The Novel Phosphodiesterase Inhibitor NM-702 Improves Claudication-Limited Exercise Performance in Patients With Peripheral Arterial Disease

Brass, Eric P.; Anthony, Richard; Cobb, Frederick R.; Koda, Isao; Jiao, Jenny; Hiatt, William R.

doi:10.1016/j.jacc.2006.07.064

Cited by 35 publications

(20 citation statements)

References 14 publications

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“…65 The efficacy signals from 2 additional phosphodiesterase type 3 inhibitors support a disease benefit for the class, albeit one that is not completely understood. 66,67 Older medications, such as pentoxifylline and naftidrofuryl, are approved for use in patients with PAD within and outside of the United States, respectively. The overall data supporting any functional benefit for treatment of patients with PAD with pentoxifylline are weak.…”

Section: Existing Medical Therapy For the Exercise Limitation In Padmentioning

confidence: 99%

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Hiatt¹,

Armstrong²,

Larson³

et al. 2015

Circulation Research

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137

118

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P eripheral artery disease (PAD) is initiated by atherogenic mechanisms common to all major vascular territories but encompasses several distinctly important clinical sequelae.1 The global burden of PAD is large and rising, with substantial morbidity and mortality found in high-, middle-, and low-income countries. 2 The atherosclerotic occlusive disease underlying PAD is associated with an exercise limitation in the majority of patients, whereas the classic symptoms of intermittent claudication, ischemic rest pain, and ischemic ulceration are less common manifestations. 3 Patients with PAD are also at increased risk of myocardial infarction, ischemic stroke, heart failure, renovascular hypertension, and vascular death reflecting the systemic atherosclerotic burden. [4][5][6] The epidemiology of Peripheral Artery Disease Compendium© 2015 American Heart Association, Inc. The diagnosis of PAD can be ascertained by simple hemodynamic measurements, in particular, the ankle-brachial index (ABI), a test performed by measuring the systolic blood pressure in each arm and the dorsalis pedis and posterior tibial arteries of each ankle. The highest of the dorsalis pedis or posterior tibial artery pressures is the numerator of the ABI specific to each leg, whereas the highest arm pressure on either side is the denominator. A ratio of <0.90 in either leg is considered hemodynamic evidence of PAD. 16 When imaged, PAD can be characterized as one or more arterial stenoses or occlusions involving the distal aorta, iliac, femoral, popliteal, or tibial arteries. 17The underlying mechanisms responsible for the functional limitations in PAD are hemodynamic in origin, which affects the supply of oxygen and substrates to metabolically active tissue: skeletal muscle in the case of intermittent claudication and skin and subcutaneous tissues in the case of critical leg ischemia. However, additional pathophysiologic mechanisms contribute to the limb manifestations, where a reduction in blood flow alone does not fully account for the exercise limitation. Recent research into the pathophysiology of this exercise limitation has identified several important sequelae resultant from the chronic hemodynamic deficit. These changes affecting the vasculature and skeletal muscle distal to the primary hemodynamic lesions likely contribute to the mechanisms of exercise limitation in PAD. These advances are reviewed here with an additional focus on identifying possible future therapeutic strategies. Symptomatic Manifestations and Exercise Limitations in PADIn the coronary circulation, plaque rupture leading to acute ischemic events is a common clinical presentation; in PAD, progressive atherosclerosis leading to chronic stenosis and occlusion, often in series, in the arteries supplying the lower extremities dominates the symptomatic manifestations.6 Limb SymptomsPatients with PAD may present with a range of limb symptoms. Most patients are either asymptomatic or have atypical limb symptoms during exercise, whereas only a third have typical symptoms of c...

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Section: Existing Medical Therapy For the Exercise Limitation In Padmentioning

confidence: 99%

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Hiatt¹,

Armstrong²,

Larson³

et al. 2015

Circulation Research

Self Cite

137

118

View full text Add to dashboard Cite

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“…42,43 However, contemporary multicenter trials using the graded treadmill test and site training (site end-point evaluation visit) have controlled this placebo response to 9% to 12% at 3 months and 13% to 23% at 6 months. 44 The cause of this placebo response is likely multifactorial. The subject's comfort and adjustment to walking on the treadmill, including optimization of gait, likely contribute.…”

Section: Treadmill Reliabilitymentioning

confidence: 99%

“…45,46 and a variety of medications. 26,37,44,47 The treadmill has been used in several drug trials of agents, including those with small effect sizes. For example, a meta-analysis of propionyl-L-carnitine demonstrated an effect size in a range of 0.11 to 0.22, whereas phosphodiesterase-3 inhibitors have effect size estimates in the range of 0.28 to 0.32.…”

Section: Treadmill Reliabilitymentioning

confidence: 99%

The Treadmill Is a Better Functional Test Than the 6-Minute Walk Test in Therapeutic Trials of Patients With Peripheral Artery Disease

2014

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“…Cilostazol has been clinically used for the treatment of chronic arterial occlusive diseases such as intermittent claudication [23][24][25][26][27]. Recently it has been demonstrated that NT-702 therapy improved the exercise performance of patients with peripheral arterial disease [14] and reduction of the walking distance in a rat experimental intermittent claudication model [13]. However, there have been no reports studying the effect of NT-702 on the vasoreactivity of spinal and cerebral resistance vessels.…”

Section: Nt-702-mediated Vasodilation Of Isolated Rabbit Spinal Artermentioning

confidence: 99%

“…NT-702 also inhibits platelet thromboxane A 2 synthase and aggregation at concentrations that inhibit rabbit phosphodiesterase [12]. Recently, it has been reported that NT-702 experimentally and clinically improves intermittent claudication in model animals [13] and humans [14], suggesting that it could be useful for the treatment of peripheral arterial disease. However, there has been no report of the effects of NT-702 on the mechanical activity of resistance vessels in the central nervous system.…”

mentioning

confidence: 99%

NT-702, a Selective Phosphodiesterase 3 Inhibitor, Dilates Rabbit Spinal Arterioles via Endothelium-Dependent and Endothelium-Independent Mechanisms

2008

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Abstract:We investigated the effects of NT-702, a selective phosphodiesterase (PDE) 3 inhibitor, on arterioles isolated from rabbit lumbar spinal cords. NT-702 caused a dose-dependent dilation of the isolated spinal arterioles. The disruption of endothelium produced a significant reduction of higher concentrations (10 -7 and 10 -6 M ), but not lower concentrations (less than 10 -8 M ), of NT-702-induced vasodilation. The NT-702-induced vasodilation of the arterioles with endothelium was not affected by pretreatment with an inhibitor of nitric oxide, cyclooxygenase, or cytochrome P-450 monooxygenase. In contrast, catalase reduced significantly the higher concentrations of NT-702-induced vasodilation only. Tetraethylammonium (TEA) completely reduced the lower concentrations of NT-702-induced vasodilation, but decreased only partially the higher concentrations of NT-702-induced vasodilation of the arterioles with endothelium. Hydrogen peroxide dilated significantly the isolated arterioles with endothelium, the response of which was reduced significantly by TEA. KT5720 (a selective protein kinase inhibitor) significantly decreased both the lower and higher concentrations of NT-702-induced vasodilation of the arterioles with endothelium. The findings suggest that NT-702 dose-dependently dilated the isolated spinal arterioles of rabbits via endotheliumdependent and endothelium-independent mechanisms. Protein kinase A (PKA)-and TEA-sensitive K + channels may be involved in the NT-702-induced vasodilation. Moreover, hydrogen peroxide may contribute in part to the endothelium-dependent higher concentrations of NT-702-induced vasodilation.

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The Novel Phosphodiesterase Inhibitor NM-702 Improves Claudication-Limited Exercise Performance in Patients With Peripheral Arterial Disease

Abstract: NM-702 used for 24 weeks by patients with claudication was associated with improvements in laboratory- and ambulatory-based exercise performance.

Cited by 35 publications

References 14 publications

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

The Treadmill Is a Better Functional Test Than the 6-Minute Walk Test in Therapeutic Trials of Patients With Peripheral Artery Disease

NT-702, a Selective Phosphodiesterase 3 Inhibitor, Dilates Rabbit Spinal Arterioles via Endothelium-Dependent and Endothelium-Independent Mechanisms

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