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Outline of Fundamental and Clinical Study on Xuezhikang®
(Chinese Academy of Medical Sciences, Cardiovascular Disease Institute of Peking Union Medical Col ege, Fu Wai Hospital of Cardiovascular Disease, 100037 Beijing) Introduction
Xuezhikang®, a lipid-regulating agent extracted from Monascus purpureus (special made red yeast rice or Hongqu) with advanced biotechnology and manufactured by Beijing WBL Peking University Biotech Co. Ltd, contains rich amount of HMG-CoA reductase inhibitor Lovastatin and many unsaturated fatty acids as well as amino acid needed by human body. It has caught wide attention since it came into market. Much clinical practice by many researchers in the past three years have proved its good effects and little side-reaction. During 22nd ~ 24th in October, 1997, a Symposium on the Development of New Drugs for Clinical Treatment of Cardiocerebrovascular Disease was organized by Chinese Medical Association, with 36 papers on Xuezhikang®. They centered on current fundamental and clinical studies on curative effects of Xuezhikang®.
Basic Theoretical Studies
In 1995, a toxicity study of Xuezhikang® on mice and rats were carried out by Li Changling and his colleagues in the School of Pharmaceutical Science Beijing Medical University. The study included: (1) Acute toxicity test: single clysis by Xuezhikang® was done on mice, but too much to test LD50. The maximum tolerance level > 16 g/kg, which is 533 times of the recommended clinical dosage. (2) Long term toxicity test: clysis by Xuezhikang® with the rate of 1g/kg or 2g/kg was done every day for 4 months. No death and toxicosis occur. The trend of weight increase was similar to that of control group. And there were no significant differences on blood biochemical index, routine urine examination, major organ index and pathological check results compared with that Effects on Blood Lipid and the Formation of Atherosclerosis In 1995, a study on lipid reduction for hyperlipoidemia rabbit and quail models treated by Xuezhikang® was carried out by Zhu Yan and his colleagues in the School of Pharmaceutical Science, Beijing Medical University. This study demonstrated that, after 30 days of administration of 0.4 g/kg/day or 0.8 g/kg/day Xuezhikang® on the endogenesis hyperlipoidemia rabbit and quail resulting from being fed with 25% casein for 2 months, dramatic reduction of TC occurred (P < 0.05). The same was true for exogenous hyperlipoidemia rabbit and quail resulting from being fed with high cholesterol food if Xuezhikang® was employed for 40 days or 2 weeks respectively. TC and TG levels decreased significantly (P <0.05 or 0.01 respectively). The decrease of TC was 33.2% and TG 43.2%. But no clear performance of elevating HDL-C level was observed. Meanwhile, morphological observation of the aorta and arcus aortae of the animal and histological analysis of sections showed an alleviation of atherosclerosis plaque, which implied the function of Xuezhikang® on suppressing the formation of atherosclerosis plaque. Zheng Xiaowei from the First Clinical Hospital of China Medical University conducted a study on the impact of Xuezhikang® on serum lipid metabolism and the formation of atherosclerosis of high cholesterol fed rabbit. This study also illustrated that the administration of Xuezhikang® 0.8 g/kg for 12 weeks could significantly decrease serum TC and moderately reduce TG level (P < 0.05) of high cholesterol diet rabbit. In comparison, the ratio of aortae atherosclerosis plaque area against aorta area reduced significantly (P < 0.05), and the foam cell layer under endarterium in treated group also decreased leading to distinct alleviation of coronary atherosclerosis morphological change. This indicated that Xuezhikang® had strong capacity in regulating blood metabolism and suppress the formation of atherosclerosis of Protection on the Functions of Vascular Endothelial Cell Zheng Xiaowei carried out a transmission electron microscopic study on vascular endothelial cell of rabbit aorta treated by Xuezhikang® for 12 weeks. The findings indicated that supermacro-structural damage of vascular endothelial cell significantly alleviated compared with that of control group. And plasma endothelin level went down with NO concentration elevated. This research proved that Xuezhikang® has the capacity to protect the function of vascular endothelial cell of rabbit fed with high cholesterol diet. This function may be one of the key mechanisms of Xuezhikang® to inhibit the formation Suppression on the Proliferation and Migration of Vessel Smooth Muscle Cell (VSMC) Yu Po from the First Clinical Hospital of Chinese Medical University observed the supermicro-structural change of VSMC through transmission electron microscope study. Methods like in vitro cultivation of aortic VSMC counting were adopted to investigate the influence of Xuezhikang® on the proliferation and migration of VSMC. The findings showed that Xuezhikang® obviously suppressed the proliferation and migration of VSMC. And it is a well known fact that proliferation and migration of VSMC is one of the key causes of atherosclerosis development and restenosis after angioplasty and vascular At the time when Zhu Yan studied the impacts on lipid metabolism for hypercholestrolenia animal models treated by Xuezhikang®, he also discovered that 0.4 g/kg or 0.8 g/kg administration of Xuezhikang® could significantly reduce liver quotient (weight of liver/ body weight) of exogenesis hyperlipoidemia rabbit ( P < 0.01) and alleviate morphological change of liver histology. It was thought that Xuezhikang® is able to inhibit lipid deposition in liver. Tong Fugong et al from the First Clinical Hospital of Chinese Medical University investigated the influence of Xuezhikang® on blood lipid and the formation of fatty liver. The findings showed that the morphological change of the treated rabbit group clearly alleviated under optical microscope observation and fatty cell change rate reduced significantly (P < 0.05). Thus, it was regarded that Xuezhikang® could inhibit the formation of fatty liver of target rabbit resulting from being fed with
Clinical Study
About 2360 patients had taken Xuezhikang® from 1995 to 1997 (excluding cases in control group). Medical experts spoke highly of the effects and security of Xuezhikang® through widespread success in clinical applications. Effects of Xuezhikang® with Different Dosage Lu Zongliang et al of Beijing Fu Wai Cardiovascular Disease Hospital reported 126 cases hyperlipoidemia treated by Xuezhikang®, with 58 cases taking 1.2 g/day and 68 cases 0.6 g/day. The results were: 8 weeks after the treatment, serum TC, LDL-C and TG went down significantly and HDL-C level grew up by a big range (P < 0.001) compared with that before treatment. The concentration change of the half-dosage group is not as high as that of full-dosage group (TC reduced by 25.7% and 11.7%; LDL-C 33.1% and 11.7%; TG 31.9% and 16.9%; HDL-C elevated by 17.0% and 6.7% respectively.) Shi Xiangyun et al from General Hospital of Navy Forces reported 81 cases hyperlipoidemia patients randomly grouped, 39 cases treated with 1.2 g/day Xuezhikang® and 42 cases with 0.9 g/day dosage for 8 weeks with distinct differences of blood lipid level occurred compared with that before the treatment (P < 0.01 ~ 0.001 respectively). It was concluded that good blood lipid regulating effect could be expected when patients take 0.9 g Xuezhikang® every evening. Local Hospital in Anyang of Henan Province also reported 52 cases of hyperlipoidemia patients randomly divided into two groups, one treated with 1.2 g/day and the other with 1.8 g/day Xuezhikang® for 8 weeks. The total efficacy of the two groups reached 76.9% and 96.2% respectively, which indicated that the administration of 1.8 g/day Xuezhikang® could enhance the total efficacy. Six Months Effects and Safety Observations of Xuezhikang® Kou Wenrong et al of Beijing Fu Wai Cardiovascular Disease Hospital reported 52 cases hyperlipoidemia patients treated by Xuezhikang® 1.2 g/day for six months. The result showed no significant differences of the changes of blood lipid level 8 weeks, 16 weeks and 24 weeks after the treatment. However, all levels were significantly different from that before the treatment (P < 0.01 ~ 0.001 respectively). After six months administration of Xuezhikang®, serum TC decreased to 5.66 mmol/L and LDL-C 3.5 mmol/L, which were in conformity with the target level of pharmaceutical treatment for hyperlipoidemia stipulated by Recommendations on the Prevention and Control of Abnormal Lipid Level in China. Relevant biochemical tests showed little abnormalities. It is implied long term, stable and safe effect of Xuezhikang® with no toxic reactions. Xu Chengbin et al from People's Hospital of Beijing Medical University observed 150 cases of hyperlipoidemia patients taking 0.6 g/day Xuezhikang® in a 6-month multi-centered clinical observation. The result showed serum TC reduction by 16%, LDL-C decrease by 24% and TG 14%, HDL-C elevation by 4%. The concentrations of TC and LDL-C six months later showed a significant difference compared with that before the treatment (every P < 0.001). Thus, it is thought that small dosage of Xuezhikang® is little in side- reaction, easy and safe in administration, low in cost and appropriate for long term treatment for patients with slight and medium high blood lipid levels. Comparison with Foreign Lipid-Regulating Agents Through many times of self control, or randomized double-blind experiments with placebo or foreign lipid-lowering medicines evidently illustrated the strong ability of Xuezhikang® in regulating blood lipid. In order to further evaluate the lipid regulation capacity or intensity of Xuezhikang® and follow international practice in terms of pharmaceutical evaluation procedures and acquire international recognition, some medical organizations in China have conducted a range of comparison studies between Xuezhikang® and foreign lipid-lowering agents. Kou Wenrong et al of Beijing Fu Wai Cardiovascular Disease Hospital reported 108 cases hyperlipoidemia patients grouped according to the concentration of blood lipid with 53 cases taking Xuezhikang® and 55 taking Simvastatin for 8 weeks. The findings showed that 1.2 g/day dosage of Xuezhikang® had the same efficacy of 10 mg/d of Simvastatin. Another report of 47 cases by Zhangge from the Second Affiliated Hospital of Kunming Medical College indicated a better LDL-C reduction result of 47 cases taking 1.2 g/day of Xuezhikang® for 4 weeks compared with that of 33 cases administrating 10 mg/d Simvastatin (reduction by 33.7% and 22.3% respectively). Lu Guoping of Affiliated Ruijin Hospital of the Second Shanghai Medical University carried out a study with 15 patients taking Xuezhikang® and 13 taking Simvastatin for 8 weeks. The result showed that 1.2 g/day of Xuezhikang® functioned similarly to Simvastatin in terms of decreasing the concentrations of serum TC, ApoB and lipoprotein a (Lpa) and elevation of ApoA1. In addition, Xuezhikang® is superior to Simvastatin in reducing serum TG. Furthermore, Zhang Linhu of Shanxi People's Hospital and Ping Qinggong from Yifanshan Hospital of Wannan Medical College reported 38 cases and 31 cases treated with 1.2 g/day Xuezhikang® and 43 cases and 28 cases respectively treated with 5 mg/d Simvastatin for 4 to 8 weeks, they found no significant differences in terms of general curative effects between the two groups. However, they did find that Xuezhikang® group behaved better to reduce serum TG than • Comparison with Pravastatin (Pravacho,Mevalotin) Jin Wei of the First Shanghai People's Hospital reported 44 hyperlipoidemia patients randomly divided into two groups with 22 cases taking Xuezhikang® and 22 taking Mevalotin for 12 weeks. The result showed that 1.2 g/day Xuezhikang® performs significantly better than Mevalotin in terms of the decrease of serum TC, LDL-C, TG, ApoB and increase of ApoA1 level. Lu Xiang of the First Affiliated Hospital of Nanjing Medical College conducted a comparison study with 19 cases treated with 1.2 g/day Xuezhikang® and 15 cases with 10 mg/d Pravacho. It was found that the two medicines had achieved similar results in serum TC reduction. But patients treated with Xuezhikang® clearly showed the improvement of their • Comparison with Lovastatin (Mevacor) Fu Honghui of the First People's Hospital from Mudanjiang City reported 152 cases of hyperlipoidemia. Based on blood lipid level, 74 patients were treated with Xuezhikang® as one group and 78 cases treated with Lovastatin as another one. The treatment lasted for 8 weeks. Research findings indicated that Xuezhikang® could reduce the concentrations of serum TC, LDL-C and TG in Wang Yanfang of Henan People's Hospital reported 86 cases of hyperlipoidemia patients with 43 cases treated by 1.2 g/day Xuezhikang® and 43 cases by 1.2 g/day Gemfibeozil for 4 weeks. The result showed that both medicines significantly declined TC, LDL-C and ApoB in the treatment. In comparison, Xuezhikang® acts better in reducing serum TC and LDL-C, whereas Gemfibeozil functions better in TG reduction and HDL-C elevation. The total efficacy of Xuezhikang® on TC reduction reached as high as 94.9%, higher than that of Gemfibeozil 71.9% (P < 0.01). Whereas the total efficacy of Gemfibeozil on TG decline reached as high as 96.5%, higher than that of Xuezhikang® 74.2% (P < • Comparison with Fenofibrate (or Lipanthyl) Zhao Qi of Tieling City Central Hospital reported 76 cases of hyperlipoidemia with 41 treated with 1.2 g/day Xuezhikang® and 35 with 0.3 g/day Lipanthyl for 8 weeks. He found that Xuezhikang® was superior to Lipanthyl in serum LDL-C reduction (P < 0.01) but inferior in TG reduction (P < 0.001). Effects on Metabolism of Sugar and Lipid of Diabetic Patients Chi jiamin of Beijing Hospital reported 100 cases type II diabetic patients with 60 cases (30 with hyperlipoidemia and the other 30 without) taking 1.2 g/day Xuezhikang® when they administrated sugar regulating agent, and the other 40 cases only taking sugar regulating agent as control group for two months. As a result, the FPG and 2h-PG level of Xuezhikang® group had declined significantly compared with that before treatment (P < 0.001), but not in control group. And the total efficacy of reducing FPG and 2h-PG by Xuezhikang® in the treatment group were obviously higher than control group ( P < 0.005 ~ 0.01). Various lipid levels of 30 patients with hyperlipoidemia gained remarkable improvement (P < 0.01 ~ 0.001 respectively). Thus, it is thought that Xuezhikang® can reduce both blood sugar and lipid level for diabetic patients associated Effects on Patients with Cerebral Infarction Gao Mingyu of Northeast Electric Industry Central Hospital also reported 30 cases of cerebral infarction patients taking 1.2 g/day Xuezhikang® for 4 weeks with total efficacy on serum TC and TG reduction of 86% and 82% respectively. Curative effects on cerebral infarction had been observed, too. It was found that striking effect occurred on 67% of the 12 slight cerebral infarction patients, 50% for 10 moderate cerebral infarction patients and 38% for the 8 severe cerebral infarction patients. This finding showed that Xuezhikang® could not only regulate lipid level, but also facilitate function rehabilitation of cerebral infarction patients and thus reduce the incidence of disabled Effects on Dialysis Patients with Renal Failure Coupled with Hyperlipoidemia Fu Honghui reported his multi-center study on the effects of Xuezhikang® on chronic renal failure patients treated with hemodialysis and peritoneal dialysis. Among the target patients, 130 hemodialysis cases were divided randomly into 80 cases taking 1.2 g/day Xuezhikang® for 8 weeks and 50 cases as control group. And 53 peritoneal dialysis patients were divided into 32 cases as treatment group fed with 1.2 g/day Xuezhikang® for 8 weeks and 21 cases as control group. It was found that after the treatment, the concentrations of serum TC, TG, LDL-C and ApoB in treatment group were dramatically lower than that of control group regardless of the type of dialysis. Whereas the HDL-C and ApoA1 levels were significantly higher than that of control group. Total efficacy of TC reduction reached by 78% and 83% respectively and of TG reduction by 90% and 91% respectively. No side-effects were observed. Usually, chronic renal failure patients elevate their blood lipid level after hemodialysis and peritoneal dialysis, this study indicated that Xuezhikang® could be safely used to treat such patients. Effects on Kidney Transplant Patients with Hyperlipoidemia Fu Honghui reported 19-case study on the effects of Xuezhikang® for kidney transplant patients with consequent hyperlipoidemia. The patients were treated with 1.2 g/day Xuezhikang® for 8 weeks and it was found that serum TC, LDL-C, TG reduced by 20.8%, 39.4% and 47.7% respectively. Only 1 case was ineffective, the total efficacy reached 94.7%. The effect was significantly and there were no side-reactions. As high serum TC and TG levels are quite common for kidney transplant patients, this study illustrated the safety, availability and effectiveness of Xuezhikang® in treating kidney transplant patients associated with hyperlipoidemia. Primary Clinical Evaluation of Xuezhikang® in America Doctor Heber of Los Angeles School of California University employed primary (non- concentrated) Xuezhikang® product (commercial name is Cholestin) to treat 83 hyperlipoidemia cases (serum TC ³ 4.16 mmol/L, TG £ 2.94 mmol/L) in a randomized double-blind placebo-controlled experiment. The patients took 2.4 g/d Cholestin (equivalent to 0.96 g/d of Xuezhikang®) for 12 weeks. And primary results showed dramatic reduction of the concentrations of serum TC, LDL-C and TG without any side- In conclusion, fundamental study on Xuezhikang® has already shifted from lipid reduction and toxic experiments on high cholesterol diet animal model to cell and molecular biology study aiming at exploring the effects of Xuezhikang® on the formation mechanism of atherosclerosis of experimental animals. It is expected that new breakthrough will occur in fundamental studies on Xuezhikang® in terms of pharmaceutical chemistry, pharmacodynamics and pharmacology. Clinical observations also evolve from single short-term effect and safety comparison study into long-term (more than 6 months) effect and safety study with different dosage. Now, it is used to treat hyperlipoidemia patients caused by diabetes, cerebral infarction, chronic renal failure dialysis or kidney transplant with some good results. However, large scale and multi-centered individual research strictly designed is needed to expand clinical applications of Xuezhikang®. And the long-term effect and safety of the medicine are being further verified by on-going large scale, long-term clinical observations for secondary prevention of coronary disease. 2008 Asiapharm Biotech Pte Ltd. All rights reserved. Information on this web site is provided for informational purposes only and is not a substitute for professional medical advice. You should not use the information on this web site for diagnosing or treating a medical or health condition. You should carefully read all product packaging. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider. Statements and information regarding dietary supplements have not been evaluated or approved by the U.S. Food and Drug Administration. 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