Effects of Cilostazol on VEGF and Oxidative Stress Biomarkers in Hemodialysis Patients With Peripheral Vascular Disease
Condition: Hemodialysis Patients; Peripheral Vascular Disease
MeSH terms: Vascular Diseases; Peripheral Vascular Diseases; Peripheral Arterial Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      Peripheral arterial disease (PAD) is the most common manifestation of systemic
      atherosclerosis and accounts for significant morbidity and mortality among end-stage renal
      disease (ESRD) patients. However, few studies have identified the prevalence and clinical
      impact of PAD in this specific population.

      Objectives: To perform a single-blinded parallel, controlled trial to examine the effect of
      cilostazol treatment on plasma VEGF levels, tissue factors , inflammatory markers (such as
      IL-6, hsCRP) levels, oxidative stress markers in ESRD patients with PAD Material and methods
      Fourty HD patients on maintenance HD for > 3months were enrolled in this prospective,
      single-blinded, randomized study. These patients were randomly allocated into 2 arms. After
      baseline assessment, patients in the treatment arm received 12 weeks of added on therapy with
      cilostazol 100mg/day. Blood pressure, heart rate, oxidative stress (malonyldialdehyde,
      protein carbonyl and ADMA), inflammatory markers (hsCRP, IL-6) and plasma, VEGF and tissue
      factors levels were measured before and after treatment.
    

Detailed description: 
      Purpose :

      Patients with end stage renal disease are at an increased risk for cardiovascular disease
      (CVD) and the annual mortality from CVD in end-stage renal disease (ESRD) patients is
      substantially higher than in the general population. Peripheral arterial disease (PAD), the
      most common manifestation of atherosclerosis, is characterized by atherosclerotic occlusive
      disease of the lower extremities. The most common symptom of PAD is intermittent
      claudication, defined as pain, cramping, or aching in the calves, thighs, or buttocks.
      However, it has been reported that over one-half of those with PAD remains asymptomatic. Rest
      pain, tissue loss, and gangrene are among the more extreme presentations of PAD and PAD has
      been a major cause for lower-extremity amputation, especially in those HD patients with
      diabetes. However, few available data stressed on the huge burden of PAD in hemodialysis (HD)
      patients. More importantly, presence of PAD in these patients is an important predictor for
      subsequent cardiovascular and overall mortality. The medical therapy of in PAD in general
      population is limited to a few antiplatelet drugs and statin in relatively few descriptive
      studies and randomized control trials. There are no appropriate randomized trials of these
      therapies in the treatment of PAD in patients with chronic kidney diseases. Hence, there are
      as yet no substantial data to support for efficacy of pharmacologic interventions of PAD in
      these specific groups of patients.

      Hypothesis

      Use of cilosatzol may be associated with increased plasma levels of VEGF and TF and
      amelioration of inflammation in HD patients with PAD.to perform a parallel, controlled trial
      to examine the effect of cilostazol treatment on plasma VEGF levels, tissue factors ,
      inflammatory markers (such as IL-6, hsCRP) levels, oxidative stress markers in ESRD patients
      with PAD.

      Many human diseases are characterized by disorders of the vasculature. In ischemic heart
      disease or peripheral artery disease, insufficient blood vasculature leads to tissue
      ischemia. Out of the many players in the angiogenesis field, the vascular endothelial growth
      factors are by far the best characterized and several VEGFs have already entered clinical use
      in a variety of human conditions. While many studies have addressed the role of angiogenesis
      and the blood vasculature in human physiology and pathology, the role of proangiogenic
      therapy in PAD has until recently attracted very little attention. VEGF is the prime hypoxia
      inducible angiogenic factor and binds VEGFR-1 and VEGFR-2. VEGF increases permeability of the
      endothelium through the formation of intercellular gaps, vesico-vascular organelles, vacuoles
      as well as fenestrations. VEGF also causes vasodilatation through the induction of the
      endothelial nitric oxide synthase (eNOS) and the subsequent increase in nitric oxide
      production. In recent years, several studies have reported beneficial effects of VEGF when
      used as a proangiogenic therapy in the setting of tissue ischemia. While proangiogenic
      therapies could be employed in the treatment of various ischemic diseases,controlling these
      processes with targeted molecular therapies remains at the heart of research.

      Cilostazol is a phosphodiesterase III inhibitor with a profound pharmacological profile.
      Cilostazol, {6[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2-(1H)- quinolinone} is
      a 2-oxoquinolone derivative (molecular weight, 369.47) that has a plasma half-life of
      10.564.4 hours after oral administration. It inhibits both primary and secondary platelet
      aggregation in response to ADP, collagen, epinephrine, and arachidonic acid. The antiplatelet
      and vasodilator properties of cilostazol have been attributed to its ability to elevate
      intracellular levels of cAMP.3 Cilostazol is currently used for treatment of symptomatic
      intermittent claudication (IC).Studies performed in diabetic patients have indicated that, in
      addition to its vasodilator and antiplatelet properties. Cilostazol may also favorably modify
      plasma lipoproteins by increasing HDL cholesterol (HDL-C) and reducing triglycerides.
      Numerous trials have evaluated the anti-proliferative properties of cilostazol and most found
      that it can prevent restenosis in patients undergoing percutaneous coronary intervention
      (PCI). In Japanese patients with type 2 diabetes, cilostazol therapy was associated with
      regression of carotid intimal thickness.

      The observed efficacy of cilostazol is not fully explained. Most investigators hypothesized
      that cilostazol exhibits its pharmacologic effects via antiplatelet, vasodilatory, and
      antithrombotic activities. Other postulated mechanisms of cilostazol action include a)
      anti-proliferative function by preventing restenosis after PCI, b) improved lipid profiles
      and c) prevent atherosclerosis via inhibition of the expression of the adhesion molecule.
      Some of these hypotheses may be valid, but clearly more confirmatory studies are needed.
      Although cilostazol has all the above properties, its effect on the expression of VEGF and
      oxidative stress biomarkers is not known For that purpose, we plan to study the changes in
      lipoprotein levels, proangiogenetic factors, inflammation, oxidative stress and endothelial
      activation following 12 weeks of cilostazol in a group of 40 HD patients. We feel that the
      present study may help to shed some lights and broaden our understanding of the
      pathophysiological mechanisms underlying the beneficial effects of cilostazol and give
      further insights on the role of antiplatelet drugs in PAD both by improving clinical symptoms
      and plausibly by reducing cardiovascular events
    

Intervention name(s): Cilostazol
Intervention type(s): Drug
Intervention MeSH terms: Cilostazol
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Treatment