Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary hypertension is a vasculoproliferative disorder which is characterized by vasoconstriction and proliferation of vascular cells within the vessel wall. Mostly addressing the increased vascular tone, prostacyclin and its analogues, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors have been approved for treatment of PAH and represent the current therapeutic options. Currently, research focuses on the development of causal treatment regimens aiming a normalization of the vessel structure. Mechanistically, increased proliferation, migration and a resistance to apoptosis of vascular cells represent key events in disease progression. In clinical relevant animal models of pulmonary hypertension, new non-vasoactive drugs could not only attenuate ("Anti-Remodeling") but reverse ("Reverse-Remodeling") the disease. These compound classes include tyrosine kinase inhibitors, elastase inhibitors, and phosphodiesterase inhibitors. For some of these agents clinical trials are already initiated which will address safety and efficacy. In addition, there is further development of new vasodilators addressing well known and new signaling pathways. Taken together, there is advanced research in the field of pulmonary vascular diseases and the efficacy of several new drugs is currently addressed in clinical trials.
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PMID:[Update in basic research in the therapy of pulmonary arterial hypertension]. 1881 88

Pulmonary arterial hypertension (PAH) has evolved from an untreatable condition to a disease for which several classes of drugs have now been approved, including various prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Because the pathogenesis of pulmonary hypertension is increasingly understood, various new substances are now under clinical investigation, including serotonin antagonists, vasoactive intestinal peptide, stimulators of soluble guanylate cyclase and tyrosine kinase inhibitors. Several of these compounds hold promise for the future therapy of PAH, especially as regression of pulmonary vascular remodeling appears to become a realistic possibility with the combination of established and novel treatments.
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PMID:Novel approaches to the pharmacotherapy of pulmonary arterial hypertension. 1912 10

Systemic sclerosis (SSc) is a chronic autoimmune disease with clinical manifestations resulting from immune activation, fibrosis development, and damage of small blood vessels. Our aim was to critically illustrate the available data on the new treatments proposed for SSc to provide a clinically oriented overview of the current evidence. PubMed was used for literature search using "scleroderma" and "therapy" to identify all articles published on indexed journals between 1972 and 2008. The search was limited to publications in English and produced a total of 3,441 references, which included 735 review articles. These citations were then screened for articles dealing with the most recent therapy options for SSc, and 214 articles were selected for evaluation and discussion. Methotrexate, cyclophosphamide, calcium channel blockers, angiotensin converting enzyme inhibitors, prostacyclin analogues, D-penicillamine, and extracorporeal photopheresis are the most widely studied treatments for SSc and were considered as practiced treatments. Other therapeutic approaches have been developed more recently and include endothelin receptor antagonists and phosphodiesterase-5 inhibitors for pulmonary arterial hypertension and peripheral vascular disease. High-dose immunosuppression and stem cell transplantation constitute a promising treatment and data from randomized controlled trials are awaited. Intravenous gamma globulins, mycophenolate mophetil, collagen tolerance induction, rituximab, fluoxetine, pirfenidone, relaxin, halofuginone, anti-TGF-beta antibodies, and tyrosine kinase inhibitors awaits more solid data. The clinical management of patients with SSc remains a challenge and currently involves practiced and newly proposed therapeutic approaches. The disease pleiomorphism poses numerous difficulties to determine ideal outcomes to be used in clinical trials.
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PMID:Recent advances in the treatment of systemic sclerosis. 1913 59

Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
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PMID:Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL. 1936 27

Pulmonary arterial hypertension is a life-threatening, vasculoproliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Drugs for the treatment of PAH mainly address the increased vascular tone. Substances like prostacyclin, endothelin-receptor-antagonists and phosphodiesterase-5-inhibitors have been approved for the treatment of PAH and represent the current therapeutic options. The development of a causal treatment aiming a normalization of the vessel wall structure is the current focus of research. The key events in disease progression are represented by increased proliferation, migration and a resistance to apoptosis of pulmonary vascular cells. Therefore, new non-vasoactive drugs are investigated in relevant preclinical animal models of pulmonary arterial hypertension. Some of these substances, like tyrosine kinase inhibitors, elastase inhibitors and phosphodiesterase-1-inhibitors, could not only attenuate (anti-remodeling) but reverse (reverse-remodeling) the disease. Additionally, new vasodilators, like soluble guanylate cyclase stimulators and activators, addressing well-known and new signaling pathways are currently under investigation. Taken together, with increasing insight into the pathology of PAH, several novel drug targets and treatments have emerged which may improve the management of patients and which efficacy is currently addressed in preclinical studies and clinical trials.
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PMID:[Update: Preclinical developments for the treatment of pulmonary arterial hypertension]. 1971 4

During the last years, therapeutic options for the treatment of pulmonary arterial hypertension (PAH) have significantly improved. However, the therapeutic concept depends on the etiology of the disease, so that an exact classification is mandatory. Currently, three substance classes are approved for the treatment of PAH (Group I of the Venice Classification): Endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. After the World Conference in Dana Point (2008), recent changes in therapeutic strategies comprise the early treatment of the disease, as well as the increased importance of an early use of combination therapy if treatment goals are not met. Several new substances are currently evaluated in clinical trials. The soluble guanylate cyclase (sGC) stimulators achieve potent, NO-independent vasodilation. Another promising pathophysiological approach is currently evaluated by the use of tyrosine kinase inhibitors - anti-proliferative drugs which inhibit or even may reverse the pulmonary vascular remodeling process. Serotonin receptor antagonists are also reported to have anti-proliferative, anti-thrombotic and anti-fibrotic effects. Other forms of pulmonary hypertension (Groups II-V) are strictly separated from PAH. Evidence on treatment with PAH specific agents is strongly needed for these groups. Patients with non-PAH pulmonary hypertension should be referred to PAH expert centers, and preferably treated in controlled studies.
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PMID:[Update: Current clinical developments in pulmonary hypertension]. 1971 5

Protein tyrosine phosphorylation is a key event accompanying sperm capacitation. Although this signaling cascade generates an array of tyrosine-phosphorylated polypeptides, their molecular characterization is still limited. It is necessary to differentiate the localization of the tyrosine-phosphorylated proteins in spermatozoa to understand the link between the different phosphorylated proteins and the corresponding regulated sperm function. cAMP plays a pivotal role in the regulation of tyrosine phosphorylation. The intracellular cAMP levels were raised in goat spermatozoa by the addition of the phosphodiesterase inhibitor, IBMX in conjugation with caffeine. Tyrosine phosphorylation was significantly up-regulated following treatment with these two reagents. Treatment of caudal spermatozoa with IBMX and caffeine, time dependent up-regulated phosphorylation of the protein of molecular weights 50 and 200 kDa was observed. Increased phosphorylation was observed with a combination of IBMX and caffeine treatment. Tyrosine phosphorylation in caput spermatozoa was not affected significantly under these conditions. The expression level of tyrosine kinase in sperm was examined with specific inhibitors and with anti-phosphotyrosine antibody. The indirect immunofluorescence staining was carried out on ethanol permeabilized sperm using anti-phosphotyrosine antibody. Western blot analysis was done using two separate PKA antibodies: anti-PKA catalytic and anti-PKA RIalpha. Almost no difference was found in the intracellular presence of the PKA RIalpha and RIIalpha subunits in caput and caudal epididymal spermatozoa. However, the catalytic subunit seemed to be present in higher amount in caudal spermatozoa. The results show that caprine sperm displays an enhancement of phosphorylation in the tyrosine residues of specific proteins under in vitro capacitation conditions.
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PMID:Regulation of tyrosine kinase activity during capacitation in goat sperm. 1980 24

Pulmonary Hypertension is a severe lung disease, which is characterized by vasoconstriction and remodelling of the vessel wall. Mostly addressing the increased vascular tone, prostacyclin and its analogues, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors have been approved for treatment of PAH and represent the current therapeutic options. Mechanistically, these vasodilators decrease pulmonary vascular resistance and reduce thereby shear stress, which is a strong proliferative stimulus per se. Beside the development of new vasodilators, current research focuses on the development of causal treatment regimens aiming a normalization of the vessel structure. Mechanistically, increased proliferation, migration and a resistance to apoptosis of vascular cells represent key events in disease progression. In this context, tyrosine kinase inhibitors like imatinib have been shown to possess reverse remodelling potential in preclinical models of pulmonary hypertension by inducing apoptosis and blocking proliferation. This book chapter describes the role of the platelet derived growth factor (PDGF) receptor and its antagonists for treatment of pulmonary hypertension.
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PMID:PDGF receptor and its antagonists: role in treatment of PAH. 2020 47

Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.
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PMID:Emerging therapies for the treatment of pulmonary hypertension. 2021 70

In this article we focus on the pathogenesis and clinical characteristics of schistosomiasis infection on the lung vasculature. Overall, the basic biology and understanding of Schistosoma immune responses and their effect on the cardiopulmonary system is limited in both animal and human models, which hinders clinical care and drug development. The inflammatory response to the eggs in the lung appears to contribute to the remodeling of the pulmonary vessels. Portal hypertension caused by parasitemia also appears to contribute to the development of pathophysiologic alterations of the pulmonary vascular bed. Antischistosomal therapy, praziquantel, used for pulmonary hypertension secondary to schistosomiasis usually has no effect, but it is given to prevent further progression of disease. Currently, there are no clinical trials for the treatment of pulmonary vascular disease secondary to schistosomiasis. Specialty drugs such as phosphodiesterase type 5 or tyrosine kinase inhibitors exhibit some interesting activity, yet are prohibitively expensive, lack safety and efficacy studies in schistosomiasis endemic populations, and tend to be limited by safety, efficacy, route of administration and compliance problems.
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PMID:Pulmonary vascular disease associated with schistosomiasis. 2113 70


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