Efficacy of Terminalia arjuna in chronic stable angina: a double-blind,placebo-controlled,crossover study comparing Terminalia arjuna with isosorbide mononitrate

BACKGROUND: Terminalia arjuna, an Indian medicinal plant, has been reported to have beneficial effects in patients with ischemic heart disease in a number of small, open studies. The need for a double-blind, randomized, placebo-controlled study with adequate sample size has long been felt. The bark extract (IPC-53) contains acids (arjunic acid, terminic acid), glycosides (arjunetin arjunosides I-IV), strong antioxidants (flavones, tannins, oligomeric proanthocyanidins), minerals. etc. and exhibits antifailure and anti-ischemic properties. METHODS AND RESULTS: Fifty-eight males with chronic stable angina (NYHA class II-III) with evidence of provocable ischemia on treadmill exercise test received Terminalia arjuna (500 mg 8 hourly), isosorbide mononitrate (40 mg/daily) or a matching placebo for one week each, separated by a wash-out period of at least three days in a randomized, double-blind, crossover design. They underwent clinical, biochemical and treadmill exercise evaluation at the end of each therapy which were compared during the three therapy periods. Terminalia arjuna therapy was associated with significant decrease in the frequency of angina and need for isosorbide dinitrate (5.69+/-6.91 mg/week v. 18.22+/-9.29 mg/week during placebo therapy, p<0.005). The treadmill exercise test parameters improved significantly during therapy with Terminalia arjuna compared to those with placebo. The total duration of exercise increased (6.14+/-2.51 min v. 4.76+/-2.38 min, p<0.005), maximal ST depression during the longest equivalent stages of submaximal exercise decreased (1.41+/-0.55 mm v. 2.21+/-0.56 mm, p<0.005), time to recovery decreased (6.49+/-2.37 min v. 9.27+/-3.39 min, p<0.005) and higher double products were achieved (25.75+/-4.81x10(3) v. 23.11+/-4.83x10(3), p<0.005) during Terminalia arjuna therapy. Similar improvements in clinical and treadmill exercise test parameters were observed with isosorbide mononitrate compared to placebo therapy. No significant differences were observed in clinical or treadmill exercise test parameters when Terminalia arjuna and isosorbide mononitrate therapies were compared. No significant untoward effects were reported during Terminalia arjuna therapy. CONCLUSIONS: Terminalia arjuna bark extract, 500 mg 8 hourly, given to patients with stable angina with provocable ischemia on treadmill exercise, led to improvement in clinical and treadmill exercise parameters as compared to placebo therapy. These benefits were similar to those observed with isosorbide mononitrate (40 mg/day) therapy and the extract was well tolerated. Limitations of this study include applicability of the results to only men with chronic stable angina but not necessarily to women, as they were not studied.     

Effect of chronic oral supplementation with vitamins on the endothelial function in chronic smokers

Cigarette smoking has been associated with endothelial dysfunction including impaired endothelium-dependent flow-mediated dilation (FMD). In cigarette smokers, increased oxygen-derived free radicals have been suspected of being one of the major causes of endothelial dysfunction, owing possibly to the inactivation of nitric oxide by free radicals. Vitamins C and E are widely used antioxidant vitamins, which have also been reported to effectively improve the endothelial function in several conditions. To test the effect of moderate-term oral antioxidant vitamin supplementation on the endothelial function in smokers, the authors evaluated the combined effect of vitamins C and E, administered in normal dosages, on FMD in young male smokers. A prospective interventional study was performed. In 15 healthy male subjects (mean age, 24.4 +/-2.5 years old). They studied FMD in the brachial artery by using high-resolution ultrasound. The vascular effects of moderate-term oral supplementation with vitamin C (1.0 g/day) and vitamin E (500 mg/day) were determined during reactive hyperemia, which causes endothelium-dependent FMD. They performed a vascular function study 3 times including before vitamin supplement, after 25 days of vitamin supplement, and 4 weeks after the cessation of the vitamin supplement. The flow-mediated dilator response measurements were repeated twice a day before vitamin supplements, and the repeatability obtained from these measurements was found acceptable (variability of FMD <2%). The oral antioxidant vitamin supplement significantly restored FMD (3.8 +/-2.2% vs 5.9 +/-2.5%; p<0.05), however, this effect disappeared 4 weeks after the vitamin supplementations ended. The combined usual dosage of vitamins C and E supplements was found to improve the endothelial function in chronic smokers.     

Terminalia arjuna Improves Cardiovascular Autonomic Neuropathy in Streptozotocin-Induced Diabetic Rats

The present study was designed to examine the therapeutic potential of Terminalia arjuna bark extract in improving cardiovascular autonomic neuropathy in Streptozotocin (STZ)-induced diabetic Wistar Albino rats. The baroreflex was evaluated by measuring the changes in heart rate with changes in arterial blood pressure induced by bolus injections of phenylephrine (vasoconstrictor) and sodium nitroprusside (vasodilator). T. arjuna bark extract, Rosuvastatin and Insulin were tested/administered therapeutically in rat model of uncontrolled diabetes. After 8 weeks of STZ administration, the reflex bradycardia and tachycardia response to hypertension and hypotension, respectively, were impaired in the diabetic group. The reflex bradycardia improved significantly after 1 month treatment of T. arjuna while the reflex tachycardia could not improve. The decreased body weight, heart rate, blood pressure and raised blood sugar in diabetic rats were not improved by T. arjuna therapy. Rosuvastatin treatment exerted similar effects while Insulin improved all the parameters. Further T. arjuna, Rosuvastatin and Insulin significantly reduced oxidative stress and inflammatory cytokine levels in diabetic rats. Results suggest that T. arjuna bark extract improves the altered baroreflex sensitivity in diabetic rats possibly through maintaining endogenous antioxidant enzyme activities and decreasing cytokine levels.     

Tetrahydrobiopterin restores endothelial function in long-term smokers

OBJECTIVES: We sought to test whether tetrahydrobiopterin (BH4) supplementation improves nitric oxide (NO) bioactivity in smokers. BACKGROUND: In smokers, endothelium-derived NO bioactivity is impaired. BH4 is an essential cofactor of NO synthase, and its deficiency decreases NO bioactivity. METHODS: Sapropterin hydrochloride, an active analogue of BH4 (2 mg/kg body weight), was administered orally to healthy male smokers and age-matched nonsmokers. Before and 3 and 24 h after sapropterin, we measured plasma levels of BH4 and examined flow-mediated vasodilation (FMV) of the brachial artery by high resolution ultrasonography, a noninvasive test of endothelial function. RESULTS: Basal plasma levels of BH4 were not different between smokers and nonsmokers. Sapropterin administration increased plasma levels of BH4 by threefold at 3 h, which returned to the baseline at 24 h. Before sapropterin, FMV was significantly smaller in smokers (p = 0.0002). Sapropterin significantly augmented endothelium-dependent vasodilation in smokers, but did not affect it in nonsmokers (p = 0.001 by analysis of variance [ANOVA]). Coadministration of N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor (20 micromol), into the brachial artery completely abolished the vasodilatory effects of sapropterin (p = 0.002 by ANOVA). Endothelium-independent vasodilation by glyceryl trinitrate was not different between smokers and nonsmokers and was not altered by BH4. CONCLUSIONS: We demonstrated that BH4 supplementation improved bioactivity of endothelium-derived NO in smokers. These observations strongly suggest that decreased NO-dependent vasodilation in smokers could be related to reduced bioactivity of BH4.     

Antioxidant and antimutagenic activities of bark extract of Terminalia arjuna

ObjectiveThe alcoholic extract of stem bark of Terminalia arjuna (ALTA) was screened for antioxidant and antimutagenic (anticlastogenic) activity.MethodsAntioxidant property was determined by 1, 1, Diphyny l, 2-Picryl hydrazyl (DPPH) assay, super oxide radical scavenging activity, lipid peroxidation assay and total polyphenolic content was determined by Folin-Ciocalteau's reagent. Antimutagenic activity was evaluated using micronucleus test in mice.ResultsThe ALTA has shown potent antioxidant activity with EC₅₀ of 2.491±0.160, 50.110±0.150 & 71.000±0.250 in DPPH assay, superoxide radical scavenging activity and lipid peroxidation assay, which is comparable with ascorbic acid with EC₅₀ of 2.471±0.140, 40.500±0.390 and 63.000±0.360 respectively. In micronucleus test, ALTA (100 & 200mg/kg, p.o.) showed significant reduction in percentage of micronucleus in both polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) and also shown significant reduction in P/N ratio.ConclusionsThese results suggested that ALTA possess significant antioxidant and antimutagenic activity.     

Effect of green tea consumption on endothelial function and circulating endothelial progenitor cells in chronic smokers.

BACKGROUND: The present study was designed to investigate the effect and relationship of endothelial function and endothelial progenitor cells (EPCs) by green tea consumption in chronic smokers. The numbers of circulating EPCs have an inverse correlation with chronic smoking and endothelial dysfunction. Green tea catechin improved endothelial dysfunction in chronic smokers. METHOD AND RESULTS: In 20 young healthy smokers, endothelial functions, defined by flow-mediated endothelium dependent vasodilation (FMD) of the brachial artery via ultrasound as well as the number of EPCs isolated from peripheral blood, were determined at baseline and at 2 weeks after green tea consumption (8 g/day). Circulating EPCs were quantified by flow cytometry as CD45lowCD34+KDR2+ cells and by acyl-low-density lipoprotein and fluorescein isotiocyanate-lectin double positive cells after culture for 7 days. Clinical characteristics and laboratory findings were not significantly different between the baseline and at 2 weeks after green tea intake. EPC levels were inversely correlated with the number of cigarettes smoked. Circulating EPCs by flow cytometry (78.6+/-72.6 vs 156.1+/-135.8 /ml, p<0.001) and cultured EPCs (118.2+/-35.7 vs 169.31+/-58.3/10 field, p<0.001) increased rapidly at 2 weeks after green tea consumption. FMD was significantly improved after 2 weeks (7.2+/-2.8 vs 9.3+/-2.4, p<0.001). The FMD correlated with EPC counts (r=0.67, p=0.003) before treatment and after 2 weeks (r=0.60, p=0.013). CONCLUSIONS: A short-term administration of green tea consumption induces a rapid improvement of EPC levels and FMD. Green tea consumption may be effective to prevent future cardiovascular events in chronic smokers.     

Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities

OBJECTIVE: Endothelial dysfunction is one of the earliest pathological effects of cigarette smoking. It has recently been suggested that endothelial progenitor cells (EPCs) could contribute to ongoing endothelial maintenance and repair. Accordingly, we tested the hypothesis that cigarette smoking is associated with EPC dysfunction. METHODS AND RESULTS: EPCs were isolated from the peripheral venous blood of 15 healthy smokers and 11 age-matched nonsmokers. The number of EPCs was significantly reduced in smokers versus control subjects (51.6+/-1.9 versus 120.3+/-10.0 per power field, p<0.001). Moreover, the functional activities of EPCs isolated from smokers were severely compromised. First, the proliferative and migratory response of EPCs isolated from smokers were reduced by 75% and 19%, respectively (p<0.05). Second, EPCs from smokers showed an important decreased adherence to HUVECs that had been previously activated with tumor necrosis factor-alpha (TNF-alpha) (p<0.01). Finally, the participation of EPCs to tube formation in a matrigel assay was reduced by 38% in smokers versus control subjects (p<0.001). We found that EPCs from smokers had a significant reduction in the expression of the endothelial cell-specific markers (VE-cadherin, KDR, and vWF). Moreover, ROS formation was significantly increased in EPCs from smokers, whereas the serum antioxidant and nitrite levels of smokers were reduced and correlated with impaired EPC number and functional activity. CONCLUSIONS: Cigarette smoking is associated with a reduced number of EPCs together with an important impairment of EPC differentiation and functional activities. Our results suggest that EPC dysfunction could contribute to impair blood vessel healing and growth in smokers.     

Noninvasive assessment of impaired endothelial function in psoriasis

The objectives of this study are noninvasive assessment of endothelial dysfunction (ED) and diagnosing the possible early vascular development of atherosclerosis in psoriasis disease (PD). Twenty-eight PD patients (study group) without any obstructive vascular involvement were compared with 28 healthy controls (control group) in terms of ED utilizing endothelium-dependent dilation as well as endothelium-independent dilation, which was assessed by measuring changes in brachial artery diameter following sublingual glyceryl trinitrate (400 μg Nitrolingual spray). All patients underwent a complete transthoracic echocardiographic and tissue Doppler study. A standard form was utilized for the documentation of the presence or absence of the known risk factors for atherosclerotic vascular disease. Statistical analysis was performed by utilizing SPSS version 11. There was no difference between patients and controls in terms of echocardiographic and tissue Doppler parameters as well as baseline brachial artery diameters. Flow-mediated dilation showed 37% impairment in study group compared with control (p < 0.05). Endothelium-independent NTG dilatation did not differ in both groups. Noninvasive methods such as ultrasonography, saving time and cost-effective, can be utilized for following outpatient PD patients for the risk of ED, which may preclude to atherosclerosis.     

空腹血糖受损并糖耐量受损患者血管内皮功能及代谢功能观察

目的：观察空腹血糖受损并糖耐量受损（ IFG＋IGT）患者血管内皮功能及代谢功能情况。方法选择IFG＋IGT者72例（ E组）,其中非肥胖30例（ E1组）,肥胖42例（ E2组）;另选择糖耐量正常的健康人群142例（ N组）,其中非肥胖75例（ N1组）、肥胖67例（ N2组）。做口服葡萄糖耐量试验及胰岛素释放试验检测血糖、免疫活性胰岛素,同时检测空腹血脂、游离脂肪酸、脂联素。采用免疫比浊法检测超敏C反应蛋白（ hs-CRP）,RIA法检测血清内皮素（ SET）。留取晨尿,采用未抽提法测定内皮素（ UET）,散射比浊法检测尿微量白蛋白（ MUA）。观察血压和腰围。彩超测定肱动脉休息时、加压及服用硝酸甘油后的内径变化,计算内皮依赖性血管舒张功能（ EDD）及内皮非依赖性血管舒张功能（ EID）指标（ΔD％、ΔD1％）。结果校正性别、年龄后,E和N组比较、E2与N2组比较及E1与N1组比较,MUA、hs-CRP、UET、SET、ΔD％、ΔD1％差异有统计学意义（P均＜0．05）;N2与N1组比较hs-CRP、UET和SET差异有统计学意义（P均＜0．05）;E2与E1组比较MUA、hs-CRP、UET和SET差异有统计学意义（P均＜0．05）。结论 IFG＋IGT患者大血管和微血管内皮功能均出现异常,尤以肥胖者为著;患者的代谢功能亦出现异常,主要表现为高血压、高血糖、脂代谢紊乱、胰岛素抵抗及胰岛分泌功能下降。     

Plasma antioxidants are associated with impaired lung function and COPD exacerbations in smokers

Low molecule weight antioxidants such as uric acid (UA), glutathione (GSH), and ascorbate (ASC) counter the effects of oxidants produced by cigarette smoke. Although dietary intake of foods rich in antioxidants has been associated with a reduced risk of smokers developing chronic obstructive pulmonary disease (COPD), the association between plasma antioxidants and COPD is less clear. In this cross-sectional study we investigated the relationship among plasma antioxidants and COPD phenotypes (severity of airflow obstruction on spirometry and history of exacerbations) in 136 smokers with normal lung function and 367 smokers with COPD. In the multivariate analysis, a lower plasma UA was associated with more severe COPD (P < 0.002) and a lower GSH was associated with a history of COPD exacerbations (P = 0.03); ASC was not associated with any COPD phenotypes. This suggests that antioxidant balance is impaired in smokers with obstruction on spirometry or a history of COPD exacerbations.     

Effects of Terminalia arjuna bark extract on apoptosis of human hepatoma cell line HepG2

AIM:To investigate the effects of Terminalia arjuna(T.arjuna)extract on human hepatoma cell line(HepG2)and its possible role in induction of apoptosis.METHODS:Human hepatoma cells were treated withdifferent concentrations of ethanolic extract of T.arjunaand its cytotoxicity effect was measured by trypan blueexclusion method and lactate dehydrogenase leakageassay.Apoptosis was analyzed by light and fluorescencemicroscopic methods,and DNA fragmentation.Themechanism of apoptosis was studied with expressionof p53 and caspase-3 proteins.Glutathione(GSH)content was also measured in HepG2 cells after T.arjunatreatment.RESULTS:T.arjuna inhibited the proliferation of HepG2cells in a concentration-dependent manner.Apoptoticmorphology was observed in HepG2 cells treated with T.arjuna at the concentrations of 60 and 100 mg/L.DNAfragmentation,accumulation of p53 and cleavage ofprocaspase-3 protein were observed in HepG2 cells afterthe treatment with T.arjuna.The depletion of GSH wasobserved in HepG2 cells treated with T.arjuna.CONCLUSION:T.arjuna induced cytotoxicity in HepG2cells in vitro.Apoptosis of HepG2 cells may be due tothe DNA damage and expression of apoptotic proteins.Depletion of GSH may be involved in the induction ofapoptosis of HepG2 cells.     

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow‐mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT). Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age‐ and sex‐matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA‐IR). A randomised double‐blind placebo‐controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated. Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium‐independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo. Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.