chemical properties; verification of their identity/purity and molecular weight; as well as, their homogeneity/stability in dosing vehicles. Many publications erroneously misuse the name, CGN, for a sample which is actually “degraded carrageenan” or “poligeenan” and also demonstrate a lack of understanding of the physical/chemical properties. Degraded carrageenan / poligeenan are not approved additives and have completely different physical/chemical and toxicological properties from CGN. Proper nomenclature is essential to good research. Some additives (CGN, guar gum, methyl cellulose) can increase viscosity at high concentrations in vehicles and, thus, may affect palatability, caloric intake and body weight gain. Due to their inherent low toxicity, it is recommended that doses of non-caloric, non-nutritive additives not exceed 5% by weight of total diet to avoid potential nutritional effects. The strong binding of additive to protein in rodent chow or infant formula can result in minimal or no gastrointestinal tract exposure. Recent examples of CGN studies demonstrate the serious misunderstanding promulgated by incorrect sample identity/purity and poor study conduct. Interpretation of new studies on additives should consider the interaction of the additives with the vehicle components, the appropriateness of animal models and dose- response.
Perhaps more than at any time in the past, there’s an enhanced level of collaborative engagement between Academia and Industry, associated with the development of new medicines and therapies for the treatment of a diverse array conditions. In looking at this process, one notices that with the spiraling costs and risks associated with discovering, developing and manufacturing new treatments, even large pharmaceutical companies find it attractive to partner ideas and technology. As a result, today, there is a renewed emphasis towards co-development, in-licensing and collaboration strategies with institutional groups including research hospitals, universities and government organizations, in order to maximize resources and capabilities. A review of the state of these types of instructional collaborations highlights how multiple creative strategies are now fostering these efforts to bring innovations to the forefront of medical treatments.Approaches such as CAR-T therapies, developed at the University of Pennsylvania and now being commercialized by industry for the treatment of cancer, highlight one example. This demonstrates how, through collaborative mechanisms, breakthrough ideas and technologies can produce break out products and enhanced treatment options for patients. The presentation will highlight a few examples to illustrate this collaborative trend between Academia and Industry.
Bcl-2, which is mainly localized to ER and mitochondria, is identified as key regulator of survival and apoptosis. Bcl-2 is reported to block cisplatin-induced apoptosis via regulating Ca2+ signal in a variety of cancer cell lines. However, its target molecule and the mechanism responsible for its inhibitory effect in ovarian cancer are undefined. Our results show that Bcl-2 overexpression reduces cisplatin-induced growth inhibition and apoptosis in SKOV3 human ovarian cancer cells. Furthermore, Bcl-2 inhibited cisplatin-induced Ca2+ release from ER to the cytoplasm and mitochondria, which reduced cisplatin-induced ER stress-mediated apoptosis and mitochondrial apoptotic pathway. Bcl-2 overexpression inhibited the cisplatin-induced increase in the number of ER–mitochondrial contact sites in SKOV3 cells. We also provide evidence that Bcl-2 reduce the anticancer activity of cisplatin toward ovarian cancer cells in vivo. These results suggests that Bcl-2 attenuates cisplatin cytotoxicity via downregulating ER–mitochondrial Ca2+ signal transduction, which may be a potential therapeutic target in ovarian cancer.
Facing an ever increasing volume of data and complexity, life science organizations need real time access to well curated information to pinpoint their focus and speed discovery of safe and effective therapies. IBM Watson Health aims to empower leaders, advocates and influencers in health through support that helps them achieve remarkable outcomes. Watson for Drug Discovery can accelerate the drug discovery process by helping researchers uncover patterns and signals hidden in unstructured data to make non-obvious connections and generate new hypothesis.
Imatinib, (Gleevec) was discovered in 1992 and is regarded as first generation drug since it is the first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML (1). It is approved in 2001 for the treatment of newly diagnosed adult and pediatric patients with Chronic Myeloid Leukemia (CML) and in patients after failure of interferon-alpha therapy. However, approximately 20-25% of patients initially treated with Imatinib need alternative therapy, due to drug resistance, which is often caused by the appearance of clones expressing mutant forms of BCR-ABL (2). Although dasatinib (3, 4) and nilotinib (4) are approved for use in CML in newly diagnosed adults, and dasatinib, nilotinib and bosutinib (3, 5) are approved for use in adults with resistance or intolerance to prior therapy that included imatinib, Phase I and II trials for dasatinib (6), nilotinib (7), and bosutinib (8, 9) demonstrate lack of efficacy and resistance in this patient population. Based on crystallographic studies, we hypothesized that the potency and selectivity of Imatinib mesylate could be improved by incorporating alternative binding groups to the N-methyl piperazine moiety of the compound. This led to the development of NRC-AN-019 (10, 11) and NRC-AN-024 (12, 13) high affinity phenyl amino pyrimidine based Bcr-Abl inhibitors. These compounds were developed using a rational drug design strategy and optimized to improve potency against the ABL kinases. However, in preclinical studies, T315I-mutated cell lines demonstrated decreased sensitivity to NRC-AN-019 and NRC-AN-024 compared with CML cell lines wild type for mutations. Omacetaxine (14) is approved by FDA for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). However, it is administered subcutaneously with non-specific mechanism of action.
Hepatocellular carcinoma (HCC) is the 5th most prevalent tumor type and second leading cause of cancer related deaths worldwide. There are many etiologic agents of HCC, but the most common are chronic infections with hepatitis B and C viruses. Although early HCC is curable by surgical resection, it is often asymptomatic and rarely diagnosed in time. There are many treatment modalities used for patients with advanced HCC, but the efficacy of each approach is fairly limited. Most recently, sorafenib and other multi-kinase inhibitors have been approved for the treatment of advanced HCC, but these only extend life for up to a year post-diagnosis. Alterations in the composition of gut bacteria have been documented in various disease states, including HCC. Given that HCC arises on the background of chronic liver disease, experiments were carried out to test the hypothesis that the re-establishment of a normal gut microbiome would impact upon the pathogenesis of chronic liver disease and HCC. To test this hypothesis, a transgenic mouse model that expressed the hepatitis B oncoprotein, HBx, was used. This model recapitulates most of the pathology and alterations in many molecular pathways that contribute to human HCC in 100% of the animals within 10-12 months. When these mice were fed with selected probiotics for several weeks prior to the appearance of dysplastic nodules, half the mice had no evidence of dysplasia, and the rest had smaller nodules and/or small regions of dysplastic cells. Similar results were observed when mice were treated for several weeks before the appearance of HCC. More than half the animals had no evidence of HCC, and those with tumors had fewer and smaller nodules. These observations suggest that manipulation of the gut microbiome could have profound influences upon the pathogenesis of chronic liver disease and hepatocellular carcinoma.
In today’s market, PBMs and Payers are trying push their current members to utilize mail-order pharmacies. According to IMS Health, only 4.6% of all prescriptions dispensed in 2016 were dispensed through mail order. Due to the aging population, mail-order pharmacies will be seeing a significant rise in patient utilization and number of prescriptions dispensed over the next 5 to 10 years. The population who grew-up with the internet (generation X and millennials) are now reaching the age where an online/mail-order pharmacy would be the preferred option, in the same way that Amazon and Alibaba are preferred methods of purchasing consumer products by these groups. The pharmaceutical industry should be ready for an exponential uptake in mail-order volume at the same growth rates retail consumers have embraced the internet sales markets. With this data in mind, pharmaceutical manufacturers, payers and pharmacies must find ways to adapt to the anticipated change in the marketplace. The data in this presentation analyzes upcoming market trends and is designed to show that an increasing number of people are utilizing the internet for purchases and daily activities, including the purchase of their drugs. As more people are adopting and using the internet for everyday purchases, internet/mail-order pharmacies will become a staple in everyday life for the next generation of patients within the targeted market. The presentation intends to show this imminent growth of this anticipated shift in the patient drug acquisition method and the time lines the upcoming generations will be embracing this method of purchase.
The National Institute for Health Research (NIHR) is the research arm of the UK’s National Health Service (NHS). It plays a key role in the UK Government’s strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, funding programmes, academic centres of excellence and data systems represent the most integrated health research system in the world. This presentation will describe how this unique research infrastructure works in practice to increase the volume of clinical trials and drive faster translation of basic science discoveries into tangible benefits for patients. It will use case study examples which how demonstrate pioneering collaborative models and innovative initiatives bring together the key players in the UK’s clinical research landscape. The speaker will have a specific focus on the delivery of clinical trials within the national health system and will cover: • The benefits of the Network approach • Bringing together the clinical communities for research success • Case study examples of delivering international research in the UK
Collaborative Drug Discovery (CDD) provides trailing innovation for today’s chemical and biological data needs, differentiated by ease-of-use and superior, secure collaborative data sharing workflows. Within the CDD Vault® software, Activity & Registration, Visualization, Inventory, and ELN capabilities all address today’s markets. Researchers need to archive, mine, and collaborate around the structure activity relationships generated from their biological screens. Collaborative hypothesis generation and evaluation allow multiple brains to synergize. In contrast, CDD’s Research Informatics Group invents bleeding edge technologies for tomorrow’s needs. For example, open source descriptors and model sharing capabilities allow for platform-independent collaborations, even for sensitive data and IP, with groups reticent to share. As a second example, the recently developed BioAssay Express (BAE) technology streamlines the conversion of human-readable assay descriptions to computer-readable information. BAE uses semantic standards to mark up bioprotocols, which unleashes the full power of informatics technology on data that could previously only be organized by crude text searching. These two newer web-technologies may be used not only with the CDD Vault, but also with non-CDD software tools. Case studies will be shared from virtual distributed company, government (NIH Neuroscience Blueprint, MM4TB), non-profit (BMGF, MRF, NPDI), and numerous leading academic collaborations.
Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this study we have evaluated the capability of the N-palmitoylethanolamide (PEA), an endogenous lipid mediator, to modulate the neuropathic pain-associated sensorial and neuropsychiatric dysfunctions. We show that PEA reduced the tactile allodynia, restored depressive-like behaviour and cognitive impairments without affecting anxiety-related behaviour in the spared nerve injury (SNI) model of neuropathic pain. Moreover, we also evaluated the possible long term potentiation (LTP) impairment in the lateral perforant pathway (LPP) by stimulating the enthorinal cortex and recording in the dentate gyrus of the hippocampus in vivo. We found a profound impairment in the LTP in the LPP in mice with peripheral neuropathy that was partially recovered by the repeated administration of PEA (10 mpk i.p.). To investigate a possible mechanism by which PEA exerts its effect, we repeated all the data onto the PPAR? null mice, demonstrating that most of the PEA effects are mediated by the interaction with this nuclear receptor. All together these data highlights a possible role of the PPAR? receptors in the brain plasticity associated with neuropathic pain and that the commercially available PEA could be a great candidate in pain treatment at least as an adjuvant therapy for reducing opioid or other analgesic drugs dosage.
This qualitative, transcendental, phenomenological study explored the challenges of 12 female executives in the pharmaceutical industry. There is a paucity of women in senior executive leadership roles in this industry. The scarcity of women leaders warranted the question of factors contributing to: Lack of organizational advancement; challenges faced in the workplace; and lessons learned from the few women executives who had reached the pinnacle of organizational success. This study explored the lived experiences of female executives in the pharmaceutical industry on the Eastern Seaboard; with a goal of understanding the phenomena from their perspective. The research question which guided this study: What are the lived experiences of female leaders ascending the corporate ladder, in the pharmaceutical industry? Two overarching themes emerged: Barriers to Ascendance and Strategies for Success. This research found the participants perceived the upper echelons of leadership in the pharmaceutical environment as being dominated by the male culture, which confirmed that gendered structures continue to exist in this industry. In addition, the participants provided advice how they succeeded despite their challenges in the workplace, through mentorship, sponsorship, networking, leadership training courses, flexibility, and self-branding and promotion.
Neuroblastoma [NB] is the most common solid tumor in infants and is responsible for 15% of all childhood cancer deaths. In this study, we evaluated an experimental therapeutic approach integrating novel mutual prodrugs [co-drugs] and biodegradable nanocarriers in preclinical models faithfully reproducing key features of high-risk NB. Methods and Result: A series of SN38-tocol conjugates constructed exhibiting progressively increasing hydrolytic activation rates were encapsulated in biodegradable NP [average size: 85±36 nm] formulated using a nanoprecipitation protocol modified to produce sub-100 nm sized nanocarriers. NP loaded with a phenolic ester co-drug were found to be most effective against both chemo-naïve and chemoresistant NB cells [IMR-32 and BE(2)-C cells derived at diagnosis and during relapse after chemotherapy, respectively] under conditions modeling different levels of exposure experienced by NB cells within the tumor. Phenolic carbonate and aliphatic ester designs were notably less efficient. In an in vivo model of previously untreated disease [IMR-32 orthotopic xenograft], nanocarriers with phenolic ester co-drug administered over 4 weeks [10 mg/kg, once a week] induced tumor regression and completely inhibited tumor growth over a 26-week period. The same co-drug/nanocarrier formulation tested against chemoresistant NB [BE(2)-C orthotopic xenograft] potently suppressed tumor growth and extended animal survival up to 7 weeks, in contrast to a marginal and transient effect of the clinically used SN-38 precursor, irinotecan [event-free survival of 3 weeks vs. 2 weeks in ‘no treatment’ and drug-free NP groups]. Conclusion: Camptothecin-mitocan co-drugs can be rationally designed as a therapeutic cargo for nanocarrier-based therapy of aggressive NB. The co-drug/nanocarrier combination strategy, whose feasibility and effectiveness against both chemosensitive and drug-resistant NB was demonstrated in the present preclinical studies, holds promise as a treatment for high-risk NB, as well as for other pediatric and adult solid tumors.
According to the European Cosmetics Regulation, it is prohibited in the European Union to market cosmetic products that have been tested on animals. In the US, the FDA does not specifically require the use of animals in testing cosmetics for safety. In the last few years, a great effort is done by researchers and industry to develop new in vitro methods. A lot of methods are now available and considered suitable for providing a reliable interpretation of the safety data. These methods range from simple cell monoculture test to more complex such as explants or specialized reconstructed human 3D tissues. In Europe, claims for cosmetic products shall be supported by adequate and verifiable evidence. The need to find innovative models to study the efficacy of a cosmetic product prior to clinical trials has become particularly urgent. Human reconstructed 3D tissues provide new insights and can also be used to demonstrate the product efficacy. Notably, colonized human 3D tissues mimic the interaction between bacteria and host and can be indicative of human responses. In the present talk, examples of the use of colonized reconstituted human tissues, such as vaginal epithelium and human epidermis, will be discussed providing a realistic and meaningful approach, applied to the case studies, to evaluate the efficacy of cosmetics in intimate hygiene and skin care.
Nanostructured lipid carriers (NLCs) are prompted as the new generation of lipid nanoparticles. Silymarin is the active component of plant S. marianum. It contains 70-80% of silymarin flavonolignan and 20-30 % chemically undefined fraction. Silymarin is gaining acceptability because of its antioxidant, anti inflammatory and anti cancer activities. Aesthetically formulated nanoformulations of silymarin can be exploited for topical and cosmetic benefits. The main objective of the present study was to evaluate the potential of silymarin- loaded nanostructured lipid carriers (SNLCs) for topical photo protective benefits. SNLCs were prepared by emulsification-ultrasonication technique and full factorial design was applied in this study. The percentage yield and percentage entrapment efficiency was found to be 77.24 % and 88.65 % respectively. The average particle size as determined by Malvern Zeta sizer was found to be 278.8 nm, polydispersity index as 0.135 and zeta potential as -20 mV. The roundness and sphericity was calculated and found to be between 0.5 to 1, confirming that the particles were very close to the round shape. The result of in-vitro percentage drug release from NLC loaded gel was found to be 89.45 % for 9 h. The in-vitro antioxidant activity of pure silymarin, silymarin loaded NLC and NLC loaded silymarin gel was estimated and compared. These white and tiny spherical nanocarriers, which appeared like small beads in SEM images can be very aptly called nanopearls. These nanopearls of Silymarin have the potential to be developed into a commercial antiaging sunprotective cream.
Introduction and objectives: Respiratory burst with neutrophil infiltration typically occurs in acute gastritis with Helicobacter pylori (H. pylori) infection. Such natural immune response fails to eradicate H. pylori, whereas severe oxidative stress-mediated injury caused by excessive reactive oxygen species (ROS) from neutrophils was identified in the stomach. Up-regulation of NADPH oxidase subunits (p22/p47-phoxes) in neutrophils plays a key role in extracellular ROS production. In our previous studies, patchouli alcohol (PA), the major active constituent of Pogostemonis Herba, showed effectively anti-H. pylori and anti-oxidant effects. In this follow-up research, we investigated the effects of PA on neutrophil recruitment and activation. Method: In in vivo experiment, H. pylori was injected into rat air pouch to explore the effects of PA (10, 20, and 40 mg/kg) on acute inflammatory response. The number of neutrophils and level of pro-inflammatory factors (TNF-? and IL-8) were detected in exudates. The volume of exudates was also measured. In in vitro assays, neutrophils were isolated by centrifugation, and activated by using 50 µg/mL H. pylori water-soluble surface protein. After treatment with PA (5, 10, or 20 µg/mL), p22/p47-phoxes gene and protein expression were detected by flow cytometry, RT-PCR, Western blot and immunofluorescence. The influence of PA on neutrophil activation genes of H. pylori (h-nap and sabA) was also investigated. Results: PA significantly reduced the volumes of exudate and the number of neutrophils in air pouch. Remarkable decrements of TNF-? and IL-8 in exudates and PEG2 in serum were also observed. Furthermore, results showed significant decrements in inhibition on p22/p47-phoxes gene and protein expression. The expression of h-nap and sabA was remarkably down-regulated after treatment with PA. Conclusion: PA can inhibit the recruitment and activation of neutrophils induced by H. pylori.
The present study aims to develop MTX-S (Methotrexate sodium) in situ gels as an effective way for the treatment of rheumatic arthritis (RA). The in situ gels composed of Pluronic F-127 as a polymer and Hydroxy Propyl Methyl Cellulose K4M (HPMC K4M) and Polycarbophil (PCL) as copolymers were manufactured by cold method. The in situ gels were characterized for gelation time, gelation temperature, syringeability, viscosity, sterility, in vitro release and drug content. The biocompatibility and efficacy of MTX-S in situ gels ascertained using histology analysis and Freund’s complete adjuvant model respectively. The results of the present study showed that the optimized formulation (M4) was thermo-sensitive and exhibited drug release of 93.26±2.39 at 96 h. Moreover, MTX-S was evenly distributed in the optimized formulation which was sterile and syringeable through 18 gauze needle. In vivo study on the wistar rats showed significant decrease in rat paw volume during a 28 day study period. Thus, MTX-S in situ gel could be successfully used for targeting specific treatment of RA.
Many drugs function as agonists of pregnane X receptor (PXR) to induce drug-metabolizing enzymes and transporters, resulting in drug toxicity or resistance. The PXR-mediated drug toxicity or resistance can be reversed by knockdown of PXR, suggesting that PXR antagonists have therapeutic value. However, potent and specific PXR antagonist with in vivo activity is lacking. By using chemical biology, structural biology, and pharmacology approaches, we have discovered a potent and selective PXR antagonist with in vivo activity. We have also developed a series of analogs for structural and functional studies, and proposed models for their mechanisms of action. These novel chemical probes have potential therapeutic utilization in overcoming drug resistance or toxicity.
Bivalent monoclonal antibody (mAb) therapeutics have had substantial impact in treatment of variety of diseases in the clinic. Bispecific mAbs (bsmAbs) are a novel class of mAbs that aim to improve drug efficacy by simultaneously working on two targets, therefore have garnered recent attention and are in clinical trials for several diseases. However, this is a relatively new approach with limited literature in clinical and non-clinical settings. Anti-A/B is a bsmAb therapeutic that targets molecules A and B, which are implicated in the pathogenesis of respiratory diseases. In a multiple dose cynomolgus monkey toxicology study, unexpected high incidence and magnitude of anti-drug antibody (ADA) responses was observed. Characterization of the observed ADA responses was conducted to understand the gross immune dominant epitope(s) of anti-A/B. This presentation discusses our strategy for assessing the ADA responses to the bsmAb and summarizes the characterization results as well as the impact of ATAs on the toxicokinetics/pharmacodynamics (TK/PD) profiles of anti-A/B.
The needs of the modern Life Sciences Industry are putting demands on the Quality Control Analytical departments of companies that have previously not been witnessed. Today this function, whilst remaining part of the Quality function, is never-the-less a significant part of the overall production process and as such needs to be fully integrated to generate the efficiencies and productivity gains associated with modern Manufacturing processes. This integration of Manufacturing, Quality Control and Quality Assurance with the application of the appropriate Process Excellence principles, provides the platform for optimized peak performance and sustainable Quality Compliance. Key to attaining this state of technological nirvana is the development of systems that are “fit for purpose” which promote greater reliability and efficiency. With proper process design in place the application of Lean Process Excellence Principles can move technical production to the next level of performance by streamlining operations, error proofing mechanisms and practices to avoid deviations and by instilling a culture of continuous improvement within the organization. For our modern industry, important in this process are two key components: - 1. The formation of the correct culture 2. A combination of digitization with Lean Process Excellence Principles These will be discussed in relation to improvement on operational efficiency and sustainable compliance.
Background: Poor initiation and implementation and premature discontinuation of anti-tuberculous therapy are major reasons for treatment failure, development of drug-resistance, and transmission to non-infected individuals. Directly Observed Therapy (DOT) is the worldwide standard, but implementation is burdensome, especially in resource-limited settings. Objective: To assess the robustness and usability of a Medication Event and Reminder Monitor (MERM) that is compatible with TB medication formats and supply chains in resource-limited settings. Methods: Usability trial employing a ‘multi-method component design’ to evaluate three sub-dimensions of usability and suboptimal design or operational issues in provider participants and new TB patients 18 years of age or older who registered from October 2015 to January 2016 in two designated Level 2 TB hospitals in the Chinese counties of Luanping and Pingquan. Results: Our sample comprised ten medical staff and thirty patients. Patients reported almost no difficulties using the MERM. Medical staff found MERM easy to use and transmission of patient data convenient. Specific recommendations for MERM improvements have been incorporated in the MERM that is now being employed in a second, ongoing CRT in China (ISRCTN35812455). Conclusion: Employing the MERM for TB medications was associated with a high degree of user performance, acceptability and satisfaction. The MERM could be part of a cost-effective expansion of tuberculosis services for high-burden countries which could generate substantial health and economic benefits for patients with TB. Additional data on the MERM usability will need to be obtained as it is scaled up in additional settings in China and other countries.
An introduction of a new antibiotics into practice acts a selective agent for resistant mutants, the appearance of which is only question of time. Multidrug resistance should invoke a comprehensive strategy. The structural diversity of the antimicrobial peptides (AMP) provides a large versatility of their mode of action. Quantitative structure - activity relation (QSAR) analysis of AMP molecules allowed to construct “designer” molecules; each of them serves as a model synthetize similarly active or even more active derivatives. The number of the synthetized active AMP molecules is >2,000. In the “card-game” between scientists and multidrug resistant pathogens, the (anionic) daptomycin (against Gram positive); and the (cationic) polimixin (in Gram negative) were considered as the (respective) last “trump” and he failure of “ruff” by these drugs would be considered as the end of the antibiotic age. Recent discoveries of synthetic proline, - and arginine-rich and their even more potential oligomer derivatives are encouraging. Another sources are the bacterium symbionts of entomo-pathogenic-nematodes; producing antimicrobial peptide complexes are designed for overcoming introducers of diverse antibiotic resistances, providing monoxenic conditions in a polyxenic environment such a way. Xenofood (a Bio-preparation made of autoclaved culture grown on standard chicken food) proved orally active against gastrointestinal pathogens and exerted no harmful effects on growing chicken in a 42-day experiment.
The PPAR?/? and their agonists have attracted considerable interest as targets for the discovery of novel ligands for the treatment of type 2 diabetes. Thus, offer an advantage to develop novel glitazars as insulin sensitizers. Some of the recently developed glitazars are terminated due to various reasons related to potency and toxicity. In this context, herein, we have made an attempt to develop some novel glitazars as dual PPAR agonists. First, we rationally designed a library of novel glitazars based on structure activity relationships, manually, using the principles of bioisosterism. The manually designed glitazars are scored for similarity with the developed 3D pharmacophore model and subjected for docking studies against PPAR? and PPAR? proteins. Additionally, molecular dynamic simulation was employed to establish and analyse dynamic behaviour of target protein-ligand complexes. Finally, designed library of 24 glitazars are synthesized. The synthesized glitazars are analysed for their structures. All the 24 glitazars were subjected for in vitro cytotoxicity assay against 3T3-L1 cells to determine the cytotoxic concentration. Further, subjected for lipid lowering and glucose uptake studies against 3T3-L1 and L6 cells, respectively. Some of these glitazars (3, 7, 8, 18, 19, 21 and 24) showed good lipid lowering as well as glucose uptake activities. CoMSIA studies are performed to establish 3D structure activity relationships. Illustration about the molecular design of glitazars, synthesis, analysis, lipid lowering activity, glucose uptake activity and SAR via 3D QSAR studies are parts of this presentation.
The decreasing effectiveness if antibiotics in treating common infections results from the spread of antimicrobial resistance (AMR), and represents a serious global public health crisis. This presentation will discuss antibiotic misuse as a primary driver for AMR, and identify specific drivers as: (i) Overuse of antibiotics in medical applications including hospitals, outpatient and nursing homes; (ii) Overuse and misuse of antibiotics in agricultural and veterinary applications; (iii) Antibiotics as environmental contaminants; (iv) International travel and trade accelerating the global movement of antibiotic resistance genes and strains. The presentation will focus on gram negative ESKAPE & ESBL pathogens and identify clinically important carbapenemase (CRE) species and their actions. The CRE producing pathogens are a first class health emergency as they confer resistance to both carbapenems and all ?-lactam antibiotics and are often associated with multidrug resistance. This presentation will cover risk factors for development and spread of CRE and a look at the global extent of AMR. We will also present effective treatment regimens for gram negative infections using carbapenem antibiotics. Solutions to help overcome AMR problems in treating both community and nosocomial infections include prudent use of antibiotics in all practice settings, and setting up a vigorous antimicrobial stewardship (AMS) program. Infectious disease management programs should include strong surveillance programs for drug resistance and antibiotic consumption, and also use of rapid diagnostics to reduce unnecessary use of antibiotics. It is estimated that from 20% to 50% of all medical antibiotic use are inappropriate and lead to AMR
Controlled release drug delivery systems (DDSs) easily injectable into the intra-articular (IA) cavity with long residence time, are beneficial for the treatment of arthropathies.1,2 Recently, the roles of galectin-3 (Gal-3) in rheumatoid arthritis (RA) have been described, presenting it as a potential immunotherapeutic target3 and triggering extensive efforts of new anti-RA drug-candidates synthesis. Triple aim of this work was (1) synthesis and screening of Gal-3 inhibitors (Gal-3i), (2) the engineering of a biodegradable injectable nanotechnology-based platform, (3) Gal-3i encapsulation within this DDS and evaluation of its activity in vivo. A novel highly affine Gal-3i with aromatic substituents introduced to type II lactosamine core [Gal-?(1?4)-GlcN] was synthesized and analyzed by NMR and MS, Kd = 590 nM to Gal-3 (4 °C).4 Hydrophobic Gal-3i was firstly encapsulated within NCs prepared using a simple solvent displacement method. The encapsulation efficiency (EE%) was 11 ± 2 % (531 ± 5 µg/mL). NCs have nanometric size (122 ± 11 nm), negative surface charge (?29 ± 5 mV) and regular spherical shape. Then, an injectable in situ hydrogel with controllable gelation time and rheological properties was developed. The hydrogel allowed 30% (v/v) NCs loading upon its self-assembly, revealing the regular structure (mean pore diameter 4.88 ± 1.12 ?m and its narrow distribution). Preliminary in vivo studies (rat acute synovitis model) demonstrated a remarkable suppression of inflammation by Gal-3i encapsulated at doses 55 ?g/kg and 200 ?g/kg, presenting Gal-3i as a lead compound for anti-RA drug candidate. The DDS showed good syringeability and viscosupplementation properties.
Silk fibroin (SF) is derived from Bombyx mori and is a protein proven to be of magnificent bio-compatibility and in-vivo bio-degradability. It is important to formulate and design the nanoparticles which are non-toxic and safe for the future clinical application. The aim of the present work was to develop Tamoxifen Citrate (TC) loaded silk fibroin (SF) based nanoparticles by aqueous solution method. The prepared nanoparticles were evaluated for its zeta potential, surface morphology, drug content, encapsulation efficiency and in-vitro drug release. The prepared nanoparticles were characterized by FTIR and X-ray diffraction. The diameters of the obtained nanoparticles were in the range of 210-250 nm, drug entrapment of 56 to 79%, loading content was found to be within 22 to 43% respectively and zeta potential of -11.6 to -15.4 mV. The XRD spectrum suggests that the characterised diffraction peaks of ?-sheets of SF with both lower & broader peak within 20-23º confirming that TC was encapsulated in nanoparticles in amorphous form. In-vitro drug release from the prepared nanoparticles was found to be 41±1.2 to 55±1.5%. Finally, from the results it was concluded that silk fibroin based nanoparticle drug delivery system could serve as a promising carrier system for better delivery of the drugs.
Docetaxel is an approved cytotoxic agent for use in treatment of breast, prostate, head and neck, gastric and non-small cell lung cancer. Fluid retention as edema, ascites or pleural effusion is a known side effect of docetaxel treatment . However, pericardial effusion has been rarely reported with docetaxel treatment [2, 3]. It is also difficult to distinguish malignant effusion  and radiation induced effusion  from docetaxel treatment related pericardial effusion. In our case, there was no other comorbidities or treatments that can explain the large amount of pericardial effusion . The patient was a female receiving docetaxel and cyclophosphamide in the adjuvant setting of resected breast cancer. After three cycles of treatment, she was admitted to the emergency room with shortness of breath and cough. On chest radiography, significant expansion of the cardiac silhouette was seen and cardiac tamponade was verified by echocardiography. The patient was treated with pericardiocentesis followed by percutaneous catheter drainage. Cytological evaluation of the fluid did not show any malignant cells. Adjuvant treatment of the patient was changed to doxorubicin and cyclophosphamide. 5-year follow-up of the patient did not show any recurrence of either breast cancer or pericardial effusion. In conclusion, pericardial effusion is a rare but life-threatening side effect of docetaxel treatment. Physicians should be aware of this side effect for accurate diagnosis and immediate treatment.
Background-Type 1 diabetes mellitus is a disease characterized by the lack of pancreatic islet ? cell function. Whole tissue transplantation appears to be viable alternative in its management due to limitation of exogenous insulin therapy. This study aims at fabrication and evaluation of microtissue encapsulating pancreatic islet ? cells (? TC-6) in alginate chitosan microcapsules using specialized spraying nozzle. Method-Microcapsules encapsulated with ? TC-6 cells were fabricated using novel spraying device producing uniform spherical microcapsules. Microcapsules were characterized for permeability using molecular weight markers, stability and cell viability using Live Dead Staining kit. Microencapsulated ? islet cells were transplanted intraperitoneally into streptozotocin (STZ) induced diabetic mice and monitored for lowering in blood glucose level and immune acceptance. Result-Spherical microcapsules with diameter in the range of 250-350 µm were formulated at an air flow rate of 250 L/Hr. The encapsulated cells in alginate capsules demonstrate prolonged viability. Cell only group rejected graft in 1 or 2 days after administration, microencapsulated group maintains normoglycemia for 35±5 days before rejection and exhibit both cellular and humoral immune responses. CD4 Tcells mediated Th2 response was predominant and thus generates humoral responses, further confirmed from elevated levels of CD45R in groups transplanted with microencapsulated ? islet cells. Conclusion-Microcapsules produced by specialized nozzle were reproducible with narrow size distribution, provides flexibility in producing different sized capsules. Our finding for in vivo study suggest that transplantation of microencapsulated ? TC-6 cells may be a viable alternative for the management of type 1 diabetes mellitus.
Bacterial attachment to surfaces and consequent biofilm formation have serious implications in the food, environmental, and medical fields. When ingested, Listeria monocytogenes can cause serious and possibly fatal illnesses in humans and animals. Spinach can get contaminated by L. monocytogenes during harvest. This study aimed to evaluate the effectiveness of six nonionic surfactants (Pluronic F68, Pluronic F127, Tween 20, Tween 40, Tween 80, and Brij 58) in disrupting L. monocytogenes biofilms on the surface of spinach leaves. Wells were washed with surfactants after incubation and then mixed on a platform shaker for 1, 5, 15, and 30 min. Then, the wells were rinsed with distilled water to remove dead cells, and fixation was conducted at 30 min at 60 °C. Our findings showed that Brij 58 most effectively removed the L. monocytogenes biofilm on spinach, followed by Pluronic F127, Tween 80, Tween 40, Tween 20, and Pluronic F68. The amount of polysaccharides and proteins secreted by Listeria increased with time. Moreover, addition of extracellular polymeric substances changed the hydrophobic properties of the leaves, which was necessary for adhesion and biofilm.
Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. There were many reports about the environmental pollutants metabolism. However, there are few studies on influence of drug transporters by environmental pollutants such as polychlorinated biphenyl, diesel exhaust particles, permethrin, heavy metals. Herein, an up-to-date review on this topic is presented. Aim: To review the potential regulatory effects of environmental pollutants on the activities of ATP-binding cassette (ABC) efflux, solute carrier (SLC) uptake drug transporters and other transporters. Method: Routinely collected literatures from Pubmed database were utilized. Results: The approaches utilized to study environmental pollutants-transporter interaction include inhibition experiments of specific transporters in cell models (e.g. Caco-2 cells), transport study using drug resistance cell lines or transgenic cell lines expressing transporters in wild type or variant. Many of transporters have been reported to exhibit either positive or negative regulator recognition such as Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Proteins (MRPs), P-glycoprotein (P-gp), Organic Anion Transporters (OATs), Organic Anion Transporting Polypeptides (OATPs), Organic Cation Transporters (OCTs), Multidrug and Toxin Extrusion Transporters (MATEs), Dopamine Transporters (DATs), Glucose transporter (GLUT), Bile Salt Export Pump (BSEP), Divalent Metal Transporter 1 (DMT1). Conclusion: Some environmental pollutants can act as regulators of the drug transporters activity, making contributions to toxicity in human exposed to environmental pollutants. Therefore, it is important to understand the mechanism of pollutants toxicity mediated by drug transporters for the effective management of environmental pollutants.
Food safety remains a concern owing to numerous cases of foodborne diseases resulting from bacterial pathogens. Listeria monocytogenes is one of the three most serious foodborne pathogens. Essential oils are volatile compounds found in the secondary metabolites of aromatic plants. Owing to their high terpenoid and phenolic compound content, these oils are potential natural antimicrobial agents for food preservation, but their low water solubility limits their efficacy and application in food. In the present study, 28 different essential oils were evaluated for their antimicrobial activities against Listeria monocytogenes. Various concentrations of essential oils were introduced into brain heart infusion broth to determine the minimum inhibitory concentration (MIC) for the pathogen. To quantitatively evaluate the effect of each oil on L. monocytogenes from a kinetic viewpoint, the experimental data were fitted to the modified Gompertz model, and the lag phase duration and maximum growth rate were calculated and compared for each essential oil at various concentrations. Overall, our experimental results indicate that frankincense, eucalyptus, and fire needle oils had the strongest inhibitory effects against L. monocytogenes with MICs lower than 2.4 µg/mL. Essential oils with moderate antimicrobial effects included key lime, cedar wood, Egyptian geranium, nutmeg, peppermint, valerian, and ylang ylang.
Currently, infectious diseases of the developing world (e.g., malaria, tuberculosis) represent a global health challenge of the 21st century and require new approaches that would allow scientists to do research more effectively. As a result of the development of web-database technologies (CDD Vault®), a collaborative approach to research on antibiotics and infectious diseases for global health has emerged. The major components of effective scientific-community based research include: (1) unifying goal or focus on common therapeutic areas/diseases; (2) multiple research areas/expertise; (3) uniform database platform for effective data accumulation and management; (4) easy access and sharing of information; (5) potential for unlimited growth. The Collaborative Drug Discovery (CDD) Vault® was built by utilizing innovative web technologies in order to provide a platform that allows scientists to archive, mine, and securely share research data with a focus on global collaborative R&D. This new collaborative technology allows researchers to build up networks of technical experts around therapeutic or target areas thus advancing research facilitating the discovery of new drug candidates. It also allows scientists to speed up research by sharing unpublished data providing new hope in the race to overcome drug resistance. An example illustrating how potential chemosensitizers that address chloroquine resistance could be identified by using the CDD Vault® database platform is presented.
A large amount of researches have been done to discover the pharmacological activities and adverse side effects of Ginkgolic acid (GAs). GA (C17:1) could be metabolized by CYPs and UGTs. Chemical inhibitor experiments indicated that rats CYP1A1/2 and CYP3A were involved in GA (C17:1) oxidative metabolism; UGT1A7 and UGT1A9 were involved in GA (C17:1) glucuronidation metabolism. Classical CYP substrates were used to investigate the inhibition effect of GA (C17:1) on the CYPs. The results showed that GA (C17:1) inhibits rat CYP2C6 with no effect on CYP 3A, CYP1A1/2, CYP2E1, CYP2D1. Three metabolites of GA (C17:1) in rat liver microsomes (RLMs) were analyzed to be two mono-hydroxylation metabolites and a glucuronidation metabolite by LC-MS/MS. The affinity of GA (C17:1) to human liver microsomes (HLMs) was less than that to RLMs. In HLMs, CYP3A4 and CYP1A2 were the two CYP enzyme isoforms that mediated the oxidative metabolism of GA (C17:1), UGT1A6, UGT1A9 and UGT2B15 were involved in GA (C17:1) glucuronidation metabolism. GA (C17:1) showed some inhibition effect on CYP2C9. This work was supported by Nature Scientific Fund of China (81173120) and The National Key Research and Development Program of China (2017YFC0908600).
Oxidative stress arises due to the imbalance between pro-oxidants and anti-oxidants and it is a major cause of pathogenesis in dengue severity. Structure and function of lipids and proteins are damaged after reacting with pro-oxidants forming lipid peroxides (LP) and protein carbonyls (PC). Severe dengue hemorrhagic fever (DHF) and dengue fever (DF) patients admitted to Colombo North Teaching Hospital, Sri Lanka, were recruited for the assessment of LP, antioxidant capacity (AOC) and PC using FOX-2 assay, ABTS decolorization assay and a commercially available kit respectively in patients at the time of admission (DHFA & DFA), critical stage (DHFC), discharge (DHFD & DFD), convalescence after 30 days (DHF-con and DF-con) and in healthy controls (HC). NOx levels were studied with modified Griess assay and Angiopoietin 1 and 2 levels were also studied in these categories of patients and healthy controls. DFA patients recorded significantly higher levels of NOx (nitrite and nitrate, p<0.05), LP (p=0.027) and PC (p<0.001) compared to DHFA. AOC in HC was significantly higher compared to different stages of dengue patients (p<0.001). These results show more damage of lipids and proteins in DFA patients and this effect may be due to more production of pro-oxidants such as reactive nitrogen and oxygen species in DFA patients. Accordingly it is evident that high levels of pro-oxidants are produced at early stage of the mild dengue (DF) infection, which may be involved in reducing the viral load effectively whereas at severe dengue, less production of the pro-oxidants at early disease stage may lead to high viral load resulting severity. Reduction of AOC in dengue patients compared to healthy controls also indicates the utilization of antioxidants to neutralize pro-oxidants produced in dengue patients. Moreover, Angiopoietin-2 levels were found to be significantly (p<0.001) elevated in the patients at the critical stage where plasma leakage is started showing the effects of increasing Angiopoietin 2 levels in inducing endothelial destability.
Phage therapy has been developed to be an alternative strategy to battle against multidrug resistance bacterial infectious agents, especially the nosocomial bacterial infections including Acinetobacter baumanii (AB). One of the main problems concerning phage therapy is that bacterium can develop to be a lysogen which becomes resistant to the same phage treatment. This lysogenic mechanism regulates when the bacterium host is infected by temperate phage which unfortunately seems to be the major kind of isolated phages by various researchers. Seldom do we isolate virulent phage which can maintain re-infection of the bacterial host by the phage’s progeny without lysogenic pathway. In this study, we isolated four bacteriophages of AB (AB-phage). Among our collective AB, many of them are susceptible to one of these AB phages. Exceptionally, one of our collective AB, called AB 121, can be infected by all of these four AB phages. Accordingly, we did an in vitro study by using these AB phages to treat the AB 121 by a single and plural phage therapy. In addition, we investigated how the lysogenic AB 121 can be treated by other different AB phages. Unexpectedly, we found that the lysogenic AB do not just withstand the primarily exposed phage, it can also resist other AB phages. This study presents another complexity of phage therapy that we should be more careful to go on with the phage therapy once the lysogen has been developed during the process of phage therapy.
The modern long acting sulphonamide antibiotic sulfametopyrazine (SMP) or sulfalene used for the treatment of chronic bronchitis, urinary tract infection and in malaria is a challenging candidate for impurity profiling. The method development, quantification and impurity profiling was performed for SMP by RP-UFLC, LCMS and 2DNMR spectroscopy. The impurity was detected by newly developed RP-UFLC and LCMS method. The chromatographic method with low-pressure gradient mode, separation was achieved using Phenomenex Hyperclone BDS C18 (5.0?m, 250×4.6mm) column with mobile phase consisting of ammonium formate buffer pH 4.0 adjusted with orthophosphoric acid (B) and acetonitrile (A) in the ratio 40:60 (v/v), with a flow rate of 1.0 ml/min and the eluent was monitored at 254 nm using PDA detector. The selected chromatographic conditions effectively separated SMP and its unknown impurity with the retention time of 3.04 and 4.12 min respectively. The drug was found to be linear in the range of 2-10 µg/ml. The LCMS studies was carried out by adapting the same chromatographic condition using ESI with a positive ion mode the fragmentation behaviour of SMP and impurity gave prominent m+1 ion peak at 281 g/mol and 449 g/mol. The detected impurity has been resolved by gradient elution mode using preparative HPLC. The chemical name of the unknown impurity was found to be N-(3,5- dimethoxypyrazin-2- yl)-4- ((3,6-dimethoxypyrazin- 2-yl)amino) benzenesulfonamide which was confirmed by HNMR, 13CNMR, COSY, HSQC and Mass spectrometry. The developed method of SMP in presence of related substance was found to be very efficient and validated following ICH guidelines.
HistoWiz automates histology and has built an intelligent tissue platform for biomedical researchers in academia and pharmaceutical industry. Their mission is to fight cancer cooperatively instead of individually. Unlike core facilities and CROs, they guarantee a 48-hour turnaround time from fixed tissue specimens to digital slides online. They shares the scanned images with researchers via a cloud system, allowing for unprecedented viewing, archival, collaboration, tagging, search and meta-analysis of histology data. They have the largest online preclinical pathology database in the world growing at 220% a year. PathologyMapTM employs a novel image-tagging technology to capture key information such as species, disease, organ, experimental treatment, genetic background and biomarker information. This online platform allows researchers to compare histology data and discover new insights from hundreds of academic institutions (e.g. MSKCC, Harvard, Johns Hopkins, CSHL, Cornell, Dana Farber, NIH, MD Anderson, Stanford, the Jackson Lab, HHMI and Cancer Research UK). It also enables the development of machine learning tools for cancer diagnosis, prognosis and personalized therapy. The three machine learning tools currently being developed at HistoWiz are automatic tumor identification, mitosis count, and image similarity search. PathologyMapTM allows cancer researchers, clinicians, medical students, computer programmers and anyone interested in learning more about histopathology to access the latest discoveries in the cancer research community.
There is nothing more critical to the healthcare industry than the public’s trust, and the time is right to maximize this trust through consensus, practice, policy and appropriate resource utilization in the pharmaceutical market. A full understanding of pharmaceutical pricing and implementation of best practices provides a cost effective system, a better distribution of treatments for the global population and methodology for consensus on individual country policies that cooperate with worldwide systems. Many models, theories and arguments present, and all should be thoroughly considered as economic changes in healthcare occur. Comprehensive and collegial agreements on drug pricing will increase public awareness as well as responsibility and accountability within pharmaceutical industries and their stakeholder partners. A thorough and global understanding is crucial. This provides for a stronger public health system, assures equal knowledge distribution for all healthcare industry participants and creates the trust that is essential.