Numerous Pharmaceutical Companies Research Articles

AN OVERVIEW ON ORAL THIN FILMS–METHODOLOGY, CHARACTERIZATION AND CURRENT APPROACH

The pharmaceutical sector is looking for new ways to deliver drugs, and one such way is through thin films. It has been said that thin films offer an alternative to traditional dosage forms. They offer rapid, local, or systemic effects and are a very flexible platform. Furthermore, patients with dysphagia, elderly, paediatrics, or bedridden patients, as well as those who have difficulty accessing water, can easily utilize these systems on their own. There are several ways to administer these drug delivery systems, including transdermally, ocularly, buccally, sublingually, and orally. One of the most creative and patient-focused novel drug delivery systems is Orodispersible Thin Films (OTF). Numerous pharmaceutical companies and academic experts worldwide are currently investigating the potential of these films for delivering drugs derived from both synthetic and natural sources. The beauty of this special drug delivery method is that, as we can see from the subjects' consumption of conventional dosage forms (tablets, capsules), they don't require water to be consumed. Furthermore, these delivery methods do a great job of encouraging patient compliance in general, especially in the case of both older and pediatric patients. This review shows a detailed review of oral thin film its applications and method of preparation; mainly focus of this research is thin film introduction to researchers and last 10 y of research on thin film with drugs and polymers used in research.

IOT Based Smart Wastewater Treatment Model for Industry 4.0 Using Artificial Intelligence

Wastewater is created by pharma firms and has become a huge worry for the ecosystem. There is a significant amount of toxins that are being dropped continuously from numerous pharmaceutical companies that causes serious damages to the environment and public health because of its comprising high organics as well as inorganic loadings and thus requirements appropriate treatment before final disposal to the ecosystem. Goal of this approach is to treat the wastewater treatment model with industrial data. Algorithms of the artificial neural network (ANN) were employed progressively to predict parameters for wastewater plants. This provision assists users to take remedial measures and function the process by the standards. It is proven as beneficial technology because of its complicated mechanism, dynamic and inconsistent changes in aspects, to overcome some of the limitations of common mathematical models for the wastewater treatment plant. The target is to achieve better prediction accuracy in wastewater treatment model. In this paper, ANN approaches are relevant to the prediction of input and effluent chemical oxygen demand (COD) for effluent treatment procedures. Artificial neural networks (ANNs) offer accurate technique modeling for complex systems using an artificial intelligence technique. Three distinct types of back-propagation ANN were devised to avoid the concentration of wastewater treatment facilities in the concentration of COD, suspended particles, and mixed liquid solids in an epidermal water treatment tank (MLSS). To anticipate COD levels in influential and effluent areas, two ANN-based techniques have been presented. The proper structure for the neural network models was identified via a variety of training and model testing methods. An efficient and robust forecasting tool has been created for the ANN model.

In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.

Dual-targeting Approach on Histamine H3 and Sigma-1 Receptor Ligands as Promising Pharmacological Tools in the Treatment of CNS-linked Disorders

With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters, or enzymes have been synthesized by numerous pharmaceutical companies and academic institutions. Since central nervous system disorders are characterized by diverse physiological dysfunctions and deregulations of a complex network of signaling pathways, optimal multipotent drugs should simultaneously and peculiarly modulate selected groups of biological targets. Interestingly, very recent studies have shown that some clinically evaluated histamine H3 receptor antagonists possess a nanomolar affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These two different biological structures, histamine H3 and sigma-1 receptors, combined, can represent a potential fruitful target for therapeutic developments in tackling numerous human diseases.

Need for online registration of the clinical trials on humans by authors!

Need for online registration of the clinical trials on humans by authors!

Cerebrospinal Fluid and Blood Biomarkers in Alzheimer's Disease

To cope with an aging society, development of disease-modifying drugs for Alzheimer's disease (AD) is essential. Currently, only symptomatic treatments that suppress clinical manifestations are available. Amyloid-β₄₂ (Aβ₄₂) is an AD-related pathogenic molecule that triggers development of AD pathology; thus, decreasing Aβ₄₂ in the brain is a promising candidate for AD therapy. Numerous pharmaceutical companies have developed therapeutic drugs against Aβ₄₂, such as β-secretase inhibitors, γ-secretase inhibitors, and anti-Aβ monoclonal antibodies, but in clinical trials for patients with mild to moderate AD, these drugs did not meet the expected endpoints. These results suggest that earlier administration of these drugs to individuals who have not yet developed cognitive decline, but have AD pathological changes in the brain or high risk of developing these changes, may be beneficial. To enable such early treatment, preclinical AD biomarkers are required. In this review, we comment on current AD biomarkers in cerebrospinal fluid and in blood. We also explain CSF/blood APL1β, which is a candidate surrogate marker for Aβ₄₂ in the brain.

Navigating the clinical trial pathway: Conception, design, execution, and results dissemination

Dr Sampalis is founder, Chief Executive Officer, and Chief Scientific Officer of JSS Medical Research Inc, founded in 1997. He is a tenured professor of Surgery and Epidemiology & Biostatistics of McGill University, the University of Montreal and University of Laval. Recognized as a leading clinical epidemiologist and one of the top trauma researchers in Canada, he possesses extensive expertise in health services research, clinical trials, and offers services as a Research and Epidemiological Consultant for numerous pharmaceutical companies, hospitals and government organizations and agencies. Mrs. Watson holds a M.Sc. in Pharmacology from Dalhousie University, and a B.Sc. from the University of Western Ontario. Her experience extends to all facets of the CRO business, and multiple therapeutic areas. She co-founded, in 1992, Integrated Research Inc, a full-service contract research organization, and served as its President and Chief Executive Officer, until merging with JSS Medical Research Inc in 2014. Mrs. Watson currently holds the position of Chief Business Officer, and is head of the business development team. Mrs. Boukas has been working with the JSS Medical Research team since its inception in the 1990s. She holds a B.A. in Psychology from McGill University with training in Epidemiology and Biostatistics, and is certified by the Society of Clinical Research Associates (SOCRA) as a Certified Clinical Research Professional (CCRP). She has over 25years' of experience in medical research management. Currently Chief Operations Officer, Mrs. Boukas has been essential in structuring and implementing programs at JSS Medical Research Inc to facilitate project management, site recruitment, data capture and study tracking. Mrs. Boukas holds a B.A. from McGill University, a Certificate in Technical Communications from Concordia University and has received compliance training from SNC Lavalin Pharma (SLP) and SOCRA. She has over twenty-five years' experience in research. Joining JSS Medical Research Inc in 1998, she currently holds the position of Executive Director of Quality Assurance (QA) where she developed and maintains the QA Program since 2004. The QA Program supports clinical studies conducted in Canada, Latin America, India and Europe. Mrs. Harvey holds a B.Sc. in Biochemistry from the Université du Québec à Montréal and a M.Sc. in Biology from McGill University. With 20years' experience in the pharmaceutical industry, she has held positions in both Commercial and Medical departments. Mrs. Harvey currently holds the position of Director, Clinical Operations at JSS Medical Research Inc, functionally and operationally overseeing a team of project and data managers in the development and implementation of clinical studies. Dr Machado obtained his medical degree from the University of Pune, India. He has over 20years' experience in multinational pharmaceutical, CRO, Bioequivalence & Phase I and Site Management Organizations, working in several therapeutic areas and phase of studies. As a founder of Venn Life Sciences, Dr Machado served as Chief Operating Officer, until joining JSS Medical Research Inc in 2011, where he is currently Vice-President, Global Operations & Integration. In addition to overseeing global operations, he is responsible for global expansion and integration of JSS Medical Research Inc through acquisitions and mergers. Mr. Bordeleau holds a B.Sc. in Biochemistry from the University of Guelph and an MBA from HEC Montreal. He has over 20years' experience in the pharmaceutical industry, including laboratory and IT research, healthcare marketing support, and IT team management. As Global Director of information Technology at JSS Medical Research Inc, Mr. Bordeleau leads a team of programmers as well as network, database and system administrators who specialize in developing, maintaining, and most importantly, improving, key software, clinical systems, infrastructure, and business processes. Dr Rampakakis received his Ph.D. from the Department of Biochemistry from McGill University, and obtained post-doctoral training, also at McGill, in Pharmacoepidemiology. With over 15years' experience in scientific research, he has contributed in the conception, design, analysis and interpretation of several large scale, national and international, registration and observational studies. He currently holds the position of Vice President of Scientific Affairs at JSS Medical Research Inc, overseeing a team of biostatisticians, epidemiologists, physicians, medical writers, and health economists.

Muscle wasting: an overview of recent developments in basic research.

The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.

Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.

Silence Is Not the Best Medicine: Requiring Disclosure of Clinical Trial Data for Abandoned Drugs

Imagine that you suffer from a debilitating disease that has no known cure. There may be hope, however, as numerous pharmaceutical companies have, for several years now, studied the condition in se...

The potential nephrotoxicity of antiretroviral drugs

The intensive studies carried out in many scientific laboratories and the efforts of numerous pharmaceutical companies have led to the development of drugs which are able to effectively inhibit HIV proliferation. At present, a number of antiretroviral agents with different mechanisms of action are available. Unfortunately, long-term use of antiretroviral drugs, however, does not remain indifferent to the patient and can cause significant side effects. In the present work, the antiretroviral drugs with a nephrotoxicity potential most commonly used in clinical practice are described. In the review attention has also been focused on the nephropathy resulting from the HIV infection alone and the influence of genetic factors on the occurrence of pathological changes in the kidney.

Planned Arthritis Guidelines Stress Exercise

Planned Arthritis Guidelines Stress Exercise

Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development

Drug toxicity is a leading cause of attrition of candidate drugs during drug development as well as of withdrawal of drugs post-licensing due to adverse drug reactions in man. These adverse drug reactions cause a broad range of clinically severe conditions including both highly reproducible and dose dependent toxicities as well as relatively infrequent and idiosyncratic adverse events. The underlying risk factors can be split into two groups: (1) drug-related and (2) patient-related. The drug-related risk factors include metabolic factors that determine the propensity of a molecule to form toxic reactive metabolites (RMs), and the RM and non-RM mediated mechanisms which cause cell and tissue injury. Patient related risk factors may vary markedly between individuals, and encompass genetic and non-genetic processes, e.g. environmental, that influence the disposition of drugs and their metabolites, the nature of the adverse responses elicited and the resulting biological consequences. We describe a new strategy, which builds upon the strategies used currently within numerous pharmaceutical companies to avoid and minimize RM formation during drug discovery, and that is intended to reduce the likelihood that candidate drugs will cause toxicity in the human population. The new strategy addresses drug-related safety hazards, but not patient-related risk factors. A common target organ of toxicity is the liver and to decrease the likelihood that candidate drugs will cause liver toxicity (both non-idiosyncratic and idiosyncratic), we propose use of an in vitro Hepatic Liability Panel alongside in vitro methods for the detection of RMs. This will enable design and selection of compounds in discovery that have reduced propensity to cause liver toxicity. In vitro Hepatic Liability is assessed using toxicity assays that quantify: CYP 450 dependent and CYP 450 independent cell toxicity; mitochondrial impairment; and inhibition of the Bile Salt Export Pump. Prior to progression into development, a Hepatotoxicity Hazard Matrix combines data from the Hepatic Liability Panel with the Estimated RM Body Burden. The latter is defined as the level of covalent binding of radiolabelled drug to human hepatocyte proteins in vitro adjusted for the predicted human dose. We exemplify the potential value of this approach by consideration of the thiazolidinedione class of drugs.

Designer drugs for discerning bugs

Almost all antibiotics used in clinical medicine owe their origin to natural compounds. Discovery of these compounds has traditionally been driven by an outward-looking Saganesque conviction (somewhere, something incredible is waiting to be known) that broad screening of many hundreds of species of bacteria and fungi would unearth novel antimicrobials. Indisputably, this approach has yielded results. More than 200 species of free-living actinomycete bacteria have been shown to produce antimicrobial compounds. Many of these compounds have been of medical value, and their usefulness could be expanded by chemical tweaking to improve pharmacological properties. The discovery and development of antimicrobial drugs has, however, been an arduous and expensive process. For instance, the macrolide antibiotic erythromycin originates in the actinomycete Saccharopolyspora erythraea and has been derivatized by numerous pharmaceutical companies over the past 50 y to yield thousands of compounds (1); a few promising leads were then subjected to lengthy pharmacokinetics testing, toxicological studies, and clinical trials in preparation for the approval process. After finally entering the clinic, the lifespan of an antimicrobial drug might be short and risks being curtailed at any time by bacterial resistance. Such considerations have caused major drug companies to opt out of antimicrobial development (2), leaving medical science without an adequate flow of new antibiotics. The drug discovery process obviously needs streamlining but not at the expense of drug testing, safety, and approval. Two studies in PNAS (3, 4) indicate how the antimicrobial pipeline might be fed with likely drug candidates that target the bacterial ribosome.

Histamine H3 Receptor Antagonists: Preclinical Promise for Treating Obesity and Cognitive Disorders

The histamine H3 receptor is an attractive G protein-coupled receptor drug target that regulates neurotransmission in the central nervous system and plays a role in cognitive and homeostatic functions. Drug discovery efforts by numerous pharmaceutical companies have focused on the preclinical development of H3 receptor antagonists for the potential treatment of attention-deficit hyperactivity disorder, dementias, schizophrenia, as well as obesity and sleep disorders. This receptor exhibits molecular, pharmacological, and functional heterogeneity that informs the preclinical development of effective antagonists. Herein, we describe the biological and chemical implications for developing H3 receptor antagonists and their therapeutic potential as disclosed through animal models of cognition, sleep, and obesity.

Inhibitors of mast cell tryptase beta as therapeutics for the treatment of asthma and inflammatory disorders

A survey of the available biological data on tryptase inhibitors suggests that there is considerable interest in tryptase as a therapeutic target particularly for the treatment of allergic asthma and inflammatory disorders. This interest was driven primarily by data from studies carried out on the cellular and in vivo actions of this serine protease over the past decade, all of which have suggested a pro-inflammatory role for tryptase. Tryptase beta is the form of interest in allergic asthma and the data from numerous studies have shown that tryptase cannot only contribute to airway bronchoconstriction and hyperresponsiveness, but may have a key role in fibrosis and ECM turnover, hallmarks of the remodeling process. Hence, inhibitors of tryptase have the potential to make an impact on fibrosis and airway wall remodelling. However, few studies, if any, have been carried out to determine the effect of tryptase inhibitors on airway remodeling and this is an area that warrants further investigation with the appropriate models because the eventual positioning of tryptase inhibitors in asthma therapy will be strengthened by data supporting an impact on airway remodeling in addition to effects on bronchial hyperresponsiveness. This review has focused on tryptase inhibitors in the pipeline and it is clear that with a few exceptions, the majority of these compounds are targeted for inhaled delivery. Finally, judging by the interest from numerous pharmaceutical companies, it appears the stage is set for tryptase inhibitors to make their mark as drugs of the future for allergic asthma and the results from clinical trials is awaited with eager anticipation.

Impact of clinical trial protocols on patient care systems at the University of Texas M.D. Anderson Cancer Center.

Clinical trial protocols represent a significant component of the research program at the University of Texas M.D. Anderson Cancer Center. Currently, there are nearly 800 active protocols using more than 150 investigational drugs. Sponsors of these trials include the National Cancer Institute, numerous pharmaceutical companies, and a variety of other funding sources. Because of our large patient base, however, routine participation in cooperative groups is limited. The impact of clinical trial protocols on patient care systems is a growing concern that is addressed primarily by the Surveillance Committee at M.D. Anderson. Like many institutional review boards, this committee reviews all protocols and must grant approval before the activation of any clinical trial. The issues of medical ethics, including a risk-benefit assessment for research subjects, equitable patient selection, safeguards for economically disadvantaged populations, and the general requirements for informed consent, also fall under the purview of this board. For any comprehensive cancer center to succeed, it must have strong research programs that enhance treatment options for patients. The crisis in financing health care significantly threatens the viability of cancer research. Reimbursement for the related costs of individuals participating in clinical trials has become a battle ground for third-party payers. The resulting economic risk is shared by health care providers and patients. As a consequence, many cancer centers, including M.D. Anderson, have initiated an economic-impact analysis for protocols as a component of the review process. This analysis includes an estimation of the patient care costs compared to the funding allocated to support the research. Future research will include pharmacoeconomic analysis and other ways to relate the costs and outcomes of treatment protocols. In the interim, we must monitor reimbursement trends for patients enrolled in clinical trials closely and amend the informed consent process to include a discussion of potential economic risk or hardship to patients if insurance claims are denied. Cancer care providers, third-party payers, the federal government, and society at large must work together to address the funding of cancer research and patient care.