Number Of Pharmaceutical Companies Research Articles

More transparency for clinical trial data: The decision by the European Medicines Agency to make clinical trial reports publicly available could provide a boon for biomedical research.

More transparency for clinical trial data: The decision by the European Medicines Agency to make clinical trial reports publicly available could provide a boon for biomedical research.

Developing Oncology Biosimilars: An Essential Approach for the Future

The treatment of many diseases, particularly cancer, has been profoundly impacted by the introduction of biologic therapies (biologics), which are incorporated into the treatment algorithms of most oncology clinical practice guidelines. Biologics are large molecular weight, structurally complex proteins that are produced via complex manufacturing processes. With the patents of key biologics, including many widely used in oncology, set to expire in the near future, a number of pharmaceutical companies have focused on developing biosimilars. While the goal of development is to demonstrate that the biosimilar product is highly similar to the reference biologic product, biosimilars should not be viewed as "generic" biologics. Generic drugs are small chemical moieties that are identical to the patent-expired "reference" small-molecule drugs. It is not possible to produce an identical copy of a biologic, so the term "biosimilar" was chosen to define an appropriately similar biologic product. Improving patient access to cancer therapies such as biologics and reducing healthcare costs are key initiatives of the US Government; the integration of approved biosimilars into clinical practice will be instrumental in accomplishing these goals.

New IVF techniques put mitochondrial diseases in focus

New IVF techniques put mitochondrial diseases in focus

TRIPS and Public Health

The efforts of developing countries to use the mechanisms provided under TRIPS to promote public health have come under pressure from industrialised countries and multinational pharmaceutical companies in a variety of ways. For example, a number of pharmaceutical companies challenged the South African legislation empowering the minister of health to issue compulsory license (granting permission to a third party to manufacture a patented drug) under certain circumstances. The law was based on the premise that expensive drugs, such as the anti retro viral (ARV) drugs used in the treatment of HIV/AIDS, were unaffordable to large sections of society and that the consequent lack of access to drugs was leading to a serious health crisis within the country. The action of the pharmaceutical industry against the South African initiative led to widespread criticism of the TRIPS agreement by the developing world, NGOs and human rights activists. The controversy led to the Doha Declaration on Public Health of November 2001.This paper outlines the events leading up to the Doha Declaration and examines whether or not the declaration provides for sufficient flexibility to fulfill the public health needs of all WTO member countries.

Insulin-like growth factor receptor type I as a target for cancer therapy

After more than 20 years of extensive work, insulin-like growth factor receptor 1 (IGF-IR) is still an attractive target for drug development. Due to its close homology to insulin receptor, IGF-IR is of interest for antibody design while antibody great specificity allows to discriminate between the two receptors. Major efforts from a large number of pharmaceutical companies are invested to evaluate the efficacy of such molecules in human without so far an obvious success. Discovery of biomarkers associated with efficacy and patient selection is one of the main challenges that we will have to deal with in order to target the appropriate patient population that will most benefit anti-IGF-IR monoclonal antibody (Mab) and combined treatments. This review will provide an overview of the current knowledge on IGF-IR axis for development of novel therapeutics in Oncology.

Progress on the research and development of human enterovirus 71 (EV71) vaccines

Enterovirus 71 (EV71) infections, which can cause severe complications, have become one of the serious public health issues in the Western Pacific region and China. To date, a number of pharmaceutical companies and institutes have initiated the research and development of EV71 vaccines as a countermeasure. As is the case with innovative vaccine development, there are several critical bottlenecks in EV71 vaccine development that must be overcome before the clinical trials, including the selection of vaccine strain, standardization of the procedure for quantifying neutralizing antibody (NTAb) and antigen, establishment and application of a reference standard and biological standards, development of animal models for the evaluation of protective efficacy, and identification of the target patient population. To tackle these technical obstacles, researchers in Mainland of China have conducted a series of studies concerning the screening of vaccine strains and the establishment of criteria, biological standards and detection methods, thereby advancing EV71 vaccine development. This review summarizes recent worldwide progress on the quality control and evaluation of EV71 vaccines.

The Chimeric Approach Reveals That Differences in the TRPV1 Pore Domain Determine Species-specific Sensitivity to Block of Heat Activation

The capsaicin-, heat-, and proton-activated ion channel TRPV1, a member of the transient receptor potential cation channel family is a polymodal nociceptor. For almost a decade, TRPV1 has been explored by the pharmaceutical industry as a potential target for example for pain conditions. Antagonists which block TRPV1 activation by capsaicin, heat, and protons were developed by a number of pharmaceutical companies. The unexpected finding of hyperthermia as an on-target side effect in clinical studies using polymodal TRPV1 antagonists has prompted companies to search for ways to circumvent hyperthermia, for example by the development of modality-selective antagonists. The significant lack of consistency of the pharmacology of many TRPV1 antagonists across different species has been a further obstacle. JYL-1421 for example was shown to block capsaicin and heat responses in human and monkey TRPV1 while it was largely ineffective in blocking heat responses in rat TRPV1. These findings suggested structural dissimilarities between different TRPV1 species relevant for small compound antagonism for example of heat activation. Using a chimeric approach (human and rat TRPV1) in combination with a novel FLIPR-based heat activation assay and patch-clamp electrophysiology we have identified the pore region as being strongly linked to the observed species differences. We demonstrate that by exchanging the pore domains JYL-1421, which is modality-selective in rat can be made modality-selective in human TRPV1 and vice-versa.

De-risking the clinical development of cholesteryl ester transfer protein inhibitors: how much is good enough?

This editorial refers to ‘Torcetrapib impairs endothelial function in hypertension’†, by B. Simic et al. , on page 1615 Modification of HDL cholesterol (HDL-C) metabolism is the next frontier in cardiovascular drug development, and modulation of cholesteryl ester transfer protein (CETP) is an important addition to our armentarium in this field. Clinical trials have shown that CETP inhibitors substantially improve blood lipid profiles by raising plasma levels of HDL-C while simultaneously lowering LDL-C over and above what can be achieved with statin therapy.1–3 The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was the first phase III trial testing the efficacy of the CETP inhibitor torcetrapib (Pfizer, New York, NY, USA) in reducing the risk of cardiovascular events. ILLUMINATE had to be halted in late 2006 after an interim analysis by the Data Safety and Monitoring Board had indicated a statistically significant increase in total mortality in the torcetrapib arm.4 Almost simultaneously, the entire clinical development programme of torcetrapib was stopped. This unexpected finding has called into question the validity of CETP as a potential therapeutic target, but it has also challenged the concept of raising HDL-C levels to reduce cardiovascular disease risk. Despite suffering from this unprecedented set back, CETP is still considered by many to be a viable therapeutic target, and other CETP inhibitors are being developed by a robust number of pharmaceutical companies. Following the publication of ILLUMINATE, analyses of the imaging trials with torcetrapib, in vitro and in vivo experiments, genetic epidemiology studies, and phase II studies with other CETP inhibitors have been used to clarify whether torcetrapib's unexpected detrimental effects were an off-target side effect of the compound itself, or a phenomenon …

Reverse Payment Settlements in the Pharmaceutical Sector: A European Perspective

On 17 January 2011, the European Commission launched , a monitoring exercise of patent settlements in the pharmaceutical sector for the second time after the Pharmaceutical sector inquiry of 2009. As was the case for the first monitoring exercise launched in January 2010, a number of pharmaceutical companies were asked to submit copies of their patent settlement agreements concluded in the European Economic Area (EEA), together with any relevant annex, amendment or related agreement.The rationale for the monitoring exercise derives from some of the findings of the Pharmaceutical Sector Inquiry, which had highlighted the possibility that some of the agreements reached by originators and generics to settle IP-related disputes (generally believed to be efficiency-enhancing tools to save money on litigation costs), may in fact turn out to have anticompetitive effects on the market. This is particularly the case for so-called “reverse payment agreements”. These are settlements that involve a payment (in direct or indirect form) flowing in a direction that intuitively appears “reverse”, as money is paid by the patent holder (the originator) to the alleged infringer – a generic firm.

Social media and compliant pharmaceutical industry promotion: The ASCO 2010 Twitter experience

Pharmaceutical and biotechnology companies are beginning to establish a significant corporate social media presence, but the extent to which tools such as Twitter are being utilized to discuss and disseminate newly available scientific data remains poorly understood. This study analyzed over 3400 tweets generated by attendees at a major global scientific conference in order to better understand the actual extent and nature of pharmaceutical and biotechnology industry discourse via Twitter. The pharmaceutical industry and its support service providers were the largest segment of ASCO Twitter oncology community users, but unlike physicians, predominantly utilized this medium for promotional dialogue as opposed to clinical news or clinical management discussion. The total number of pharmaceutical companies that utilized Twitter on site as an adjunct to other public relations channels was small. This first-in-kind analysis uncovers key best practices for compliant pharmaceutical and biotechnology social media...

Glycine Transporter-1: A New Potential Therapeutic Target for Schizophrenia

The hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory site on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. A recent double blind phase II study demonstrated that the novel GlyT-1 inhibitor RG1678 has a robust and clinically meaningful effect in patients with schizophrenia. In this article, the author reviews the recent findings on the GlyT-1 as a potential therapeutic target of schizophrenia.

Glycine Transport Inhibitors for the Treatment of Schizophrenia~!2009-09-10~!2009-09-21~!2010-05-27~!

Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) shows antipsychotic activity in patients with schizophrenia. Accordingly, a number of pharmaceutical companies have developed novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. This paper provides an overview of the various GlyT-1 inhibitors and their therapeutic potential.

Editorial:[Novel Therapeutic Drugs for Neuropsychiatric Disorders

Editorial:[Novel Therapeutic Drugs for Neuropsychiatric Disorders

Glycine Transport Inhibitors for the Treatment of Schizophrenia

Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) shows antipsychotic activity in patients with schizophrenia. Accordingly, a number of pharmaceutical companies have developed novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. This paper provides an overview of the various GlyT-1 inhibitors and their therapeutic potential.

Phosphoinositide 3-Kinase Gamma (PI3Kγ) Inhibitors for the Treatment of Inflammation and Autoimmune Disease

Phosphoinositide 3-kinase gamma (PI3Kgamma) is a lipid kinase in leukocytes that generates phosphatidylinositol 3,4,5-trisphosphate to recruit and activate downstream signaling molecules. Distinct from other members in the PI3K family, PI3Kgamma is activated by G-protein coupled-receptors responding to chemotactic ligands. PI3Kgamma plays an important role in migration of both myeloid and lymphoid cells. It is also required for other leukocyte functions such as neutrophil oxidative burst, T cell proliferation and mast degranulation. Mice with PI3Kgamma inactivated by genetic or pharmacological approaches are protected from disease development in a number of inflammation and autoimmune disease models. The function of PI3Kgamma depends on its kinase activity and therefore it has been suggested by many reports that small molecules inhibiting its kinase activity could be promising for the treatment of inflammation and autoimmune diseases. Over the last five years, a number of pharmaceutical companies have reported a wide variety of PI3Kgamma inhibitors, of which several x-ray crystal structures with PI3Kgamma have been elucidated. The structural characteristics and selectivity profiles of these inhibitors, in particular thiazolidinones and 2-aminoheterocycles, and those disclosed in related patent applications are summarized in this review.

Pharmaceutical expectations and CRO expectations – how can we best get them to agree?

AbstractA large number of pharmaceutical companies now use contract resource organisations (CROs) for the reporting of their clinical trials, use in data monitoring committees (DMCs) or for consultancy work. High expectations are placed on the CRO to create the best possible results, in the fastest possible time for the least possible cost. This paper intends to explore the expectations from both interested parties, resulting in some possible solutions/suggestions to make the working relationship easier, more efficient and with less stress on either side.

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

Targeting Cyclooxygenase and Nitric Oxide Pathway Cross-Talk: A New Signal Transduction Pathway for Developing More Effective Anti- Inflammatory Drugs

Cyclooxygenase (COX) and nitric oxide synthase (NOS) are two isoenzyme families that both implicated in the inflammatory process. Indeed, the activities of both enzymes are so important that two of the most important classic drugs, Aspirin and Nitroglycerin, are directly related to the COX pathway and NO pathway, respectively. Although Aspirin has been used as an anti-inflammatory drug since 1876, it was not until 1970s that its action has been shown to be involved in inhibition of the Cox enzyme, being a class of drugs known as non-steroidal anti-inflammatory drugs(NSAIDs). This signaling pathway has led to extensive research led by a number of pharmaceutical companies in the race to make more effective anti-inflammatory drugs, such as ibuprofen and colecoxib to name but a few. Similarly, the nitroglycerin has been used to treat angina more than a hundred years, its only until late 1980s its drug action by releasing nitric oxide gas have been recognized. There are not however, many anti-inflammatory drugs that specially target NOS or more specifically, iNOS, although there are various studies and trial that are investigating the effect of iNOS inhibition in various inflammatory conditions such as sepsis and other chronic illness including cancer. More recently, COX pathway has been found to be regulated by NO pathway and therapeutic potentials of NO-releasing aspirin hybrid drugs has been developed. In this review, we will discuss both pathways and their cross talk and pharmaceutical potentials for future therapeutic development based on these signaling transduction pathways. Keywords: Cyclooxygenase, NSAIDs, prostaglandin, nitric oxide, iNOS, septic shock

Is the randomized controlled drug trial in Europe lagging behind the USA?

Performance of randomized controlled drug trials (drugRCTs) adds to the scientific output, scientific knowledge, scientific training and up-to-date status of healthcare and may drive economy. The purpose of this study was to benchmark Europe's position on drugRCTs relative to the rest of the world, and to identify factors that may drive this performance. The number of scientific publications on drugRCTs, indexed in PubMed and Thomson Scientific/Web of Science database over the period 1995-2004, was used as a proxy measure for the quantitative drugRCT output. The international citation impact of these publications was used as a proxy measure for the qualitative drugRCT output. Country's origin of 103 211 publications was determined. After adjustment for population size, the number of drugRCT publications from Europe, USA and Australia/Japan was 102, 124 and 44 publications per million inhabitants, respectively. The proportional increase in publication output from 1995 until 2004 was lower in Europe compared with the USA and Australia/Japan (29.1, 40.1 and 63.4%, respectively). The number of citations per publication was 4.9 in Europe, 7.0 in the USA and 3.4 in Australia/Japan. Within Europe, the UK, Germany and Italy produced most publications. Country-specific factors associated with publication output in Europe were the number of pharmaceutical companies with headquarters in a country (R(2) = 0.71, P < 0.001), national R&D expenditures by pharmaceutical companies (R(2) = 0.63, P < 0.001) and health-related R&D expenditures by national governments (R(2) = 0.22, P = 0.052). When adjusted for population size, quantitative and qualitative performance of drugRCTs in Europe lags behind the USA but is ahead of Australia/Japan. Several factors appear to explain the differences, among which are the number of headquarters of pharmaceutical companies in a country, the research expenditures by pharmaceutical companies, as well as health-related R&D expenditures of a country. To enhance and strengthen Europe's position, researchers may strengthen their collaborations with local pharmaceutical companies, and national governments could increase their budgets for medical research funding.

The British Society for Antimicrobial Chemotherapy Resistance Surveillance Project: a successful collaborative model

The British Society for Antimicrobial Chemotherapy (BSAC) Resistance Surveillance Project was initiated in light of the need for UK-wide surveillance of antibacterial resistance in key clinical pathogens. The Project comprises two defined-protocol programmes that cover a range of important pathogens and antibacterials related to community-acquired respiratory tract infection and bloodstream infection, respectively. The Respiratory Programme has reported quantitative susceptibility data for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected from across the UK and Ireland since 1999. The Bacteraemia Programme has reported the susceptibility of a wide range of Gram-positive and -negative organisms since 2001. The sustainability of the Programmes relies on a unique collaborative funding model: sponsorship is provided by a number of pharmaceutical companies in return for the inclusion of their investigational or marketed agents in the study alongside a core panel of established antibacterials. The sponsors have changed over time according to their interest in participating. Results for marketed agents are communicated in a timely manner through the BSAC web site and by presentation and publication, and for investigational agents with the agreement of their sponsors. The Project satisfies the requirement for sustainable defined-protocol high-quality resistance surveillance across the UK and Ireland.