Pharmacokinetics and hemodynamic effects of the phosphodiesterase III inhibitor saterinone in patients with chronic heart failure

Kieback, Arne; Iven, H.; Stolzenburg, K.; Eichner, E. Randy; Ruckdeschel, W.; Baumann, Gert

doi:10.1016/s0167-5273(03)00030-5

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…Saterinone, 12 another compound undergoing clinical evaluation purportedly combines PDE activity with alphaadrenoceptor antagonism to contribute to an enhanced vasodilatory effect [103]. Anagrelide, 13 was first described as an anti-platelet agent with anti-PDE3 activity [104].…”

Section: Clinical History Of Pde3 Inhibitorsmentioning

confidence: 99%

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Thompson¹,

Manganiello²,

Degerman

2007

CTMC

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The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.

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Section: Clinical History Of Pde3 Inhibitorsmentioning

confidence: 99%

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Thompson¹,

Manganiello²,

Degerman

2007

CTMC

View full text Add to dashboard Cite

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“…The therapeutic potential of the PDE3 enzymes has been indicated by the fact that PDE3A-deficient mice are viable [6], and because PDE3 inhibitors have been found to have beneficial effects in some chronic heart failure patients [7,8]. In addition, the use of inhibitors, and the phenotypes of PDE3 gene-knockout mice, have implicated PDE3 enzymes in the regulation of diverse cellular processes that are relevant to health and disease, including lipolysis in adipocytes [9][10][11], glycogenolysis, myocardial contractility, smooth muscle relaxation, platelet activation and aggregation [12], meiotic maturation in oocytes [6,13], proliferation of rat mesangial cells, secretion of insulin from pancreatic β-cells [14,15], and renin secretion [16].…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428

Rubio

Campbell

Morrice

et al. 2005

Biochemical Journal

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PDE3A (phosphodiesterase 3A) was identified as a phosphoprotein that co-immunoprecipitates with endogenous 14-3-3 proteins from HeLa cell extracts, and binds directly to 14-3-3 proteins in a phosphorylation-dependent manner. Among cellular stimuli tested, PMA promoted maximal binding of PDE3A to 14-3-3 proteins. While p42/p44 MAPK (mitogen-activated protein kinase), SAPK2 (stress-activated protein kinase 2)/p38 and PKC (protein kinase C) were all activated by PMA in HeLa cells, the PMA-induced binding of PDE3A to 14-3-3 proteins was inhibited by the non-specific PKC inhibitors Ro 318220 and H-7, but not by PD 184352, which inhibits MAPK activation, nor by SB 203580 and BIRB0796, which inhibit SAPK2 activation. Binding of PDE3A to 14-3-3 proteins was also blocked by the DNA replication inhibitors aphidicolin and mimosine, but the PDE3A-14-3-3 interaction was not cell-cycle-regulated. PDE3A isolated from cells was able to bind to 14-3-3 proteins after in vitro phosphorylation with PKC isoforms. Using MS/MS of IMAC (immobilized metal ion affinity chromatography)-enriched tryptic phosphopeptides and phosphospecific antibodies, at least five sites on PDE3A were found to be phosphorylated in vivo, of which Ser428 was selectively phosphorylated in response to PMA and dephosphorylated in cells treated with aphidicolin and mimosine. Phosphorylation of Ser428 therefore correlated with 14-3-3 binding to PDE3A. Ser312 of PDE3A was phosphorylated in an H-89-sensitive response to forskolin, indicative of phosphorylation by PKA (cAMP-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding. Thus 14-3-3 proteins can discriminate between sites in a region of multisite phosphorylation on PDE3A. An additional observation was that the cytoskeletal cross-linker protein plectin-1 coimmunoprecipitated with PDE3A independently of 14-3-3 binding.

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Clinical Pharmacokinetics of Drugs in Patients with Heart Failure

2013

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Heart failure is one of the leading causes of death in developed countries, and its prevalence is expected to increase further in the coming years. While the pharmacokinetic changes observed in patients with heart failure have been reviewed twice in Clinical Pharmacokinetics, approximately a quarter century has passed since the latest article was published in 1988. Since then, many important classes of agents (e.g. ACE inhibitors, angiotensin receptor antagonists and inotropes) have been introduced for the treatment of heart failure. The aim of the present article is to update the information regarding the pharmacokinetics of these drugs. For this purpose we have made a systematic survey of literature using MEDLINE, EMBASE and Japan Centra Revuo Medicina (in Japanese) and found a total of 111 relevant publications for 58 drugs. Heart failure is a pathophysiological state where the damaged heart, from whatever causes, no longer pumps enough blood for the needs of body tissues at rest or during the normal daily activities. The spectrum of heart failure ranges from acute decompensated heart failure (including circulatory shock) to chronic compensated or decompensated heart failure. Because hypoperfusion of organs may influence drug absorption from the gastrointestinal tract, distribution into tissues and elimination either by the liver or kidneys, it is conceivable that the pharmacokinetics of many drugs may be altered in patients with heart failure. The pharmacokinetic changes of drugs in these patients in the light of a physiologically based pharmacokinetic model are discussed, since this model can interpret altered pharmacokinetics in terms of changes in the binding of drugs in plasma and tissue, blood flow to drug-eliminating organs and intrinsic activity of drug elimination. Pharmacokinetic changes of drugs after intravenous administration are described here in Part 1 and those after oral administration will be discussed in Part 2 in a later issue of the Clinical Pharmacokinetics. Reviewing the retrieved data, it was considered that patients with asymptomatic or compensated chronic heart failure seem to have no or minimal alterations in the pharmacokinetics of parenterally administered drugs as long as there was no concurrent liver and/or kidney dysfunction. In contrast, it was found that the systemic clearance of at least six drugs (i.e. milrinone, carperitide, molsidomine, theophylline, ciclosporin and hydralazine) was reduced after intravenous administration by 50 % or more in patients with acute decompensated heart failure or chronic severe heart failure (New York Heart Association class III or IV) as compared with healthy subjects. Because there is a paucity of information regarding the pharmacokinetics of drugs in patients with severe heart failure, close attention should be paid to monitoring the efficacy of these agents and their associated adverse effects.

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Pharmacokinetics and hemodynamic effects of the phosphodiesterase III inhibitor saterinone in patients with chronic heart failure

Cited by 3 publications

References 22 publications

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428

Clinical Pharmacokinetics of Drugs in Patients with Heart Failure

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