Salviae miltiorrhizae radix and puerariae lobatae radix herbal formula improves circulation, vascularization and gait function in a peripheral arterial disease rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: DG is a herbal formula, containing the root of Salvia miltiorrhiza Bunge (Danshen) and the root of Pueraria lobate (Willd.) Ohwi (Gegen), has a history of usage in China for cardiovascular protection and anti-atherosclerosis. AIM OF THE STUDY: The present study aims to determine the beneficial effect of DG on the hind-limb ischemia rat model which mimics peripheral arterial disease (PAD) and its vasodilative effect on isolated femoral artery. MATERIALS AND METHODS: The vasodilatory effects were assessed by contractile responses to DG in the isolated femoral artery and its underlying mechanisms were evaluated by the involvement of endothelium, potassium channel and calcium channel. For hind-limb ischemia study, treatment outcomes were assessed by evaluating hind-limb blood flow, functional limb recovery, muscle histology and angiogenesis. RESULTS: Our results demonstrated positive dose-dependent vasodilatory response to DG via an endothelium-independent mechanism that involved inwardly rectifying K+ channels and Ca2+ channels. We also demonstrated significant improvement in blood perfusion and micro-vessel density in the ischemic limb and positive effects in functional limb recovery. CONCLUSION: In conclusion, our study supported the potential use of DG as a novel treatment for symptomatic PAD.

Herb-drug interaction of gastrodiae rhizoma on carbamazepine: A pharmacokinetic study in rats.

OBJECTIVE: Gastrodiae Rhizoma (GR), is a traditional Chinese Medicine that has been used for neurological disorders, including epilepsy. Epilepsy patients may be treated with adjunctive therapy of GR with antiepileptic drugs (AEDs). In particular, carbamazepine (CBZ) is of high potential to interact with concurrent treatment of Chinese Medicine. This study was to investigate the herb-drug interactions of GR and CBZ, an AED, through pharmacokinetic approach in rats. METHODS: We adopted a high-performance liquid chromatography (HPLC) system to quantify the plasma level of CBZ and its metabolite (carbamazepine-10, 11-epoxide, CBZE). The method was validated as per instructions under United States Food and Drug Administration (USFDA) guidance. For the herb-drug interaction study, rats were randomly divided into four different treatment groups: single-dose CBZ treatment, single-dose CBZ/GR treatment, 2-week course of CBZ treatment and 2-week course of CBZ/GR treatment. RESULTS: Our results demonstrated the auto-induction of CBZ metabolization when comparing single-dose with 2-week course of CBZ treatment. Pharmacokinetic interactions were noted in concomitant use of GR with CBZ by comparing two single-dose treatments (CBZ versus CBZ/GR). Our data showed that GR increased the mean residence time (MRT0-t) and the time taken to reach the maximum concentration (Tmax) of CBZ in single-dose of CBZ/GR treatment. The maximum drug concentration (Cmax) of CBZ was reduced in single-dose CBZ/GR treatment. When comparing the 2-week course of CBZ treatment with the 2-week course of CBZ/GR treatment, the MRT0-t and half-life of CBZ were increased. The AUC0-t, the Cmax and the half-life of CBZE were increased. CONCLUSION: CBZ/GR treatment may reduce the auto-induction of CBZ over 2 weeks. While the reduction of auto-induction could enhance the therapeutic effects of CBZ, it could also lead to an increase in neurological side effects and non-neurological adverse effects. Our results provided preclinical evidence of herb-drug interaction, which may have implications for epilepsy patients treated with GR.

A randomized placebo controlled trial of an innovative herbal formula in the prevention of atherosclerosis in postmenopausal women with borderline hypercholesterolemia.

BACKGROUND: Danshen (Salvia miltiorrhiza) and Gegen (Radix puerariae) (D&G) are two herbs frequently used for the treatment of angina and other cardiac symptoms in Chinese materia medica. Recent studies have demonstrated their cardio-protective and anti-atherosclerosis effects. Earlier we have conducted two clinical trials in 2004 and 2007 which demonstrated such effects in extremely high risk patients. STUDY OBJECTIVE: The aim of the study was to demonstrate the safety and effectiveness of D&G in the prevention of atherosclerosis in postmenopausal women with early hypercholesterolemia. DESIGN: The study was designed as a randomized, double-blinded, placebo-controlled trial with a 12-month treatment period. SUBJECT: A population based sample of 165 postmenopausal women aged 47-65 were included in the trial. Only women who experienced menopause for more than 12 months were recruited. INTERVENTIONS: The eligible subjects were randomized to take the D&G preparation (two capsules), or image-identical placebo capsules (two capsules) daily, in a double-blind and parallel fashion for 12 month. MEASUREMENTS: The postmenopausal women with mild hypercholesterolemia (mean age 56.5 ± 4.1 of treatment group and 56.0 ± 3.8 years of placebo group) were randomized to the D&G group or placebo group for trial treatment. Carotid intima-media thickness (IMT) was used as the surrogate marker and was measured using high resolution ultrasound. Lipid profile was also tested. RESULTS: Baseline characteristics were comparable between the two groups. After 12 months, there were no significant changes in the blood pressures and general biochemical profiles in both groups, however, there was a remarkable decrease in serum low density lipoprotein (LDL) cholesterol (-6.92%) and total cholesterol (TC) (-5.85%) in the D&G group compared with the placebo group (-3.21% and -3.42%) when compared with the baseline. The carotid intima-media thickness (IMT) decreased 1.52% from baseline in the D&G group (p < 0.004) but the decrease was only 1.13% in the placebo treatment group (p = 0.009) after 12 months treatment. Twelve adverse events were reported (six in placebo group and six in D&G group) but none of them was directly relevant to the study herbal preparation. CONCLUSIONS: Postmenopausal women with early hypercholesterolemia tolerated D&G well. D&G improved the carotid intima thickness, lowered LDL and total cholesterol. D&G therefore can be recommended for the prevention of atherosclerosis in postmenopausal women with hypercholesterolemia.

Ten years' research on a cardiovascular tonic: a comprehensive approach-from quality control and mechanisms of action to clinical trial.

Objective. Mortality arising from cardiovascular pathologies remains one of the highest. Maintenance of cardiovascular health therefore remains a universal concern. Interventional therapies and medications have made impressive advances, but preventive measures would be of the same importance. Method. Ten years' search for a simple herbal formula has resulted in a two-herb combination, consisting of Salviae Miltiorrhizae Radix et Rhizoma and Puerariae Lobatae Radix. The formula has been studied extensively on cardiovascular biological platforms and then put on three clinical trials. Results. In the laboratory, the formula was found to have the biological effects of anti-inflammation, anti-oxidation, anti-foam cell formation on vascular endothelium, and vasodilation. Clinical trials using ultrasonic carotid intima thickness as a surrogate marker showed very significant benefits. No significant adverse effects were encountered. Conclusion. It is therefore recommended that the herbal formula could be used as an adjuvant therapy in cardiac patients under treatment or as a preventive agent among the susceptible.

Gene expression profiling on the molecular action of danshen-gegen formula in a randomized placebo-controlled trial of postmenopausal women with hypercholesterolemia.

The Danshen-Gegen formula (DG) is a traditional Chinese herbal formula which has long been used to treat cardiovascular disease. DG was found to be a cardiovascular tonic in our recent research. However, a comprehensive investigation of the molecular mechanism of DG in cardiovascular disease has not been performed. The aim of this study was to clarify the transcriptional profiling of genes modulated by DG on postmenopausal women by using DNAmicroarray technology. We obtained 29 whole blood samples both from DG-treated and placebo-treated subjects. Blood lipid profile and intima-media thickness (IMT) were measured. Affymetrix GeneChip was used to identify differentially expressed genes (DEGs), followed by validation by the real-time PCR method. The results showed that DG-treated group has a significant improvement in IMT and lipid profile as compared to placebo-treated group. For the genomic study, the DG-treated group has a higher number of DEGs identified as compared to the placebo-treated group. Two important biological processes of "regulation of systemic arterial blood pressure by hormone" and "regulation of smooth muscle proliferation" have been identified by GePS in the DG-treated group. No significant biological process and cellular components were identified in the placebo-treated group. This genomic study on the molecular action of DG in postmenopausal women gathered sufficient molecular targets and pathways to reveal that DG could improve neointima thickening and hypertension.

Cardiovascular Protective Effects of Adjunctive Alternative Medicine (Salvia miltiorrhiza and Pueraria lobata) in High-Risk Hypertension.

Introduction. Hypertension in association with diabetes (DM), renal impairment (RI), and left ventricular hypertrophy (LVH) increases the risk of future cardiovascular events. We hypothesize, traditional herbal medicines Danshen and Gegen (D&G) have beneficial effects on atherogenesis in these high-risk hypertensive subjects. Subjects and Methods. 90 asymptomatic hypertensive subjects associated with LVH (63.3%), DM (62.2%), or RI (30%) were randomized to receive D&G herbal capsules 1 gm/day, 2 gm/day, or identical placebo capsules in double-blind and parallel fashion for 12 months. Brachial flow-mediated dilation (endothelium-dependent dilation, FMD) and carotid intima-media thickness (IMT) were measured by ultrasound. All data were analyzed using the Statistical Package for Social Sciences in Windows 16.0. Results. Their mean age was 55 ± 8 years, and 74.4% were male. After 12 months of adjunctive therapies and compared with baseline, there were no significant changes in blood pressure, heart rate, hematological, glucose, and creatinine profiles in both placebo and D&G groups. FMD improved significantly during D&G (P = 0.0001) and less so after placebo treatment (P = 0.001). There was a mild but significant decrease in carotid IMT after D&G (P < 0.001) but no significant changes after placebo. A trend of better improvement in FMD after higher versus lower D&G dosages was seen. D&G were well tolerated, with no significant adverse events or blood biochemistry changes. Conclusion. D&G adjunctive treatment was well tolerated and significantly improved atherogenesis in high-risk hypertensive patients, with potential in primary atherosclerosis prevention.

The efficacy and tolerability of adjunctive alternative herbal medicine (Salvia miltiorrhiza and Pueraria lobata) on vascular function and structure in coronary patients.

BACKGROUND: Danshen and gegen (D&G) have long been used in treatment of angina and other cardiac symptoms in Chinese materia medica. Recent pharmacological studies suggest their therapeutic values. We aimed to evaluate the efficacy and safety of Salvia miltiorrhiza (danshen) and Pueraria lobata (gegen) in secondary prevention. METHODS: One hundred (100) consecutive coronary patients (mean age 58 +/- 8 years) were randomized to adjunctive treatment with D&G combination (3 g) or placebo (6 capsules) for 24 weeks in double-blind parallel fashion, followed by optional open-label D&G (1.5 g/day) for 6 more months. Brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) were measured using ultrasound. RESULTS: Baseline characteristics were similar between the 2 groups. After 24 weeks and compared with baseline, there were no significant changes in blood pressures, blood hematological and biochemical profiles, or folate and homocysteine levels in both groups, but there was a mild decrease in low density lipoprotein (LDL) cholesterol in both groups (p < 0.05). Brachial FMD improved during D&G (p < 0.001) and less so during placebo treatment (p < 0.05), while improvement in carotid IMT was observed only in the D&G group (p < 0.05). After open-label D&G treatment for 6 more months (n = 45), further improvement in both brachial FMD (p < 0.0001) and carotid IMT (p < 0.0001) was observed. Eight (8) adverse events were reported-6 during placebo and 2 during D&G treatment-requiring treatment termination in 2 patients (on placebo). CONCLUSIONS: D&G adjunctive treatment in coronary patients was well tolerated and effective in improving vascular function and structure. These two herbs may become a novel agent for secondary prevention.

Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation.

PURPOSE: Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with endothelial dysfunction that can be improved with short-term folic acid supplementation. The current study aimed to assess whether folic acid supplementation could produce longer-term improvements in homocysteine levels and arterial endothelial function. SUBJECTS AND METHODS: Twenty-nine healthy adults with hyperhomocysteinemia were selected from 89 volunteers enrolled in a community-based atherosclerosis screening project. All subjects were given folic acid (10 mg/d) for 1 year. Fasting plasma homocysteine levels were measured by high-performance liquid chromatography. Arterial endothelial function was measured as flow-mediated dilation of the brachial artery using high-resolution B-mode ultrasound. RESULTS: Folic acid supplementation for 1 year was associated with a significant increase in mean (+/-SD) plasma folate levels (24 +/- 5 nmol/L to 40 +/- 5 nmol/L; P < 0.001) and a significant decline in homocysteine levels (9.0 +/- 1.7 micromol/L to 7.9 +/- 2.0 micromol/L; P < 0.001). Flow-mediated dilation also improved significantly, from 7.4% +/- 2.0% to 8.9% +/- 1.5% (P <0.0001), but there was no change in nitroglycerin-induced (endothelium-independent) responses. CONCLUSIONS: These results demonstrate that long-term folic acid improves arterial endothelial function and has potential implications for the prevention of atherosclerosis in adults with hyperhomocysteinemia.

Homocysteine, endothelial dysfunction, and coronary artery disease: emerging strategy for secondary prevention.

Atherosclerosis is an important medical problem of the 21st century, but traditional risk factors could only account for 50% of the problem. Hyperhomocysteinemia is emerging as an independent atherosclerosis risk factor, associated with folate deficiency, renal failure, and relative deficiency of MTHFR (C677T polymorphism) or other enzymes depending on gender, age, and smoking status. Hyperhomocysteinemia has been reported to occur in 11-22% of western people, in 3-5% of normal asymptomatic Chinese subjects aged 18-70 years in Hong Kong, Macau, Sydney, and San Francisco, 23-36% of Chinese in Hong Kong with premature coronary artery disease, and 29% of a nonselective series of coronary subjects in Hong Kong. Evidence is accumulating that documents its associations with atherosclerosis disease in both case-control observations and prospective cohort studies, in vitro experiments, and in vivo experimental models in both animals and human subjects, as well as the successful improvement by homocysteine-lowering of endothelial function as surrogate atherosclerosis endpoints in asymptomatic human and coronary patients (secondary prevention). A number of large scale homocysteine-lowering trials are currently underway for stroke and heart attacks prevention. Collectively these trials will include more than 65,000 patients at high-risk for cardiovascular and stroke events, and should provide a reliable evidence-base for prevention.