Clinical Trial on Coronary Heart Disease

A Phase I/II study of a Ganoderma lucidum extract in patients with coronary heart disease

Shufeng Zhou1, Yihuai Gao2, Guoliang Chen3, Xihu Dai4, and Jingxian Ye5

1Division of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Science, the University of Auckland; 2Landcare Research Auckland, Private Bag 92170, Auckland, New Zealand; 3Shanghai Academy of Agricultural Sciences, Shanghai, China; 4Fuzhou General Hospital of Nanjing Military Region of the Peoples’ Liberation Army, Fuzhou, Fujian; 5Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China.

Correspondence author: Dr Shufeng Zhou, MD, PhD

Division of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Science, AucklandUniversity, Auckland, New Zealand.

Ph: 0064 9 3737599 (Ex 6414); Fax: 0064 9 3737556; Email: shufeng.zhou@auckland.ac.nz

Running title: Phase I/II study of Ganopoly in patients with coronary heart disease

Abstract

The polysaccharides and triterpenes isolated from Ganoderma lucidum have shown hypolipidemic, hypotensive and anti-thrombotic effects. This double-blind, randomized and multi-centered study was designed to evaluate the clinical effect and safety of a G. lucidum extraction (Ganopoly) in patients with chronic heart disease (CHD). Patients were randomly assigned to receive Ganopoly (n = 88) or placebo (n = 82) for 12 weeks. Effect of therapy on improvement of major symptoms, electrocardiogram (ECG) changes and serum cholesterol level was investigated. Ten patients were lost to the trial, leaving 80 in each group to be assessed after 12 weeks. The results indicate patients in both groups were similar with respect to age, sex, serum cholesterol level, and disease duration. Ganopoly treatment significantly improved the primary symptoms (chest pain, palpitation, angina pectoris and shortness of breath) of CHD in 75-83% of the patients compared to the control group (0-5%). The percentage of abnormal ECG also significantly decreased from 74 to 45% in the treatment group, compared to a decrease of 76% to 74% in the control group. Serum cholesterol levels decreased significantly after 12 weeks of Ganopoly therapy to the baseline values, whereas cholesterol levels remained unchanged in the control group. Ganopoly is well tolerated and appeared to be active in patients with CHD.

Key words: Ganoderma lucidum, Ganopoly, Coronary heart disease, ECG.

Introduction

Coronary heart disease (CHD) is the leading cause of death in the world. The major risk factors associated with this disease include cigarette smoking, diabetes, obesity, hypertension, hyperlipids, smoking, and low HDL cholesterol levels (Poulter, 1999). Observational data have clearly established that CHD risk factors tend to cluster in individuals, the impact of coexisting risk factors is greater than additive, and indeed is usually multiplicative. CHD is clearly a multifactorial disease with risk factors that tend to cluster and interact in an individual to determine the level of coronary risk. The current trend towards a more holistic approach in CHD risk evaluation and preventive management appears logical based on evidence from animal-experimental, observational, and clinical trial evidence (Poulter, 1999; Chien et al., 2000).

The treatment of CHD involves a comprehensive approach using diet, exercise, removal or control of risk factors, and drug administration. Many types of drugs have been used to treat CHD: nitroglycerin, calcium channel blockers, angiotensin converting enzyme inhibitors, etc. However, some side effects have been associated with the use of these drugs. For example, calcium channel blocker may reduce the cardiac contraction force, thus it is not appropriate for CHD with heart failure. Further improvements in the treatment of CHD are needed. A number of studies have shown that herbal medicine has potential for the treatment of CHD. Ganoderma lucidum has been used as a tonic and remedy for many generations (Shiao et al., 1994; Wasser and Weis, 1999). It has demonstrated efficacy in various chronic diseases, such as hepatopathy, diabetes, CHD and cancer (Gao, 2000). The polysaccharides and triterpenes isolated from G. lucidum are the major active components, which have shown hypotensive and hypolipidemic effects (Eo et al., 1999a,b; Eo et al., 2000), and may have a role in the treatment of CHD.

G. lucidum preparations are often used In Asia as an adjunct to or as the sole therapy for the treatment of CHD and for cardioprotection. Some open non-randomized clinical studies have been published in oriental languages. mainly in Chinese and Japanese, whereas no clinical trials of G. lucidum used to treat CHD have been reported in English (Gao, 2000). Ganopoly, an aqueous extract of G. lucidum, which mainly contains polysaccharides, has been marketed as an over-the-counter (OTC) product in New Zealand, Australia, Hongkong and Taiwan. This prospective, double-blind, controlled and randomized clinical study aimed to investigate the efficacy and safety of Ganopoly in patients with CHD.

Materials and Methods

Patients

Male and female patients aged 18 to 75 years with CHD were eligible for enrollment. The presence of CHD was confirmed by a comprehensive medical and physical examination, which included past history, blood biochemistry, and heart ultrasound scanning. Some patients had >50% blood vessel narrowing in one main coronary artery confirmed by catheter imaging examination.

Patients were excluded if they had any severe disease of another vital organ; clinically significant hematologic, hepatic, metabolic, renal, rheumatologic, neurological or psychiatric disease; anaphylactic reactions; clinically significant cardiac or cardiovascular abnormalities other than CHD; chronic obstructive pulmonary disease; abnormal carbon monoxide diffusion capacity; organ grafts; severe or disabling illnesses; systemic bacterial or fungal infection; clinically significant bleeding disorders; evidence of malignant neoplastic disease within 5 years; average daily intake of alcohol exceeding 50 g of ethanol; drug abuse within the previous year.

A total of 170 subjects were initially screened for eligibility from January 1996 through December 1998. Patients were screened for eligibility using the following assessments: medical and heart disease history; physical examination, biochemical and hematological profiles, clinical chemistry, urinalysis, and use of concomitant medications, heart blood vessel imaging and ultrasound scanning. The ethics committees at the participating centers approved the study, and all patients gave written informed consent before enrollment.

Drug treatment

Eligible patients were randomly assigned to receive either Ganopoly or placebo (600 mg/capsule of the same shape and colour) at a dose of 1 capsule, three times daily orally before meals for 12 weeks. The drug and placebo were provided by Encore International Co., Auckland, New Zealand. Patients were also instructed to follow the diet recommended by the Chinese Heart Disease Association.

Clinical assessment

Patients were monitored during the treatment. At its completion, they were assessed for vital symptoms and signs, weight, concomitant medication or illness, clinical chemistry, hematological profile, lipid profile, urinalysis, and adverse events. Symptoms were graded as ? (lack), + (minor, 1-2 symptoms, without impact on work and life), ++ (mild, 3-5 symptoms, some impact on life and work), and +++ (severe, >5 symptoms, stop work).

The endpoints for the efficacy assessment were symptom improvement (at least a grade decrease of symptoms), lipid lowering effect, and ECG improvement. The safety variables included a standard clinical laboratory screen, plasma lipids (triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol), body weight, blood pressure, adverse events, and hypoglycemic events. Clinical laboratory test results were categorized as normal, high, or low based on laboratory reference ranges. Adverse events were defined as events reported before treatment that were exacerbated during treatment or as events reported during treatment or within 7 days after the study drug was stopped. A serious adverse event was defined as any event, whether treatment related or not, that posed a medically significant hazard to the patient was fatal, life-threatening, or permanently disabling or required hospitalization.

Statistical analysis

Changes between baseline and the last treatment at 12 weeks were evaluated for all efficacy variables, with the last observation carried forward. Data compiled at baseline and 12 weeks were analysed by two-way analysis of variance by ranks. Median values of quantities, such as age and days since diagnosis, were compared using Wilcoxon’s rank-sum test. Test results for treatment group effects were considered statistically significant if P < 0.05. For clinical laboratory tests, an unpaired Student’s t-test examining the mean change from baseline to the end of study was performed.

RESULTS

Patient demographics

Patients in both groups were similar with respect to age, sex, serum cholesterol level, and disease duration (Table 1). In the Ganopoly group, there were 88 patients with 49 men and 39 women, where there were 82 patients in the control group with 46 men and 36 women. The median age of all patients was 52.7 yrs. Ten patients were not assessable for response and adverse effects because they were lost to follow-up or refused further therapy before 12 weeks of treatment.

Efficacy evaluation

At the end of treatment (12 weeks), 80 patients were assessed in Ganopoly and control group. Ganopoly treatment significantly improved the primary symptoms of CHD in 75-83% of the patients compared to the control group (0-5%). These symptoms include chest pain, palpitation, angina pectoris and shortness of breath. Consistently, ECG examination revealed that Ganopoly treatment significantly decreased the percentage of abnormal results from 74% to 45%, whereas there was no significant decrease (76% to 74%) in the control group. Serum cholesterol levels decreased significantly after 12 weeks of Ganopoly therapy with respect to the baseline values (Figure 1; P < 0.05), whereas cholesterol levels remained unchanged in the control group.

Adverse effects

Safety results for all patients were recorded during treatment. Ganopoly was well tolerated, with eight side-effect events (4 dry mouth and 4 nausea) recorded (all were mild-to-moderate, Grade I). Ganopoly was not associated with hematologic, liver, renal, or biochemical toxicity.

DISCUSSION

This prospective double-blind, placebo-controlled and multi-centered clinical study was designed to investigate the efficacy and safety of Ganopoly in patients with confirmed CHD. The results showed Ganopoly significantly improved the common symptoms of CHD, decreased the serum cholesterol level, and improved the abnormal ECG in many patients, whereas this was not observed in the control group. Ganopoly was well tolerated. The results indicate the potential use of G. lucidum preparations in the treatment of CHD. Since there is increasing interest in the application of herbal medicines to treat patients with various chronic diseases such as CHD (Vickers, 2000), it can be expected more well-designed clinical trials will be reported, and more anti-CHD remedies will be identified from edible mushrooms, in particular from Ganoderma species, which are highly ranked in Oriental traditional medicine. There are increasing investigations in the field of hypotensive and hypolipidemic polysaccharides and triterpenes from edible mushrooms. However, there is a paucity of reliable and objective comparative data on the anti-CHD activity of G. lucidum preparations. To the best of our knowledge, this study was the first of this kind of clinical trial with a G. lucidum preparation to show the anti-CHD efficacy in patients.

The mechanism of anti-CHD activity of Ganopoly is unknown. Preclinical studies have shown the anti-hypertension, anti-hyperlipidemia and anti-thrombotic action of polysaccharides and triterpenes of G. lucidum (Gao, 2000). Other activities, such as improvement of heart capillary blood circulation and oxygen-carrying ability, may also be beneficial effects of Ganopoly for patients with CHD. Polysaccharides and triterpenes from G. lucidum have also shown cardioprotection effect by increasing nitric oxide production. It is apparent that more studies are needed to identify more active components from G. lucidum and their mechanisms of action in CHD.

Table 1. Demographic profiles of patients with CHD.

Characteristic Ganopoly group Control group
No. of patient 88 82
Age (yrs) 54.2 ? 9.8 (36-65) 55.4 ? 11.1 (39-64)
Gender (M/F) 49/39 46/36
Cholesterol (׼/font> ULN) 2.1 ? 1.2 2.2 ? 1.1
Duration of disease (yrs) 5.2 ? 1.5 (0.4-15.2) 5.5 ? 1.7 (0.9-14.1)
ECG abnormality (%) 74 76
>50% narrowing of one major coronary artery 28 25

Data are mean ? SD (range). ULN = Upper limit normal. ECG abnormality includes depressed ST-t segment, or elevated ST segment.

Figure legends

Figure 1. Serum cholesterol levels at the start and 12 weeks in patients with CHD.

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