The Experts below are selected from a list of 11328 Experts worldwide ranked by ideXlab platform
Hossein Ardeschir Ghofrani - One of the best experts on this subject based on the ideXlab platform.
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targeting cancer with Phosphodiesterase Inhibitors
Expert Opinion on Investigational Drugs, 2010Co-Authors: Rajkumar Savai, Soni Savai Pullamsetti, Gamalandre Banat, Norbert Weissmann, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Ralph T SchermulyAbstract:Importance of the field: For many cancers, there has been a shift from management with traditional, nonspecific cytotoxic chemotherapies to treatment with molecule-specific targeted therapies that are used either alone or in combination with traditional chemotherapy and radiation therapy. Accumulating data suggest that multi-targeted agents may produce greater benefits than those observed with single-targeted therapies, may have acceptable tolerability profiles, and may be active against a broader range of tumour types. Thus, regulation of cyclic nucleotide signalling is properly regarded as a composite of multiple component pathways involved in diverse aspects of tumour cell function. The impairment of cAMP and/or cGMP generation by overexpression of PDE isoforms that has been described in various cancer pathologies, and the effects of PDE Inhibitors in tumour models in vitro and in vivo, may offer promising insight into future cancer treatments because of the numerous advantages of PDE Inhibitors.Areas ...
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Phosphodiesterase Inhibitors for the treatment of pulmonary hypertension
European Respiratory Journal, 2008Co-Authors: Martin R Wilkins, Friedrich Grimminger, John Wharton, Hossein Ardeschir GhofraniAbstract:The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by Phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation. An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of Phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that Phosphodiesterase type 5 Inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study.
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nitric oxide pathway and Phosphodiesterase Inhibitors in pulmonary arterial hypertension
Journal of the American College of Cardiology, 2004Co-Authors: Hossein Ardeschir Ghofrani, Joanna Pepkezaba, Joan Albert Barbera, Richard N Channick, A Keogh, M A Gomezsanchez, Meinhard Kneussl, Friedrich GrimmingerAbstract:Pulmonary hypertension (PH) is a disease of various origins. Nitric oxide-a potent vasodilator-is a key player of pulmonary vasoregulation. Nitric oxide signaling is mainly mediated by the guanylate cyclase/cyclic guanylate monophosphate pathway. The effects of this second messenger system are limited by enzymatic degradation through Phosphodiesterases (PDEs). Recently, beneficial effects of the oral PDE-5 inhibitor sildenafil (originally approved for the treatment of erectile dysfunction) were reported for the treatment of PH. We provide a brief overview of the experimental and clinical application of PDE Inhibitors in the field of PH. In particular, studies reporting the clinical effectiveness of sildenafil are highlighted. This agent, despite oral application, displays characteristics of a pulmonary selective vasodilator. In addition, evidence shows that sildenafil is operative mainly in the vasculature of well-ventilated areas of the lung. However, to date, controlled randomized trials proving the efficacy of this approach for the treatment of pulmonary arterial hypertension are lacking. The results of such studies have to confirm the current encouraging findings before recommendations regarding the use of PDE-5 Inhibitors as a new treatment for PH can be made.
Friedrich Grimminger - One of the best experts on this subject based on the ideXlab platform.
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targeting cancer with Phosphodiesterase Inhibitors
Expert Opinion on Investigational Drugs, 2010Co-Authors: Rajkumar Savai, Soni Savai Pullamsetti, Gamalandre Banat, Norbert Weissmann, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Ralph T SchermulyAbstract:Importance of the field: For many cancers, there has been a shift from management with traditional, nonspecific cytotoxic chemotherapies to treatment with molecule-specific targeted therapies that are used either alone or in combination with traditional chemotherapy and radiation therapy. Accumulating data suggest that multi-targeted agents may produce greater benefits than those observed with single-targeted therapies, may have acceptable tolerability profiles, and may be active against a broader range of tumour types. Thus, regulation of cyclic nucleotide signalling is properly regarded as a composite of multiple component pathways involved in diverse aspects of tumour cell function. The impairment of cAMP and/or cGMP generation by overexpression of PDE isoforms that has been described in various cancer pathologies, and the effects of PDE Inhibitors in tumour models in vitro and in vivo, may offer promising insight into future cancer treatments because of the numerous advantages of PDE Inhibitors.Areas ...
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Phosphodiesterase Inhibitors for the treatment of pulmonary hypertension
European Respiratory Journal, 2008Co-Authors: Martin R Wilkins, Friedrich Grimminger, John Wharton, Hossein Ardeschir GhofraniAbstract:The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by Phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation. An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of Phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that Phosphodiesterase type 5 Inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study.
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nitric oxide pathway and Phosphodiesterase Inhibitors in pulmonary arterial hypertension
Journal of the American College of Cardiology, 2004Co-Authors: Hossein Ardeschir Ghofrani, Joanna Pepkezaba, Joan Albert Barbera, Richard N Channick, A Keogh, M A Gomezsanchez, Meinhard Kneussl, Friedrich GrimmingerAbstract:Pulmonary hypertension (PH) is a disease of various origins. Nitric oxide-a potent vasodilator-is a key player of pulmonary vasoregulation. Nitric oxide signaling is mainly mediated by the guanylate cyclase/cyclic guanylate monophosphate pathway. The effects of this second messenger system are limited by enzymatic degradation through Phosphodiesterases (PDEs). Recently, beneficial effects of the oral PDE-5 inhibitor sildenafil (originally approved for the treatment of erectile dysfunction) were reported for the treatment of PH. We provide a brief overview of the experimental and clinical application of PDE Inhibitors in the field of PH. In particular, studies reporting the clinical effectiveness of sildenafil are highlighted. This agent, despite oral application, displays characteristics of a pulmonary selective vasodilator. In addition, evidence shows that sildenafil is operative mainly in the vasculature of well-ventilated areas of the lung. However, to date, controlled randomized trials proving the efficacy of this approach for the treatment of pulmonary arterial hypertension are lacking. The results of such studies have to confirm the current encouraging findings before recommendations regarding the use of PDE-5 Inhibitors as a new treatment for PH can be made.
William R Bishai - One of the best experts on this subject based on the ideXlab platform.
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adjuvant host directed therapy with types 3 and 5 but not type 4 Phosphodiesterase Inhibitors shortens the duration of tuberculosis treatment
The Journal of Infectious Diseases, 2013Co-Authors: Mamoudou Maiga, Nicole C Ammerman, Mariama C Maiga, Anatole Tounkara, Sophia Siddiqui, Michael A Polis, Robert L Murphy, William R BishaiAbstract:Background. Shortening tuberculosis treatment could significantly improve patient adherence and decrease the development of drug resistance. Phosphodiesterase Inhibitors (PDE-Is) have been shown to be beneficial in animal models of tuberculosis. We assessed the impact of PDE-Is on the duration of treatment in tuberculous mice. Methods. We analyzed the time to death in Mycobacterium tuberculosis–infected mice receiving type 4 PDE-Is (rolipram and cilomilast) and the impact on bacterial burden, time to clearance, and relapse when types 3 and 5 PDE-Is (cilostazol and sildenafil, respectively) and rolipram were added to the standard treatment. We investigated pharmacokinetic interactions between PDE-Is (cilostazol and sildenafil) and rifampin. Results. The type 4 PDE-Is rolipram and cilomilast accelerated the time to death in tuberculous mice. The addition of rolipram to standard tuberculosis treatment increased bacterial burden and did not decrease the time to bacterial clearance in the lung, while the addition of the cilostazol and sildenafil reduced the time to clearance by 1 month. Cilostazol and sildenafil did not have negative pharmacokinetic interactions with rifampin. Conclusions. Type 4 PDE-Is may increase the severity of tuberculosis and should be carefully investigated for use in patients with latent or active tuberculosis. Cilostazol and sildenafil may benefit tuberculosis patients by shortening the duration of therapy.
Jos Prickaerts - One of the best experts on this subject based on the ideXlab platform.
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Phosphodiesterase Inhibitors roflumilast and vardenafil prevent sleep deprivation induced deficits in spatial pattern separation
Synapse, 2020Co-Authors: Pim R A Heckman, Jos Prickaerts, Femke Roig Kuhn, Frank Raven, Youri G Bolsius, Peter Meerlo, Robbert HavekesAbstract:Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the Phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE Inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE Inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.
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investigational Phosphodiesterase Inhibitors in phase i and phase ii clinical trials for alzheimer s disease
Expert Opinion on Investigational Drugs, 2017Co-Authors: Jos Prickaerts, Pim R A Heckman, Arjan BloklandAbstract:ABSTRACTIntroduction: Phosphodiesterase (PDE) Inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE Inhibitors in Alzheimer’s disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies.Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE Inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE Inhibitors will also be discussed with respect to adverse effects including safety and tolerability.Expert opinion: The limited available data of clinical studies with PDE Inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion ...
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Phosphodiesterase Inhibitors as a target for cognition enhancement in aging and alzheimer s disease a translational overview
Current Pharmaceutical Design, 2014Co-Authors: Pim R A Heckman, Carine Wouters, Jos PrickaertsAbstract:Phosphodiesterase Inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer’s disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 Inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.
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Phosphodiesterase Inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats
Neuropsychopharmacology, 2009Co-Authors: Kris Rutten, E L Van Donkelaar, Linda Ferrington, Eva Bollen, Paul A Kelly, Arjan Blokland, Harry W.m. Steinbusch, Jos PrickaertsAbstract:Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats
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selective Phosphodiesterase Inhibitors a promising target for cognition enhancement
Psychopharmacology, 2009Co-Authors: Kris Rutten, Jos Prickaerts, Arjan Blokland, Harry W.m. Steinbusch, Olga A H ReneerkensAbstract:Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently Phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP.
Bilha Fischer - One of the best experts on this subject based on the ideXlab platform.
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diadenosine 5 5 boranated polyphosphonate analogues as selective nucleotide pyrophosphatase Phosphodiesterase Inhibitors
Journal of Medicinal Chemistry, 2010Co-Authors: Shay Eliahu, Joanna Lecka, François Bigonnesse, Sébastien A. Lévesque, Julie Pelletier, Michael Haas, Georg Reiser, Bilha FischerAbstract:Nucleotide pyrophosphatase/Phosphodiesterases (NPPs) hydrolyze extracellular nucleotides and dinucleotides and thus control purinergic signaling. Enhanced NPP activity is implicated in health disorders such as osteoarthritis and cancer. We designed novel diadenosine polyphosphonate derivatives as potential NPP Inhibitors. Analogues 1−4 bear a phosphonate and/or boranophosphate group and/or a 2′-H atom instead of a 2′-OH group. In comparison to ATP, analogues 1−4 were barely hydrolyzed by human NTPDase1, -2, -3, and -8 (<5% hydrolysis) and NPP1 and -3 (≤13%) and were not hydrolyzed by ecto-5′-nucleotidase, unlike AMP. These derivatives did not affect NTPDase activity, and analogues 1 and 2 did not inhibit ecto-5′-nucleotidase. All analogues blocked ∼80% of the NPP2-dependent hydrolysis of pnp-TMP, a specific NPP substrate, and inhibited the catabolism of pnp-TMP (Ki and IC50 both found to be between 10 and 60 μM), Ap5A, and ATP by NPP1. The activity of NPP3 was inhibited to a lesser extent by the new analo...