A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication

Brass, Eric P.; Cooper, Leslie T.; Morgan, Roger; Hiatt, William R.

doi:10.1016/j.jvs.2011.09.004

Cited by 19 publications

(18 citation statements)

References 19 publications

(25 reference statements)

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“…Although the safety of treadmill testing has not been evaluated extensively in the PAD population, 1 study included comprehensive hemodynamic and ECG monitoring during exercise in a large cohort and identified no safety concerns, including no changes indicative of cardiac ischemia during testing. 37 This finding is consistent with the reported adverse event experience from clinical trials using peak treadmill testing involving thousands of patients with PAD. However, most patients with PAD have underlying coronary artery disease; therefore, ECG monitoring during all peak treadmill exercise tests in this population is recommended to enhance patient safety.…”

Section: Conduct Of the Exercise Testsupporting

confidence: 84%

“…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%

“…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. 26,37,47 Indeed, no intervention demonstrated to be effective has failed to demonstrate improvement in 1 or more clinical trials using graded treadmill testing.…”

Section: Treadmill Reliabilitymentioning

confidence: 99%

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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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Section: Conduct Of the Exercise Testsupporting

confidence: 84%

Section: Treadmill Reliabilitymentioning

confidence: 99%

Section: Treadmill Reliabilitymentioning

confidence: 99%

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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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“…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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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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“…In contrast, anti-platelet activities of K-134 are more potent than cilostazol. K-134 is currently being developed for treating intermittent claudication associated with peripheral arterial diseases [14] and the beneficial effects of PDE3 inhibitors on peripheral arterial disease are attributable to not only antiplatelet activity but also vasodilatory activity or some chronic unknown effects [11], [13], as no studies have shown a benefit of other antiplatelet drugs such as acetylsalicylic acid and clopidogrel [15]. Meanwhile, the potent anti-platelet activity of K-134 also make it a potential alternative agent for preventing secondary cerebral infarction because antiplatelet therapy for secondary stroke prevention has been proved to be beneficial in clinical trials [3].…”

Section: Discussionmentioning

confidence: 99%

K-134, a Phosphodiesterase 3 Inhibitor, Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model

et al. 2012

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BackgroundK-134 is a more potent antiplatelet drug with a selective inhibitory effect on phosphodiesterase 3 (PDE3) compared with its analogue, cilostazol.ObjectivesThis study was performed to compare the ameliorating effects of K-134 and cilostazol on brain damage in an experimental photothrombotic cerebral infarction model.Methods and ResultsWe investigated the effects of oral preadministration of PDE3 inhibitors in a rat stroke model established by photothrombotic middle cerebral artery (MCA) occlusion. K-134 significantly prolonged MCA occlusion time at doses >10 mg/kg, and reduced cerebral infarct size at 30 mg/kg in the stroke model (n = 12, 87.5±5.6 vs. 126.8±7.5 mm3, P<0.01), indicating its potent antithrombotic effect. On the other hand, the effects of cilostazol on MCA occlusion time and cerebral infarct size are relatively weak even at the high dosage of 300 mg/kg. Furthermore, K-134 blocked rat platelet aggregation more potently than cilostazol in vitro. Also in an arteriovenous shunt thrombosis model, K-134 showed an antithrombotic effect greater than cilostazol.ConclusionsThese findings suggest that K-134, which has strong antithrombotic activity, is a promising drug for prevention of cerebral infarction associated with platelet hyperaggregability.

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A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication

Abstract: K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population.

Cited by 19 publications

References 19 publications

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

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

K-134, a Phosphodiesterase 3 Inhibitor, Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model

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