Involvement of ICAM-1 in bone metabolism: a potential target in the treatment of bone diseases?

Bone diseases such as osteoporosis, osteoarthritis and rheumatoid arthritis (RA) affect a great proportion of individuals, with debilitating consequences in terms of pain and progressive limitation of function. Existing treatment of these pathologies has been unable to alter the natural evolution of the disease and, as such, a clearer understanding of the pathophysiology is necessary in order to generate new treatment alternatives. One therapeutic strategy could involve the targeting of intercellular adhesion molecule-1 (ICAM-1; CD54). In bone, ICAM-1 is expressed at the surface of osteoblasts (Obs) and its counter-receptor, leukocyte function-associated antigen-1 (LFA-1; CD11a), at the surface of osteoclast (Oc) precursors. ICAM-1 blockade between the Ob and the pre-Oc results in an inhibition of Oc recruitment and a modulation of inflammation, which could potentially help in controlling disease activity in bone pathologies. So far, clinical studies on ICAM-1 blockade in bone diseases have been limited to RA. A better understanding of the implication of this adhesion molecule in Ob/Oc interactions and inflammatory mediation in the bone pathological state, however, is needed. As new discoveries on the role of this adhesion molecule are being reported, ICAM-1 could become a potential target for other bone diseases as well.     

Involvement of α-interferon in HIV-1 induced immunosuppression. A potential target for AIDS prophylaxis and treatment

Since the immune system is impaired in the course of HIV-infection, the purpose of any AIDS vaccine therapy should be the restoration in the patient of an adequate immunocompetence to enable him to respond to the antigenic stimulus represented by the virus. In the present investigation we have shown the anti proliferative action on activated T-cells in culture of: sera taken from HIV-infected, but not seronegative individuals; T lymphocytes taken from seronegative subjects and infected in vitro with HIV but not non infected cells; native α-IFN and the time-dependent inactivation of this activity by formaldehyde treatment of α-IFN. Thus is confirmed the major contribution provided by α-IFN to the immunosuppression occurring in the course of HIV-infection. These results also strongly support the new AIDS vaccine therapy strategy based on the administration to HIV-infected patients of inactivated, but still immunogenic α-IFN. To the a-IFN treatment could also be combined the administration of fixed autologous suppressive cells. The induction of γ-IFN in addition to α-IFN production by stimulation of cells from healthy donors with gp120 should encourage the use of a vaccine combining both inactivated α-IFN and γ-IFN. On the other hand, the IL-12 cytokine with its potential to restore compromised cell-mediated functions associated with HIV infection should also be a valuable adjuvant treatment.     

Is the mineralocorticoid receptor a potential target for stroke prevention?

In recent years, it has become increasingly clear that the extra-renal effects of aldosterone play an important role in the pathogenesis of cardiovascular disease. Stroke is one of the leading causes of death in the Western world, and MR (mineralocorticoid receptor) antagonism is a potential preventative therapy for patients at risk of both ischaemic and haemorrhagic strokes. This protective effect of MR antagonism appears to occur at the level of the cerebral vasculature and may be related to the expression and activation of the EGFR (epidermal growth factor receptor) and the degree of vessel wall collagen deposition.     

Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Selective non-peptide antagonists for the neurokinin 3 (NK₃) receptor first became available about twenty years ago. Although the understanding of the role of the NK₃ receptor in the brain has been greatly complicated by marked species differences in its distribution and by pharmacological heterogeneity, studies with brain-penetrant non-peptide NK₃ receptor antagonists in animals have indicated that these compounds may find utility in a number of psychiatric diseases, including schizophrenia, anxiety and depressive disorders. However, clinical studies with selective NK₃ receptor antagonists in these psychiatric conditions have been disappointing and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for CNS disorders. The purpose of this article is to provide a critical overview of the available data on NK₃ receptor antagonists in the psychiatry research and development field, by reviewing the behavioral and neurochemical effects of these agents in both preclinical and clinical studies.     

Telaprevir: a new hope in the treatment of chronic hepatitis C?

More than 180 million people worldwide have chronic hepatitis C (CHC) virus infection, a major cause of liver cirrhosis and its life-threatening complications including liver failure, portal hypertension, and hepatocellular carcinoma. With the current standard of care of pegylated interferon-alpha and ribavirin (PEG-IFN-α/RBV), the chances of sustained viral clearance or “cure” are only 40%–50% for genotype 1 infection, which is the most common genotype in western populations. Consequently, there has been a drive to develop new agents specifically targeting essential components of the viral life cycle, such as the hepatitis C virus (HCV) NS3/4A serine protease. Perhaps the most advanced HCV protease inhibitor in clinical development is telaprevir, which has been shown to improve treatment outcomes when combined with PEG-IFN-α/RBV in genotype 1 infection, and is currently undergoing phase 3 study. In this review, we summarize the pharmacology, pharmacokinetics, and results of phase 1 and 2 clinical trials of telaprevir, and discuss the likely role of this agent in the future management of CHC.     

Why target apoptosis in cancer treatment?

Defective apoptosis (programmed cell death) represents a major causative factor in the development and progression of cancer. The ability of tumor cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens. Our understanding of the complexities of apoptosis and the mechanisms evolved by tumor cells to resist engagement of cell death has focused research effort into the development of strategies designed to selectively induce apoptosis in cancer cells. This article will review the underlying mechanisms of apoptosis and the ways in which tumor cells modulate these processes to promote their survival and evaluate the efficacy of current clinical approaches aimed at exploiting these defects to selectively induce apoptosis in tumor cells.     

Role of tumor necrosis factor alpha in the pathogenesis of atrial fibrillation: A novel potential therapeutic target?

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and a major cause of morbidity and mortality. Although the fundamental mechanisms underlying AF remain incompletely understood, atrial remodeling, including structural, electrical, contractile, and autonomic remodeling, has been demonstrated to contribute to the substrate for AF maintenance. Accumulating evidence shows that tumor necrosis factor alpha (TNF-α) plays exceedingly important roles in atrial remodeling. This article reviews recent advances in the roles of TNF-α in the pathogenesis of AF, elucidates the related mechanisms, and exploits its potential usefulness as a novel therapeutic target.