Current Opinion in Pharmacology

Cardiovascular pharmacology in the post-blockbuster era.

Publication Date: 2010 Mar 2 PMID: 20202904
Authors: Brandes, R. P.
Journal: Curr Opin Pharmacol

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Pharmacology of glucocorticoids in rheumatoid arthritis.

Publication Date: 2010 Mar 2 PMID: 20202903
Authors: Spies, C. M. - Bijlsma, J. W. - Burmester, G. R. - Buttgereit, F.
Journal: Curr Opin Pharmacol

Glucocorticoids (GCs) provide one of the most effective treatments for rheumatoid arthritis (RA); however, their long-term use is marred by undesired side effects. Increased understanding of the mechanisms of glucocorticoid action enables the development of novel drugs, such as SEGRAs or liposomal glucococorticoids, trying to improve their benefit/risk ratio. But also trying to optimise the use of conventional glucocorticoids is a sensible approach. One example is a new modified release prednisone tablet formulation that has been recently shown to be clinically and significantly better than the conventional immediate-release preparation with respect to reducing morning stiffness of the joints. The 'old spear' can also be sharpened by collecting clear-cut evidence on the efficacy and safety of conventional glucocorticoid therapy and deriving from that reliable evidence-based recommendations. This short review summarises the current knowledge in this regard, with particular emphasis on recently published articles.

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Current aspects of anti-CD20 therapy in rheumatoid arthritis.

Publication Date: 2010 Feb 26 PMID: 20189875
Authors: Jacobi, A. M. - Dorner, T.
Journal: Curr Opin Pharmacol

Although B cells represent major contributors to rheumatoid arthritis (RA) pathogenesis, their precise roles in the induction and maintenance of abnormal immune activation in this entity remains poorly understood. As proof of principle, rituximab, a chimeric B cell depleting anti-CD20-antibody, has demonstrated that depletion of B cells can substantially improve signs and symptoms as well as physical function and inhibit radiologic progression that led to the approval of this agent to treat patients with moderate to severe RA lacking response to TNF-alpha blocking agents in 2006. Placebo-controlled clinical trials as well as subsequent studies and experiences further contributed to our understanding of the mechanism of action of rituximab, but a number of open questions remain. This review summarizes some lessons learned from B cell depletion in RA including particular safety aspects. Of importance using this therapy is that it apparently provides the highest likelihood of response in seropositive RA patients. This observation differentiates it from other currently available therapies and closes the conceptual loop that the underlying immunopathogenesis involves B cells requiring 'targeted' therapy.

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Purinergic signalling and bone remodelling.

Publication Date: 2010 Feb 25 PMID: 20189453
Authors: Orriss, I. R. - Burnstock, G. - Arnett, T. R.
Journal: Curr Opin Pharmacol

Accumulating evidence suggests that extracellular nucleotides, signalling through P2 receptors, could play an important role in modulating bone cell function. ATP and other nucleotides can stimulate the formation and resorptive activity of osteoclasts (bone-destroying cells) in addition to inhibiting bone mineralisation by osteoblasts. This review discusses the current understanding of the effects of extracellular nucleotides on skeletal cells.

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Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases.

Publication Date: 2010 Feb 19 PMID: 20172761
Authors: Taylor, P. C.
Journal: Curr Opin Pharmacol

Tumor necrosis factor-alpha (TNF) has been unequivocally validated as a therapeutic target in a number of immune-mediated inflammatory disorders (IMIDs). There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF. But approaches to TNF inhibition differ and currently include mAbs (infliximab, adalimumab, and golimumab), either chimeric or human in sequence, a PEGylated Fab' fragment (certolizumab), and an IgG1-TNFR2 fusion protein (etanercept). It is emerging that the pharmacological properties of these three anti-TNF subtypes differ with respect to Fc function, binding of tmTNF and the possible consequences of this, as well as the ability to form complexes. The mode of administration of each agent, clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety.

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Role of the adaptive immune system in hypertension.

Publication Date: 2010 Feb 16 PMID: 20167535
Authors: Harrison, D. G. - Vinh, A. - Lob, H. - Madhur, M. S.
Journal: Curr Opin Pharmacol

Recent studies have shown that both innate and adaptive immunity contribute to hypertension. Inflammatory cells, including macrophages and T cells accumulate in the vessel wall, particularly in the perivascular fat, and in the kidney of hypertensive animals. Mice lacking lymphocytes are resistant to the development of hypertension, and adoptive transfer of T cells restores hypertensive responses to angiotensin II and DOCA-salt challenge. Immune modulating agents have variable, but often-beneficial effects in ameliorating end-organ damage and blood pressure elevation in experimental hypertension. The mechanisms by which hypertension stimulates an immune response remain unclear, but might involve the formation of neoantigens that activate adaptive immunity. Identification of these neoantigens and understanding how they form might prove useful in the prevention and treatment of this widespread and devastating disease.

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New aspects in vascular gene therapy.

Publication Date: 2010 Feb 15 PMID: 20163988
Authors: Karvinen, H. - Yla-Herttuala, S.
Journal: Curr Opin Pharmacol

Advances in clinical gene therapy have been modest although significant progress has been made during the past few years. New viruses have been introduced and new results have been collected from preclinical and clinical studies. This review will focus on cardiovascular and especially proangiogenic gene therapy. Recent results from preclinical developments and clinical trials will be discussed.

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SIRT1-a metabolic sensor that controls blood vessel growth.

Publication Date: 2010 Feb 9 PMID: 20149740
Authors: Guarani, V. - Potente, M.
Journal: Curr Opin Pharmacol

Blood vessels deliver nutrients and oxygen to cells and tissues in the body. When blood supply is insufficient new vessels form to meet the metabolic tissue requirements. Several studies have examined the cellular and molecular principles of blood vessel formation, yet little is known about how vessels sense and integrate environmental signals originating from nutrient- and oxygen-deprived tissues to achieve functional vascular patterning. The NAD(+)-dependent deacetylase SIRT1 mediates adaptation to environmental stresses by adjusting cellular responses to the energetic state of the cell and recent studies highlight important functions of SIRT1 in regulating vascular growth, shape, and function. Here, we review the emerging role of SIRT1 as a metabolic sensor coupling energy and oxygen homeostasis to the growth and function of the vasculature.

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Isoform specific functions of Nox protein-derived reactive oxygen species in the vasculature.

Publication Date: 2010 Feb 9 PMID: 20149739
Authors: Schroder, K.
Journal: Curr Opin Pharmacol

The family of NADPH oxidases consists of seven members that are all producing reactive oxygen species (ROS). In the cardiovascular systems three NADPH oxidases are expressed: Nox1, Nox2 and Nox4, which all exhibit different physiological functions such as regulating blood pressure, mediating growth factor signaling and controlling cell proliferation. In this article the recent research concerning the specificity and function mediated by NADPH oxidases will be reviewed.

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