Wong E.H.F.,Astrazeneca |
Tarazi F.I.,Harvard University |
Pharmacology and Therapeutics | Year: 2010
Schizophrenia, bipolar disorder and unipolar depression are multi-dimensional and severely disabling psychiatric diseases with a strong need for improved pharmacotherapies with better adherence, long-term outcome and patient functionality. Progress has been achieved with the emergence of tailored multi-target agents (MTAs), such as second-generation antipsychotics for schizophrenia, with expanding clinical utility in bipolar disorder and depression. Better understanding of how these MTAs exert their beneficial and undesirable clinical effects in terms of receptor interaction remains an area for further elucidation, which may provide insight towards a new generation of individualized, and optimized therapies. This review explores to what extent the receptor signature of MTAs informs about their clinical action and therapeutic utility. Compelling clinical validation exists only for a limited number of molecular targets (e.g. D2 receptor blockade, serotonin transport inhibition), indicating overall high attrition and poor translation of predictive preclinical pharmacology. Nevertheless, recent advances have identified promising novel approaches for schizophrenia, bipolar disorder and depression that require further clinical validation. It is hoped that the expanding clinical and mechanistic knowledge garnered from the use of existing MTAs will provide additional opportunities for "reverse translation" and towards target validation. There is considerable scope for further developing and applying the knowledge linking receptor signature to clinical activity to drive stronger target validation, and ultimately support rational development of the next generation of MTAs for the improved treatment of schizophrenia and mood disorders. © 2010 Elsevier Inc.
Mund C.,Schering |
Lyko F.,German Cancer Research Center
BioEssays | Year: 2010
Over the past few years several drugs that target epigenetic modifications have shown clinical benefits, thus seemingly validating epigenetic cancer therapy. More recently, however, it has become clear that these drugs are either characterized by low specificity or that their target enzymes have low substrate specificity. As such, clinical proof-of-concept for epigenetic cancer therapies remains to be established. Human cancers are characterized by widespread changes in their genomic DNA methylation and histone modification patterns. Epigenetic cancer therapy aims to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. In this review, we provide an overview about the known functional roles of DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases in cancer development. The available data identify several examples that warrant further consideration as drug targets. Future research should be directed toward targeted enzyme inhibition and toward exploring interactions between epigenetic pathways to maximize cancer specificity. Copyright © 2010 WILEY Periodicals, Inc.
Voth M.,Schering |
Rosenberg M.,Bayer AG |
Breuer J.,Bayer AG
Investigative Radiology | Year: 2011
Objective: To assess the clinical safety and tolerability of the macrocyclic contrast agent gadobutrol (Gadovist/Gadavist) overall and in specific patient populations based on clinical trials and postmarketing experience. Materials and Methods: In total, 5545 patients enrolled in 34 prospective clinical studies were evaluated in an integrated analysis of safety. Of all enrolled patients, 4549 received gadobutrol at a dose of ≤0.09 mmol/kg body weight to a maximum of 0.51 mmol/kg body weight, with most patients (53.5%) receiving the recommended dose of >0.09 to 0.11 mmol/kg body weight. Data include comparisons with other extracellular contrast agents and subgroup analyses in pediatric patients, and patients with allergic disposition, renal impairment, hepatic impairment, or cardiovascular disease. Furthermore, worldwide postmarketing safety surveillance results, including nephrogenic systemic fibrosis reports, based on more than 5.7 million estimated applications are described. Results: One or more adverse events (AEs) assessed as related to the administration of gadobutrol were reported by 182 (4.0%) of the 4549 patients who participated in clinical trials. This is comparable to the incidence observed with the comparator contrast agents (74/1844 patients, 4.0%). The most common AEs, independent of drug relationship, were headache, nausea, feeling hot, and dysgeusia. The favorable safety profile of gadobutrol was also demonstrated in the following specific subpopulations in whom similar incidence rates were seen: pediatric patients aged 2 to 17 years (8/138 patients, 5.8%), patients with severe or moderate renal impairment (9/366 patients, 2.5%), patients with severe or moderate hepatic impairment (9/214 patients, 4.2%), and patients with cardiovascular disorders (42/1506 patients, 2.8%). Having been established in controlled clinical trials, this safety profile was also confirmed by postmarketing surveillance data. With more than 5.7 million estimated administrations of gadobutrol, a total of 1175 (0.02%) suspected adverse drug reactions have been reported. The most serious adverse reactions seen in postmarketing surveillance included rare reports of cardiac arrest, respiratory arrest, anaphylactoid shock, and nephrogenic systemic fibrosis. Incidence and type of AEs from postmarketing surveillance were consistent with the established safety profile. Conclusion: The comprehensive analysis of safety data obtained from 34 clinical studies demonstrates that gadobutrol has an excellent safety profile and a positive benefit risk profile when used in patients in need of contrast-enhanced magnetic resonance imaging. Gadobutrol was well tolerated by adults, by children, by patients with impaired liver or kidney function, and by patients with cardiovascular disease. The favorable safety profile is confirmed by the available postmarketing surveillance data and is compared with that of other gadolinium-based contrast agents. © 2011 by Lippincott Williams & Wilkins.
Oh S.,Wistar Institute |
Rankin A.L.,Wistar Institute |
Rankin A.L.,Schering |
Caton A.J.,Wistar Institute
Immunological Reviews | Year: 2010
CD4+CD25+ regulatory T (Treg) cells can play a critical role in the prevention of autoimmunity, as evidenced by the cataclysmic autoimmune disease that develops in mice and humans lacking the key transcription factor forkhead box protein 3 (Foxp3). At present, however, how and whether Treg cells participate in the development of rheumatoid arthritis (RA), which has both systemic manifestations and a joint-targeted pathology that characterizes the disease, remains unclear. In this review, we describe work that has been carried out aimed at determining the role of Treg cells in disease development in RA patients and in mouse models of inflammatory arthritis. We also describe studies in a new model of spontaneous autoimmune arthritis (TS1 × HACII mice), in which disease is caused by CD4+ T cells recognizing a neo-self-antigen expressed by systemically distributed antigen-presenting cells. We show that TS1 × HACII mice develop arthritis despite the presence of CD4+CD25+Foxp3+ Treg cells that recognize this target autoantigen, and we outline steps in the development of arthritis at which Treg cells might potentially act, or fail to act, in the development of inflammatory arthritis. © 2009 John Wiley & Sons A/S.
Schering | Date: 2014-01-13
The compounds and the synthesis of [F-18]-labeled L-glutamic acid, [F-18]-labeled L-glutamate, their derivatives as set forth in formula (I) and their uses are described.