Rationale and Design of the Enoximone Clinical Trials Program

Lowes, Brian D.; Shakar, Simon F.; Metra, Marco; Feldman, Arthur M.; Eichhorn, Eric J.; Freytag, J. William; Gerber, Mark E.; Liard, J. F.; Hartman, Craig; Gorczynski, Rick; Evans, Gwyn A.; Linseman, Jennifer V.; Stewart, Jennifer; Robertson, Alastair D.; Roecker, Ellen B.; DeMets, David L.; Bristow, Michael R.

doi:10.1016/j.cardfail.2005.10.013

Cited by 24 publications

(21 citation statements)

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“…120 This situation creates the potential to selectively activate cAMP/PKA-dependent signaling in specific cellular compartments by the use of selective phosphodiesterase inhibitors. That approach was recently attempted in a Phase 3 trial using the phosphodiesterase 3 selective inhibitor enoximone in combination with ␤-blockade to couple inhibition of ␤ 1 -AR adverse biological signaling with restoration of 16 Ser phospholamban phosphorylation, 122 which is reduced in the failing heart. 123 Although this 1854-patient clinical trial was not positive on its primary end points, it demonstrated promise in patients with the most severe LV dysfunction.…”

Section: Compartmentation Of Intracellular Signaling In Microdomains mentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Treatment of Chronic Heart Failure With ␤-AdrenergicReceptor Antagonists A Convergence of Receptor Pharmacology and Clinical CardiologyMichael R. BristowAbstract: Despite the absence of a systematic development plan, ␤-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that ␤-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into Phase 3 trials. Success then came relatively quickly, and within 8 years multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy, through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting. (Circ Res. 2011;109:1176-1194.)Key Words: heart failure Ⅲ adrenergic receptors Ⅲ ␤-blockers Ⅲ norepinephrine Ⅲ drug development "I love it when a plan comes together" -Colonel John "Hannibal" Smith, The A-Team ␤ -Adrenergic blocking agents are now considered firstline therapy for chronic heart failure. 2 Between 1971 and 2001, ␤-blockers as a drug class went from contraindicated to being universally declared a highly effective new therapy for chronic heart failure with systolic dysfunction. As depicted in Figure 1, this 180-degree turn required the convergence of initially disconnected lines of basic and clinical investigation, none of which was systematically planned by the usual purveyors of drug development, large pharmaceutical companies. However, as for the typical outcome of Colonel Hannibal Smith's unconventional and dubious tactical schemes, 1 the end result was highly successful. This review provides some of the historical highlights, summarizes current knowledge, and provides thoughts on the future of ␤-blocker and antiadrenergic therapy. Historical Highlights Discovery of Adrenergic ReceptorsIn 1948, Raymond Ahlquist reported evidence for two types of adrenergic receptors, 3 which, "for convenience," he termed alpha and beta. The evidence was based on 2 distinct rank orders of agonist potency for a variety of pharmacological responses, plus the ability to inhibit the vasoconstrictor or uterine contraction responses of the ␣ group, with 3 different compounds (dibenamine, ergotoxine, or tolazoline) that would later be termed ␣-blocking agents. At the time of Ahlquist's landmark work, the...

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Section: Compartmentation Of Intracellular Signaling In Microdomains mentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

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151

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“…26 In particular, a case has been made for adding PDE 3 inhibition to ␤-blockade to eliminate the proapoptotic ␤1-adrenergic signaling but retain the stimulatory action of cAMP on sarcoplasmic reticulum function. Unfortunately, the recent data of the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) on combined enoximone and ␤-blockade in patients with advanced heart failure revealed no benefit in terms of mortality and hospitalization.…”

Section: Article P 388mentioning

confidence: 99%

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

2006

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C yclic adenosine monophosphate (cAMP) is a tightly regulated second messenger that is critically involved in many intracellular processes. In cardiomyocytes, the activation of a number of membrane receptors, notably ␤-receptors and muscarinic receptors, acts through stimulatory or inhibitory G-proteins (G␣s/G␣i) on adenylyl cyclase (AC), which synthesizes cAMP from ATP. cAMP is degraded by phosphodiesterases (PDE). Thereafter, cAMP activates protein kinase A (PKA), which, in turn, through phosphorylation of L-type calcium channels, ryanodine receptors, phospholamban, and troponin I, improves excitationcontraction coupling and increases heart rate, as well as contraction amplitude and relaxation. PKA also phosphorylates nuclear cAMP-response element binding proteins to activate transcription. 1 There are at least 9 isoforms of AC; the mammalian myocardium expresses mainly AC V and VI. AC V is the predominant isoform in adult cardiac tissue, whereas AC VI expression decreases with age. Both isoforms are phosphorylated by PKA and thereby inhibited, thus providing a feedback regulation and potential desensitization pathway. 2,3 Transgenic mice with cardiac-directed overexpression of AC VI have normal cAMP and cardiac function at rest but increased responses in both cAMP and function to ␤-adrenergic stimulation, 4 as confirmed in the present study by Takahasi et al. 5 Article p 388The prevailing notion is that increased myocardial cAMP in settings of acute myocardial ischemia is detrimental. In fact, ␤-adrenergic agonists that increase cAMP formation disrupt perfusion-contraction matching and promote infarction in controlled animal models of myocardial ischemia, both by increasing myocardial energetic requirements and by an unfavorable flow redistribution away from the ischemic subendocardium. 6 Apart from increasing infarct size, cAMP promotes ventricular tachyarrhythmias in ischemia/reperfusion. 7 Although increased cAMP acutely increases left ventricular function in heart failure, most trials with either ␤-adrenergic agonists or PDE inhibitors have revealed increased mortality, possibly secondary to tachyarrhythmias. 1 The present article by Takahashi et al 5 challenges the concept that cAMP in subacute myocardial infarction with heart failure is bad. They subjected transgenic mice with cardiac-directed overexpression of AC VI to permanent coronary ligation and found 17-fold-elevated AC protein content and 4.3-fold-increased cAMP formation, along with reduced mortality, over a 1-week observation period. The reduced mortality in the AC VI-overexpressing mice was associated with a nonsignificant increase in ventricular extrasystoles but reduced bradyarrhythmias. The better conduction properties in the AC VI-overexpressing mice were not mechanistically explained but are possibly related to connexin 43 expression, which is reduced in heart failure 8 and increased by catecholamines in a PKA-dependent manner. 9 Reduced mortality is a robust and undisputable end point in mice and humans, and in this respect, the present...

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“…The rationale for the use of PDE3 inhibitors in the setting of heart failure derives from the observation that failing human myocardium exhibits decreased levels of cAMP and cAMP-mediated signaling that can be corrected by PDE3 inhibition [45][46][47][48][49]. Short-term effects of PDE3 inhibition in patients with heart failure are well-described.…”

Section: Pde3 Inhibitors In Clinical Usementioning

confidence: 98%

Phosphodiesterase inhibition in heart failure

et al. 2008

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Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes-which differ with respect to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation-have been identified. Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways in heart failure.

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Rationale and Design of the Enoximone Clinical Trials Program

Cited by 24 publications

References 68 publications

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

Phosphodiesterase inhibition in heart failure

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