Effects of sarpogrelate, eicosapentaenoic acid and pitavastatin on arterioslcerosis obliterans-related biomarkers in patients with type 2 diabetes (SAREPITASO study).

BACKGROUND: The aim was to evaluate the significance of arteriosclerosis obliterans-related biomarkers in patients with type 2 diabetes mellitus (T2DM), and to compare the effects of sarpogrelate, eicosapentaenoic acid (EPA) and pitavastatin on these markers. PATIENTS AND METHODS: Seventy-two arteriosclerosis obliterans patients with T2DM were classified into two groups, pitavastatin with either sarpogrelate (PS) or EPA (PE). We observed no differences in all biomarkers between the PS and PE groups before treatments. RESULTS: The levels of body mass index, hemoglobin A1c, soluble E-selectin, soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1 and platelet-derived microparticle in the PE group decreased significantly after treatment. The ankle branchial pressure index and adiponectin levels significantly increased in the PE group after treatment compared with the PS group. CONCLUSION: These results suggest that combination therapy using pitavastatin and EPA possesses an antiatherosclerotic effect and may be beneficial for prevention of vascular complications in patients with T2DM.

[Lower-extremity artery disease (LEAD)]. / L'artériopathie oblitérante des membres inférieurs chez la femme.

Women have a risk of LEAD (lower-extremity artery disease)similar to men's risk. Symptoms are often absent, atypical or underestimated, leading to diagnosis in the most severe stages. Medical care is often less well adapted. In cases of revascularization, women have a higher morbidity rate than men, regardless of the severity grade and procedure chosen.

Attenuation of transplant arteriosclerosis by oral feeding of major histocompatibility complex encoding chitosan-DNA nanoparticles.

One promising approach for the induction of transplant tolerance is the pre-treatment of transplant recipients with donor MHC-alloantigen. Our study focuses on the oral delivery of MHC-antigen encoding genes via chitosan-DNA nanoparticles to modulate the alloimmune response in order to reduce the development of transplant arteriosclerosis, the hallmark feature of chronic rejection after heart transplantation. Therefore, we performed fully allogeneic mouse abdominal aortic transplants using C57BL/6 (H2(b)) mice as donors and CBA.J (H2(k)) mice as recipients. Aortic grafts were analyzed by histology and morphometry on day 30 after transplantation, levels of circulating alloantibodies were detected by FACS analysis. Pre-treatment of recipient mice with chitosan-DNA nanoparticles encoding for K(b), one of the MHC-I molecules of the donor, resulted in a significant reduction of intimal proliferation compared to untreated controls. When Ovalbumin was fed instead of K(b) encoding nanoparticles (K(b)-NP) or Balb/c (H2(d)) grafts were used instead of C57BL/6 (H2(b)) grafts as antigen controls, both groups showed no reduction of intimal thickness indicating an antigen-specific mechanism. In addition, analysis of peripheral blood of the transplanted mice showed significant suppression of alloantibody formation in the K(b)-NP fed group compared to all other allogeneic transplanted groups suggesting modulation of the humoral immune response. These results demonstrate the potential of chitosan-DNA nanoparticles to induce K(b)-specific tolerance and to reduce the development of transplant arteriosclerosis.

[Effects of Tongxinluo capsule on atherosclerosis obliterans in iliofemoral artery of rabbits].

OBJECTIVE: To explore the effects of Tongxinluo capsule (TXL) on the atherosclerosis obliterans (ASO) in iliofemoral artery of rabbits. METHOD: Rabbits were randomly divided into 7 groups: sham, model, TXL (0.8, 0.4, 0.2 g x kg(-1)), Tongsaimai tablet (0.8 g x kg(-1)) and Laishike (0.002 g x kg(-1)). The animal model of ASO was established with a combined method of mechanical trauma, immunologic injury and high fat fodder feeding. Rabbits were administrated the drugs 8 weeks after surgery. The levels of TC, TG, HDL-C and LDL-C in serum were determined at the time points below: pre-experiment (0 week), pre-drug administration (8 weeks post-surgery), 4 weeks after drug administration (12 weeks post-surgery), 8 weeks after drug administration (16 weeks post-surgery), 12 weeks after drug administration (20 weeks post-surgery). Meanwhile, the behavioral study was performed, the distal skin temperature of the injured hind limb detected. The histopathological changes in iliofemoral artery were examined after opacification. RESULT: The levels of TC, TG, LDL-C, VLDL-C and TC/HDL-C were decreased significantly in serum of ASO rabbits. The severity of lameness in the injured hind limb was improved. The distal skin temperature was increased. The thickness and the ratio of intima area of the iliofemoral artery of the injured hind limb were decreased, while the stenosis extent was improved. CONCLUSION: TXL might be beneficial to modulate blood lipid, as well as the prevention and treatment for ASO.

[Secondary prevention and conservative therapy of obliterative arteriosclerosis]. / Az arteriosclerosis obliterans szekunder prevenciója és belgyógyászati kezelése.

The author gives an overview of the main ways of medical therapy for patients with peripheral arterial obliterative disease. The importance of possible modification of the risk factors is emphasized especially beneficial effects of supervised walking-based exercise program. It is considered proven that the antiplatelet therapy and antilipidemic treatment reduce the risk of progressive atherosclerotic processes. The author summarizes the mechanisms and clinical effects of drugs influencing haemostation and haemorheology as well as vasodynamic agents. The results of clinical trials show a marked improvement of intermittent claudication by combination of preventive and therapeutic ways in majority of patients with peripheral arterial obliterative disease.

[Importance of "health foods", EPA and DHA, for preventive medicine].

The "lifestyle-related disease" has been increasing in Japan as the population advances in age and the food culture becomes westernized. Although prevention, treatment and therapy for this disease have been attempted using certain kinds of food and nutritive elements, so-called "health foods" such as DHA and EPA, which are mostly contained in fish oil, have been a special focus within these attempts. There have been many reports regarding the pharmacological functions and the mechanisms of DHA and EPA. Also, in the past few years, it has become possible to produce ingestible DHA and EPA oils, oils for chemical compounds, oils for animal feed, and highly purified DHA and EPA for medical and pharmaceutical use. EPA ethyl ester has a wide market as a preventive medicine in Japan. Initially in 1990, this medicine was administered in cases of arterisclerosis obliterans, using its anti-platelet aggregation ability. Four years later, in 1994, its effectiveness in triglyceride reduction was recognized, and its application was extended to cases of hyperlipidemia, which has remarkably broadened its market. Clinical studies with DHA have shown improvement in senile dementia (cerebral thrombosis, Alzheimer's disease), atopic dermatitis, and the ability to focus on moving objects, as well as control of aggressiveness against others caused by stress, and prevention of hyperlipidemia, hypertension, and cancer.

[Arteriosclerosis obliterans(ASO) in diabetic patients].

The major risk factors of arteriosclerosis obliterans(ASO) in diabetic patients are age, male gender, smoking, poor glycemic control, hypertension, and dyslipidemia. Thus, to prevent the development and progression of ASO, intensive intervention in the risk factors should be required. HOPE study reported that treatment of ACE-inhibitor in the patients with ASO for 5 years clearly decreased the relative risk for incidence of cardiovascular events comparing with the placebo group. Furthermore, UKPDS Group demonstrated that the adjusted odds ratios to the development of ASO for each 1% HbA1c increase and each 10 mmHg systolic blood pressure increase were respectively 1.28 and 1.25 from multivariate analysis. However, optimal levels of HbA1c and blood pressure for prevention of ASO still have not been suggested. Therefore, large-scale intervention trial in Japanese diabetic subjects should be needed.

Effects of LDL apheresis and vitamin E-modified membrane on carotid atherosclerosis in hemodialyzed patients with arteriosclerosis obliterans.

BACKGROUND: Hemodialysis patients manifest accelerated atherosclerosis. Hemodialysis is associated with oxidative stress, which can be partially prevented with the use of a vitamin E-coated dialyzer. Adsorption of low-density lipoprotein (LDL) has been applied in the treatment of arteriosclerosis obliterans (ASO). The aim of the present study was to determine whether the vitamin E-coated dialyzer and/or LDL apheresis affects carotid atherosclerosis in hemodialysis patients with ASO. METHODS: Thirty hemodialysis patients with ASO were divided into four treatment groups: treatment with conventional cellulose or synthetic membranes (group A, n = 12), treatment with vitamin E-coated membrane (group B, n = 7), treatment with conventional membrane and LDL apheresis (group C, n = 6), and treatment with vitamin E-coated membrane and LDL apheresis (group D, n = 5). Carotid artery intima-media thickness (IMT) and arterial stiffness assessed by pulse wave velocity (PWV), plasma C-reactive protein (CRP) and interleukin (IL)-6 were measured before and 10 weeks after treatment and compared between groups. All values were referred to measurements after LDL apheresis. RESULTS: IMT and PWV, plasma CRP and IL-6 showed little change in group A throughout the experimental period. These decreased slightly from the baseline value in group B, but the change was not significant. In group C, IMT decreased from 1.12 +/- 0.24 to 1.02 +/- 0.18 mm (p < 0.05), and PWV decreased from 2,266 +/- 380 to 1,968 +/- 342 cm/s (p < 0.05). Plasma CRP and IL-6 concentrations also decreased significantly compared with baseline (p < 0.05). In group D, IMT decreased from 1.18 +/- 0.26 to 0.92 +/- 0.18 mm (p < 0.01), and PWV decreased from 2,284 +/- 390 to 1,786 +/- 284 cm/s (p < 0.01). Plasma CRP and IL-6 levels also decreased significantly compared with baseline (p < 0.01). CONCLUSION: These data suggest that LDL apheresis and the vitamin E-coated membrane dialysis in combination may prevent further progression of atherosclerosis in hemodialysis patients with ASO.

Inhibition of vascular smooth muscle cell proliferation and arterial intimal thickening by a novel antiproliferative naphthopyran.

Smooth muscle cell proliferation plays an important role in neointimal thickening after vascular injury and may contribute to restenosis after angioplasty. Development of suitable pharmacological agents modulating smooth muscle cell proliferation is critical for further investigation of vascular hyperplasia and its prevention. In the present study, we report a novel series of compounds that inhibit smooth muscle cell proliferation and arterial intimal thickening after balloon angioplasty. LY290181 (2-amino-4-[3-pyridyl]-4H-naphtho [1, 2-b]pyran-3-carbonitrile) and LY290293 (2-amino-4-[3-pyridyl]-4H-naphtho [1, 2-b]pyran-carbonitrile) produced a dose-dependent inhibition of DNA synthesis and proliferation of vascular smooth muscle cells in culture. Fifty percent inhibition (IC50) of cell proliferation was produced by 20 nM LY290181 or LY290293. Cell growth inhibition was not due to cell death, as demonstrated by the release of intracellular lactate dehydrogenase and by the reversibility of inhibition upon washing. Inhibition of smooth muscle cell proliferation was achieved in cells stimulated by either serum or individual growth factor such as platelet-derived growth factor, fibroblast growth factor or epidermal growth factor. In the rat model of balloon injury to carotid artery, LY290181 and LY290293 produced 61% (P < .005) and 48% (P < .005) inhibition of intimal thickening when administered p.o. at 100 and 120 mg/kg/day, respectively, over a 2-week period. Inhibition of intimal thickening (70%, P < .005) by LY290293 was also demonstrated when the compound was administered s.c. at 10 mg/kg/day. These studies demonstrate that naphthopyrans LY290181 and LY290293 are potent inhibitors of smooth muscle cell proliferation in vitro and that they produce substantial reduction in arterial intimal thickening in a balloon injury model when administered systemically.

Prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis paniculata nees and fish oil. Experimental studies of effects and mechanisms.

Restenosis rate after coronary angioplasty has been up to 30%-40%. To solve this problem, we studied the effects of Andrographis Paniculata Nees (APN) and fish oil (FO, omega 3 polyunsaturated fatty acids over 70%) on atherosclerotic stenosis and restenosis after experimental angioplasty and the relevant mechanisms of APN and FO. Preliminary results showed that APN can significantly alleviate atherosclerotic iliac artery stenosis induced by both deendothelialization and high cholesterol diet (HCD) and restenosis following angioplasty in rabbits. FO showed the same but milder effects than APN did. Both APN and FO significantly inhibited blood monocytes to secrete growth factors in vivo. Ca(++)-ATPase activity of cell membrane of atherosclerotic rabbits was significantly decreased, while APN or FO, especially the former alleviated this reduction. Refined extract of APN significantly decreased in vitro resting platelet [Ca++]i and in vivo the resting and thrombin-stimulated platelet [Ca++]i after oral administration of APN for 2 weeks. APN significantly inhibited cell growth or DNA synthesis in dose-dependent manner. In conclusion because of the mechanisms described above, APN can alleviate atherosclerotic artery stenosis induced by both deendothelialization and HCD as well as lower restenosis rate after experimental angioplasty. The effects of APN are evidently superior to those of FO.

Experimental studies on prevention of atherosclerotic arterial stenosis and restenosis after angioplasty with Andrographis Paniculata Nees and fish oil.

In order to search for effective drugs to reduce restenosis incidence after coronary angioplasty, we studied the effects of a Chinese herb, extract of Andrographis Paniculata Nees (APN), and Fish Oil (FO) on atherosclerotic stenosis and restenosis after experimental angioplasty. Preliminary results showed that APN can significantly alleviate atherosclerotic iliac artery stenosis induced by both deendothelialization and high cholesterol diet (control group, stenosis incidence 100%, stenotic severe degree 60.53 +/- 31.03%, of which 30% arteries (6) are total occlusion; FO group: stenotic incidence and severe degree are 77% and 53.00 +/- 21.17%, respectively, and in APN group they are 70% and 25.39 +/- 10.52%, respectively, P < 0.01), and follow-up angiography 4 weeks after angioplasty showed that dilated iliac arteries in control group all had severe restenosis, but in APN group no or only mild restenosis occurs, and in FO group restenosis is as severe as stenotic degree prior to angioplasty. These preliminary results suggest that APN and FO can significantly alleviate stenosis induced by deendothelialization and high cholesterol diet and restenosis after angioplasty, while the former has a more marked effect. The above findings lead the authors to conclude that APN may play an important role in preventing restenosis after coronary angioplasty, but FO may be useful in reducing the extent of of restenosis after coronary angioplasty.

Reocclusion prophylaxis with dipyridamole combined with acetylsalicylic acid following PTA.

After primary successful PTA, 199 patients were randomized into one of three treatment groups, namely, placebo or a combination of 75 mg dipyridamole with either 330 mg (high dose) or 100 mg (low dose) acetylsalicylic acid (ASA) tid. The duration of treatment was six months. Of the 199 patients admitted to the study, 156 completed the six-month trial period. Not all patients had a second angiogram, and in these cases clinical findings were used in the evaluation. Evaluation of the combined angiographic and clinical results showed improvement or no deterioration in 37% of patients in the placebo group compared with 49% in the low-dose and 61% in the high-dose ASA groups respectively. The only statistically significant difference observed was between the placebo group and the group treated with dipyridamole and high-dose ASA (p = 0.01). This difference remained statistically significant at p = 0.039 if only the angiographic findings were considered for group comparison. It cannot, however, be concluded from this study that 75 mg dipyridamole in combination with 100 mg ASA tid is more effective in preventing reocclusion after PTA than in combination with 330 mg ASA tid.

[Arteriosclerosis: a challenge for the surgeon. Prevention and postoperative care (author's transl)]. / Die Arteriosklerose als chirurgische Aufgabe. Vorsorge und Nachsorge

A review of the possibilities for primary and secondary prevention of arteriosclerosis is followed by a critical analysis of long-term therapy with anticoagulants and platelet aggregation inhibitors with regard to the prevention of occlusive vascular disease (with a review of the pertinent retrospective and prospective studies).