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See detailAmantadine, Apomorphine and Zolpidem in the Treatment of Disorders of Consciousness
Gosseries, Olivia ULg; Charland-Verville, Vanessa ULg; Thonnard, Marie ULg et al

in Current Pharmaceutical Design (2014), 20

Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to ... [more ▼]

Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes in the neurological status in patients, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents' therapeutic mechanisms on cerebral function. In order to enhance our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient's etiology, diagnosis, time since injury and overall condition. [less ▲]

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See detailState-of-the-art methodologies for the discovery and characterization of DNA G-quadruplex binders.
Pagano, Bruno; Cosconati, Sandro; Gabelica, Valérie ULg et al

in Current Pharmaceutical Design (2012), 18(14), 1880-99

Nowadays, the molecular basis of interaction between low molecular weight compounds and biological macromolecules is the subject of numerous investigations aimed at the rational design of molecules with ... [more ▼]

Nowadays, the molecular basis of interaction between low molecular weight compounds and biological macromolecules is the subject of numerous investigations aimed at the rational design of molecules with specific therapeutic applications. In the last decades, it has been demonstrated that DNA quadruplexes play a critical role in several biological processes both at telomeric and gene promoting levels thus providing a great stride in the discovery of ligands able to interact with such a biologically relevant DNA conformation. So far, a number of experimental and computational approaches have been successfully employed in order to identify new ligands and to characterize their binding to the DNA. The main focus of this review is the description of these methodologies, placing a particular emphasis on computational methods, isothermal titration calorimetry (ITC), mass spectrometry (MS), nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence spectroscopies. [less ▲]

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See detailIn Silico Dynamic Molecular Interaction Networks for the Discovery of New Therapeutic Targets
Vujasinovic, Todor; Zampera, André Sinisa; Jackers, Pascale ULg et al

in Current Pharmaceutical Design (2010), 16(20), 2241-2251

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding ... [more ▼]

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding basic molecular processes and complex biological systems in which new properties often emerge from the combination of these elementary processes. This approach culminates in the development of computer-based mathematical models of physiological and pathophysiological processes. We review the state of the art in dynamic modelling, with emphasis on two complementary approaches: the modelling of small systems that is mostly developed by academic teams and aims at understanding generic biological properties, and the modelling of large systems that is mostly implemented by industrial companies and aims at the generation of new therapeutic strategies. We also provide an example of such large-scale modelling applied to the identification of drug targets for neurodegeneration. [less ▲]

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See detailAlternative splicing: a promising target for pharmaceutical inhibition of pathological angiogenesis?
Munaut, Carine ULg; Colige, Alain ULg; Lambert, Charles ULg

in Current Pharmaceutical Design (2010), 16(35), 3864-76

In eukaryotes, genes consist in coding sequences (exons) interspersed with non-coding ones (introns). The regulation of alternative inclusion/exclusion of exons, or part of exons, during the maturation of ... [more ▼]

In eukaryotes, genes consist in coding sequences (exons) interspersed with non-coding ones (introns). The regulation of alternative inclusion/exclusion of exons, or part of exons, during the maturation of the pre-mRNA into mRNA (alternative splicing) allows a dramatic increase of the protein versus the gene repertoire. In a number of cases, alternative splicing decision generates proteins with distinct, sometimes opposite, functions from a given gene. Angiogenesis is the process of vascularisation in physiological conditions and a series of pathologies, including cancer where it favours tumour progression and dissemination of metastasis. In this issue, we discuss some key examples showing how alternative splicing may induce a switch from anti-angiogenic to pro-angiogenic functions and reciprocally. For some of these splicing events, the molecular mechanisms that trigger alternative splicing toward one or the other direction start to be elucidated. The emergence of strategies enabling to regulate alternative splicing opens new routes for anti-angiogenic therapies. [less ▲]

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See detailThe platelet ATP and ADP receptors.
Oury, Cécile ULg; Toth-Zsamboki, Emese; Vermylen, Jos et al

in Current Pharmaceutical Design (2006)

This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists ... [more ▼]

This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists, antagonists and inhibitors that allow their pharmacological discrimination. [less ▲]

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See detailFrom the design to the clinical application of thromboxane modulators
Dogné, Jean-Michel ULg; Hanson, Julien ULg; de Leval, Xavier et al

in Current Pharmaceutical Design (2006), 12(8), 903-923

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of ... [more ▼]

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H-2 (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several Compounds have been launched on the market and others are tinder clinical evaluation. In the first part of this review. we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part. we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock.. preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis. [less ▲]

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See detailOral and intravenous ibandronate in the management of postmenopausal osteoporosis: A comprehensive review
Reginster, Jean-Yves ULg

in Current Pharmaceutical Design (2005), 11(28), 3711-3728

Convenient strategies are needed for postmenopausal osteoporosis management. Current oral bisphosphonates are effective and generally well tolerated, but are hampered by strict dosing requirements. Less ... [more ▼]

Convenient strategies are needed for postmenopausal osteoporosis management. Current oral bisphosphonates are effective and generally well tolerated, but are hampered by strict dosing requirements. Less frequent dosing schedules are expected to improve adherence to therapy and hence outcomes. Ibandronate is a potent, nitrogen-containing bisphosphonate in ongoing clinical development exploring its potential to be administered less frequently than at weekly intervals. Uniquely, ibandronate can be administered either orally or as an intravenous (i.v.) injection, with a between-dose interval of >2 months. In postmenopausal women, oral ibandronate, when administered either daily or intermittently, has demonstrated robust antifracture efficacy at the spine (62% [p=0.0001] and 50% [p=0.0006] risk reduction versus placebo), accompanied by significant increases in bone mineral density (BMD) at the spine and hip, and suppression of bone turnover markers. Studies of intermittent i.v. ibandronate injections in postmenopausal women have shown dose-related BMD gains and bone turnover marker suppression comparable to those obtained after a similar duration of treatment with the proven effective oral ibandronate regimen. Furthermore, in a trial conducted in patients with corticosteroid-induced osteoporosis, intermittent i.v. ibandronate injections reduced vertebral fracture risk by 62% versus an active control (p=0.043). In all these trials, the oral and i.v. ibandronate regimens were well tolerated. Ongoing, large multinational clinical trials are investigating two intermittent ibandronate regimens: once-monthly oral and intermittent i.v. injections. These simple ibandronate regimens are expected to provide the optimal combination of efficacy, tolerability and patient convenience, leading to improved treatment adherence and thus, enhanced outcomes in postmenopausal osteoporosis. [less ▲]

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See detailMolecular pathways involved in apoptotic cell death in the injured cochlea: Cues to novel therapeutic strategies
Lallemend, François; Lefèbvre, Philippe ULg; Hans, Grégory ULg et al

in Current Pharmaceutical Design (2005), 11(17), 2257-2275

Most hearing loss results from lesions of the sensory cells and/or neurons of the auditory portion of the inner ear. To date, only the cochlear implantation offers long-term hearing-aid benefit, but still ... [more ▼]

Most hearing loss results from lesions of the sensory cells and/or neurons of the auditory portion of the inner ear. To date, only the cochlear implantation offers long-term hearing-aid benefit, but still with limited performance and expensive cost. While the underlying causes of deafness are not clear, the death or hair cells and/or neurons and the loss of neuronal contacts are key pathological features. Pinpointing molecular events that control cell death in the cochlea is critical for the development of new strategies to prevent and treat deafness, whether in combination or not with cochlear implant therapy. [less ▲]

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See detailNew features in the treatment of androgen-independent prostate cancer.
Closset, Jean ULg; Ammar, Hayet; Nguyen, Viet-Ha et al

in Current Pharmaceutical Design (2004), 10(5), 513-22

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the ... [more ▼]

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the cancer is diagnosed at a more advanced age. Prostate cancer evolves from an androgen dependant stage to stage where it escapes from all anti-androgenic treatments. The patient usually dies within two years following the diagnosis of advanced cancer. Therefore, it is of great interest to develop new therapies for androgen independent prostate cancer. The androgen independent evolution of prostate cancer is a complex phenomenon at the cellular and molecular levels. It includes an increased sensitivity to growth factors, the control of proliferation pathways, apoptotic and survival pathways as well as the control of angiogenesis. Epidemiological studies have also suggested that certain vitamins or phyto-oestrogens could protect against prostate cancer development. The present review attempts to present an overview of the fundamental research in cellular signalling which could be interesting as target for the treatment of androgen independent prostate cancer. Also the potential interest of non-androgenic steroids was reviewed for the same goal. [less ▲]

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See detailStrontium ranelate in osteoporosis
Reginster, Jean-Yves ULg

in Current Pharmaceutical Design (2002), 8

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