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Core Nutritional Products :: The Scientific Rediscovery of an Ancient Chinese Herbal Medicine: Cordyceps sinensis (Part 2) ::
| The Scientific Rediscovery of an Ancient Chinese Herbal Medicine: Cordyceps sinensis (Part 2) |
THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE
Volume 4, Number 4, 1998, pp. 429-457
Mary Ann Liebert, Inc.
The Scientific Rediscovery of a Precious Ancient Chinese
Herbal Regimen: Cordyceps sinensis
Part II
JIA-SHI ZHU, M.D., Ph.D., 1,4 GEORGES M. HALPERN, M.D., Ph.D.,2
and KENNETH JONES3
1Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
2University of California, Davis, California.
3Armana Research, Inc., Gibsons, B.C., Canada.
4Current address: Zhi Dao Tower, 12th Floor, Shanghai Medical University, Shanghai, 200032 China.
ABSTRACT
Cordyceps sinensis (Berk.) Sacc. is a time-honored tonic food and herbal medicine in China, where recent research has shown that many of its traditional uses may be viewed from the basis of pharmacological activities. The ongoing exploration of C. sinesis in its wild form and cultured, fermented mycelial products derived from it, are reviewed from English and Chinese literature. Part II concludes the series with a review of C. sinensis in preclinical in vitro and in vivo studies, and open-label and double-blinded clinical trials on the respiratory, renal, hepatic, cardiovascular, immunologic, and nervous systems, and its effecgs on cancer, glucose metabolism, inflammatory conditions, and toxicological studies. In Part I, which appeared in the Fall 1998 issue of this journal (4(3):289-303), we discussed the effects of C. sinensis on antisenescence, endocrine and sexual functions, atherosclerosis, hyperlipidemia, and free radicals.
EFFECTS ON THE RESPIRATORY SYSTEM
The use of Cordyceps (Cordyceps sinensis [Berk.] Sacc.) in the treatment of respiratory diseases is centuries old. Cordyceps has an extensive history of use in the treatment of chronic bronchitis, especially in elderly patients, and of asthma, chronic obstructive pulmonary disease (COPD), tuberculosis, cor pulmonale, and ohter diseases of the respiratory system. Some of these applications may be related to the ability of Cs-4 to affect trachael and bronchial functions.
Pre-clinical pharmacology of Cordyceps in the respiratory system
One of the most interesting pharmacological effects of natural Cordyceps and its fermentation products on the respiratory tract involves expectoration and cough, with improved pulmonary functions. In preclinical animal studies (Wan F, Zhang S. Clinical observations of fermented Cordyceps sinensis (Cs-4) in antitussive, expectorant, and antathematic effects. Unpublished report, Nanchang, Jianhxi China: Jiangxi Institute of Medical Sciences, pp. 35-39.), Cs-4 extracts (6 g/kg, i.g.) increased intratrachael secretion (+114% to +197%; p<0.01 to <0.001) in rats with a peak during the second hour after Cs-4 treatment, therefore facilitating expectoration. Similar results were found after natural Cordyceps treatment (+141% to +251%; p<0.01 to <0.001). Along with the increases in trachea secretion volume, Cordyceps also increased dye secretion through the trachael mucosa. After treatment with natural Cordyceps (3.1 g/kg,p.o.) or other fermented mycelial products of Cordyceps (2.5 g/kg, p.o.), mice were administrated phenol red. Secretion of phenol red was dramatically increased (+66% to +61%) in mice treated with natural Cordyceps and its fermentation product, as compared to placebo controls (p<0.05) (Wang and Zhao, 1987).
In addition to the increase in trachael secretion, Cordyceps has also been proven to show an antitussive function. For instance, treatment with Cs-4(5 g/kg, i.g.) was effective against experimental ammonia-induced cough in mice. Cough-latent period was significantly prolonged by about 5 times and cough frequency was decreased by two-thirds in the Cs-4 group, as compared to placebo controls (p<0.001 and <0.001) (Wan F, Zhang S. Clinical observations of fermented Cordyceps sinensis (Cs-4) in antitussive, expectorant, and antathematic effects. Unpublished report, Nanchang, Jianhxi China: Jiangxi Institute of Medical Sciences, pp. 35-39). These effects of Cs-4 were similar to those of codeine at a dose of 60mg/kg.
It was also demonstrated that Cs-4 plus cultured medium could significantly relax trachael smooth muscles in trachea isolated from guinea-pigs with histamine-induced spasm (Wan F, Zhang S. Clinical observations of fermented Cordyceps sinensis (Cs-4) in antitussive, expectorant, and antathematic effects. Unpublished report, Nanchang, Jianhxi China: Jiangxi Institute of Medical Sciences, pp. 35-39). Length of the histamine-pretreated trachea increased 7.5 times after adding Cs-4 (5 mg/mL) to the medium, as compared to placebo controls (p<0.01). Another study also demonstrated that natural Cordyceps (2.17 g/kg) and Cs-4(1.74 g/kg) could significantly prolong the latent period (5.44-and 4.75-fold of controls, respectively; both p<0.01) of asthma development induced by acetylcholine in guinea pigs (Wang and Zhao, 1987). Further increases in the latent period (7.58-and 7.25-fold of controls, respectively; both p<0.01) were also seen after guinea pigs received natural Cordyceps (1.08 g/kg) or Cs-4 (0.87 g/kg) treatment in combination with aminophylline (63.5 mg/kg). Similarly, natural Cordyceps and a fermented mycelial product of Cordyceps (SMIH8819) displayed relaxation effects on twitch contractions of the trachea (Tsunoo et al., 1995).
Table 1. Summary of Clinical Efficacy of Cs-4 In The Treatment of Respiratory Diseases
| REFERENCE
|
CS-4 DOSAGE
|
WEEKS OF TREATMENT
|
TOTAL PATIENTS
|
IMPROVED PATIENTS
|
SUCCESFULL TREATMENT %
|
| Han (1995)
|
3 grams / day
|
2-12
|
100
|
92
|
92%
|
| Qu et.al.(1995) |
3 grams / day
|
4
|
30
|
26
|
87%
|
| Zhen & Deng (1995) |
3 grams / day
|
4
|
20
|
17
|
85%
|
| Yang (1985) |
4.5 grams / day
|
4
|
27
|
21
|
78%
|
| Zheg et. al. (1985) |
4.5 grams / day
|
4
|
20
|
18
|
90%
|
Patients with respiratory diseases were treated with Cs-4 (dose and length of treatment indicated). The clinical improvement rates were significantly greater than negative controls (all p>0.01)
Clinical use of Cordyceps to improve respiratory functions
Several studies have demonstrated an improvement in clinical symptoms of respiratory diseases aftr the administration of a Cordyceps-containing medication. For example, the vast majoirity of patients with various respiratory diseases, such as chronic bronchitis, bronchial asthma, or cor pulmonale, reported a significant clinical improvement after Cs-4 treatment (Table 1) (Han, 1995). In another clinical trial (Qu et al., 1995), Cs-4 treated patients with various respiratory diseases, with or without antibiotics, were as improved as a positive control group treated with a known, effective drug, Bai-Ling capsule (Swnnematium sinese Yin et Shen sp. nov.) (Table 1). In other studies, Cs-4 treatment of patients suffering from chronic bronchitis or bronchitis with asthma resulted in very high rates of clinical improvement, versus the representative contol groups (Table 1) (Zheng and Deng, 1995; Yang, 1985; Zheng et al., 1985). Improvements in respiratory capacity were also noted in these studies (Table 2) (Zheng et al., 1985).
Combined use in treating cor pulmonale
Cs-4 has also been used in combination with other drugs to treat patients suffering from cor pulmonale, either acute or recurring acutely with first-degree to third-degree heart-lung dysfunction (Lei and Wang, 1995). Addition of Cs-4 to the basic treatment of oxygen inhalation and antibiotics resulted in a highly improved overall rate of therapeutic effect when symptoms, including asthma, cough and expectoration, sleep, emotional-spiritual state, respiratory functions, and heart functions, were assessed (Table 3). This improvement was significantly greater than the overall effective rate reported for the control group, which received basic therapy without Cs-4. The results indicated a greater improvement in quality of life for the patients after administration of Cs-4.
Clinical use in treating cough as an equivalent of asthma
The combined use of Cs-4 (3 g/day for 10 days) with Western medicines (astemizole 10 mg/day and ketotifen 2 mg/day) in the treatment of patients with cough as an equivalent of asthma was in one study associated with an 81% improvement rate (n - 32), which was greater than the 61% rate observed for a control group (n = 18) treated with Western medicine alone (p<0.05) (Qiuo and Ma, 1993). In addition, the patients in the Cs-4 group experienced faster relief of their cough symptoms (within 5 days on average) as compared to the control group (9 days). Among the asthmatic patients, the 10-day treatment with Cs-4 resulted in improved ventilation functions: the forced expiratory volume in first-second (FEV 1.0) was increased by approximately 15% from the pretreatment baseline.
Table 2. Changes in Pulmonary Functions in Chronic Bronchitis Patients After Cs-4 Adjuvant Treatment
| TEST
|
NUMBER
|
DIFFERENCE (POST MINUS PRETEST) VALUES
|
P VALUE
|
| Timed Vital Capacity |
20
|
300 ±307
|
<0.01
|
| Ratio of FEV1:FEV (%) |
20
|
7.3±6.8
|
<0.01
|
| Ratio of FEV3:FEV |
20
|
5.9±1.6
|
<0.01
|
| Maximum Breathing Capacity |
20
|
11.02-17.82
|
<0.01
|
| Maximum Breathing Capacity (%) |
20
|
8.25-10.1
|
<0.01
|
Patients with chronic bronchitis were treated with Cs-4 (3 g/day, 1 month). FEV1 forced expiratory volume in the first second; FEV3 forced expiratory volume in the first 3 seconds. Data are adapted from Zheng et al. (1985)
EFFECTS ON THE KIDNEYS
In accord with the most recognized action of Cordyceps in traditional Chinese medicine (TCM), pharmacological studies of the “kidney tonic” tend to bear out this time-honored traditional use. China’s physicians have made extensive use of Cordyceps in the treatment of chronic renal diseases, including chronic nephritis, chronic renal dysfunction or failure, chronic pyelonephritis, and nephrotic syndrome. Studies have shown that Cordyceps could improve kidney functions and act against the damage caused by certain nephrotoxic chemicals.
Table 3. Clinical Improvement of Patients with Cor Pulmonale by Cs-4 Adjuvant Treatment
Clinical improvement
With Cs-4 Without Cs-4
n % n %
Shortness of breath 45 90% 20 67%
Cough and expectoration 46 92% 18 60%
Sleep 48 96% 21 70%
Emotional-spiritual state 46 92% 18 60%
Pulmonary function 48 96% 16 53%
Heart function 46 92% 18 60%
Total effective rate 92.0% 61.5%
Patients with cor pulmonale were treated either with (n = 50) or without (n = 30) Cs-4 (4.5 g/day) for 30 days. Data are adapted from Lei and Wang (1995).
Effects on renal functions
Cheng et al. (1992) found that as compared to chronic renal failure (CRF) model controls, natural Cordyceps treatment (0.5 g/kg, for 4 months) greatly decreased the mortality of CRF rats, reduced blood urea nitrogen (BUN; -25%) and serum creatinine (SCr; -56%), and improved anemia (hemoglobin, +13%) (all p>0.005) Cheng et al., 1992). In addition, natural Cordyceps significantly enhanced the transformation rates of splenic lymphocytes and promoted the rate of production of interleukin-2 (IL-2) receptor (+78%, p<0.005) and expression of IL-2 (+21%, p<0.005) in lymphocytes, suggesting a correlation of the functional improvement of the cell-mediated immune system and a delay in the deterioration of renal functions.
In 30 patients with CRF, treatment with Cs-4 significantly improved renal functions (Chen et al., 1986) SCr was significantly reduced; creatinine clearance (Ccr) increased dramatically; and BUN was significantly reduced (Table 4). In addition, there was a dramatic improvement in anemia after Cs-4 therapy: hemoglobin and red blood cells (RBC) were increased significantly, while transformation rates of lymphocytes also increased significantly.
In another study, patients with chronic renal dysfunction who received Cs-4 treatment showed very significantly reduced BUN and SCr, along with a very noticeable improvement of symptoms (Table 5) Jiang and Gao, 1995). In association with reduced renal functions, patients with renal failure or dysfunction often suffer from hypertension, proteinuria, and anemia. A 15% decrease in average arterial blood pressure was observed, while urinary proteins were also decreased dramatically. In addition, catalytic increases in superoxide dismutase (SOD) were demonstrated in the patients after one month of Cs-4 treatment. The increase in total SOD was associated with a marked decrease in serum lipoperoxide, suggesting an increas in the oxygen free radical scavenging capacity to reduce oxidative cellular damage.
Clinical studies have shown that a Cordyceps-induced renal function improvement in patients with renal failure significantly coincided with changes in T-cell subgroups (Table 6) (Guan et al., 1992; Chen et al., 1984). These results suggest a possible correlation of improvement of renal dysfunction by Cordyceps with a modulation of T-cell mediated immune functions.
Protection from kidney toxicity
Renal protective effects of Cordyceps against aminoglycoside antibiotics and cyclosporine A nephrotoxicity were tested both in animals and humans. Cs-4 (0.08 g/kg) was administered to rats for 7 days in combination with gentamicin (160mg/kg), while a gentamicin control group
Table 4. Improvement of Kidney Functions by Cs-4 in 30 Patients with Renal Failure
Hemoglobin RBC SCr Creatinine clearance BUN
Pretreatment 1.00 1.00 1.00 1.00 1.00
Post-treatment 1.08 1.07 0.91 1.40 0.81
Difference +0.08 ) 0.03 +0.08 ) 0.04 -0.09 ) 0.03 +0.40 ) 0.07 -0.19 ) 0.06
p value <0.02 <0.05 <0.02 <0.001 <0.01
Patients with chronic renal failure were treated with Cs-4 (6 g/day) for 30 days.
RBC, red blood cell count; SCr, serum creatinine; BUN, blood urea nitrogen.
Data are adapted from Chen et al. (1986) and are expressed as fractions of mean pretreatment values received an equal volume of water (Zheng et al., 1994). After the treatment, increases in accumulated 24-hour urine N-acetyl---D-glucosaminidase (NAG), an index for aminoglycoside antibiotic-induced renal damage, appeared to be significantly attenuated by 61% in the rats receiving Cs-4/gentamicin cotreatment, when compared to the gentamicin model rate (p<0.02). No significant increase was found in urinary sodium excretion in Cs-4-treated rats compared to normal rats; while gentamicin-model rats showed an average 2.7-fold increase in urine sodium excretion (p<0.01). Notably, apparent regeneration of renal tubular cells was found in the Cs-4-treated rats when examined under a microscope. According to increases in isotope incorporation into cultured renal tubular cells,
Table 5. Improvement of Kidney Functions by Cs-4 in 37 Patients with Renal Failure
BUN Creatinine Arterial pressure Urinary proteins SOD LPO
Pretreatment 1.00 ) 0.42 1.00 ) 0.42 1.00 ) 0.13 1.00 ) 0.90 1.00 ) 0.39 1.00 ) 0.37
Post-treatment 0.66 ) 0.31 0.61 ) 0.30 0.85 ) 0.07 0.37 ) 0.30 0.51 ) 0.34 0.65 ) 0.17
p value <0.001 <0.001 <0.01 <0.01 <0.001 <0.001
Patients with chronic renal failure were treated with Cs-4 (5 g/day) for 1 month.
BUN, blood urea nitrogen, SOD, superoxide dismutase, LPO, lipoperoxide.
Data are adapted from Jiang and Gao (1995) and are expressed as fractions of mean pretreatment values.
Table 6. Improvement of Kidney Functions and Associated Changes in T-Cell
Subgroups by Natural Cordyceps in 51 Patients with Renal Failure
BUN SCr Hemoglobin OKT4 Ratio of OKT4/ T8
Pretreatment 1.00 ) 0.23 1.00 ) 0.50 1.00 ) 0.18 1.00 ) 0.16 1.00 ) 0.24
Post-treatment 0.75 ) 0.31 0.69 ) 0.25 1.18 ) 0.21 1.13 ) 0.14 1.16 ) 0.16
p value <0.05 <0.05 <0.05 <0.05 <0.05
Patients with chronic renal failure were treated with natural Cordyceps (3-5 g/day) for 10-12 months.
BUN, blood urea nitrogen; SCr, serum creatinine.
Data are adapted from Guan et al. (1992) and are expressed as fractions of mean pretreatment values.
Serum prepared from Cs-4-treated rats appeared to produce dramatic stimulatory effects on tubular cell proliferation, as compared to that of the gentamicin control serum (p<0.01). In their conclusion, the authors reported that gentamicin nephrotoxicity appeared to be largely compromised by cotreatment with Cs-4, indicating a nephroprotective effect of Cs-4.
Administration of water extracts of natural Cordyceps protected rats from acute renal damage in proximal tubular cells and accelerated recovery of real functions. After the rats were treated with kanamycin (250 mg/kg plus dextran, 3 g/kg) to produce an acute renal failure (ARF) model, total mortality of the ARF rats was significantly less in the Cordyceps treatment (10 g/kg) group, as compared to the kanamycin control group (p<0.05) (Zheng et al., 1992). BUN and SCr were significantly lower in the Cordyceps group than in the controls (p<0.01 and <0.05), and urine osmolarity was higher in the Cordyceps-treated rats (both p<0.05). Microscopic examination in multiple view fields of kidney sections in a double-blind fashion demonstrated that the 5-day natural Cordyceps treatment ameliorated acute damage/death of proximal tubular cells of rats and significantly accelerated the process of recovery. Histological damage of tubular cells, greatly attenuated after the 5-day Cordyceps treatment, was found in association with a significant decrease in lysosomal acid phosphatase activity, as compared to diffuse pathological changes in the controls.
Another ARF animal model was created by treatment of rats with gentamicin (140 mg/kg). The rats were administered gentamicin in combination with either placebo or natural Cordyceps (1 g/day) for 7 days. In association with a significant recovery of BUN, SCr, NAG, and histology, catalytic activity of Na+-K+-ATPase nearly doubled in the kidney cortex in the Cordyceps-treated rats compared to contreols (p<0.01), indicating a more active cellular sodium pump.
In rats treated with natural Cordyceps (0.5 g/kg) in combination with cyclosporin A (30 mg/kg by gavage every other day for 3 months), microscopic examination revealed that Cordyceps could reduce chronic interstitial edema-hemorrhage-fibrosis and tubular denaturation-necrosis in the rat kidney, when compared to control rats that received only cyclosporin A (Zhao and Li, 1993a). These morphological benefits were associated with lower BUN in the Cs-4 group after 8 (-19.4%) and 10 weeks (-39.3%) treatment and reduced secretion of endogenous EGF in urine (all p<0.01), compared to that observed in cyclosporin A controls.
A histological study of renal damage was performed in rats after a combined therapy with: (1) natural Cordyceps and cyclosporin A in an acute experiment, or (2) natural Cordyceps and cyclosporin A in a subchronic study (Zhao and Li, 1993b). Observations were compared with those in control rats threated with only cyclosporin A. In both the acute and subchronic studies, natural Cordyceps prevented morphological damages induced by cyclosporin A (Table 7).
After the results in animals, protective effects of natural Cordyceps against kidney damage by aminoglycoside antibiotics were examined in senior patients with no history of renal diseases (Bao et al., 1991). The patients were given amikacin (intramuscular injection or intravenous perfusion) for treatment of their acute infectious diseases: acute recurrence of chronic bronchitis, pneumonia, pleuritis, acute upper respiratory infection, and acute enteritis. With double the dose on the first day, patients in the experimental group received natural Cordyceps in combination with the amikacin treatment. Patients in a control group received the amikacin treatment plus placebo capsules. After the therapy, accumulated 24-hour urinary NAG was found to have significantly increased 4 times from the pretreatment baseline after the therapy in the control group, while it had only doubled from the baseline in the Cordyceps-treated group, which was significantly lower than controls (Table 8).
CS-4 has been also used to treat patients with gentamicin toxicity. In an open label, controlled clinical trial (Bi et al., 1994), patients diagnosed with gentamicin nephrotoxic damage were given Cs-4 daily, while another 28 patients diagnosed with gentamicin toxicity in a control group received cotreatment with gentamicin, adenosine triphosphate (ATP), coenzyme-A, and cytochrome-C. The rate of 6-day complete clinical recovery was significantly higher in the experimental group than in the control group (p<0.01), and the number of days required for urine tests to become normal was significantly lower in the Cs-4 group compared to controls (Table 9).
Postsurgical care has greatly benefited from the ability of cyclosporin A to reduce immune
Table 7. Renal-Protective Functions of Natural Cordyceps on Morphology of Rat Kidneys with Renal Damage Induced by Cyclosporin A
Cyclosporin A + placebo Cyclosporin A + Cordyceps p value
Experiment 1 Area of proximal convoluted tubule Area of distal convoluted tubule n 12 1.00 ) 0.19 1.00 ) 0.20 12 1.27 ) 0.20 1.87 ) 0.44 <0.01 <0.01
Experiment 2 At 2 weeks Area of proximal convoluted tubule Area of distal convoluted tubule Area of glomerulus Area of interstitium At 4 weeks Area of proximal convoluted tubule Area of distal convoluted tubule Area of glomerulus Area of interstitium n 26 1.00 ) 0.14 1.00 ) 0.25 1.00 ) 0.13 1.00 ) 0.16 1.00 ) 0.12 1.00 ) 0.21 1.00 ) 0.15 1.00 ) 0.13 26 1.05 ) 0.13 1.09 ) 0.22 1.27 ) 0.20 0.94 ) 0.14 1.38 ) 0.26 1.39 ) 0.55 1.15 ) 0.20 0.68 ) 0.24 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.01 <0.05
Rats were treated with cyclosporin A (experiment 1 50 mg/kg for 15 days, experiment 2: 30 mg/kg for 3 months), in combination with either placebo or natural Cordyceps (experiment 1: 1.0 g/kg; experiment 2. 05 g/kg)
Data are adapted from Zhao and Li (1993) and are expressed as fractions of mean values for placebo controls.
rejection by organ recipients. However, nephrotoxicity of cyclosporin A (a potent immune suppressor) has been a clinical problem during solid organ transplantation, especially kidney transplantation. A clinical study showed that the combined use of a fermented mycelial product of Cordyceps (East-China Pharmaceuticals, Hangzhou, China) and cyclosporin A (5 mg/kg per day) for 15 days in 30 kidney transplant patients produced better clinical outcomes than in controls receiving
Table 8. Changes of Urinary N-Acetyl-B-D-
Glucosaminidase (NAG) in Patients
Receiving Amikacin Treatment and Renal
Protective Activity of Natural Cordyceps
NAG
Placebo group Cordyceps group p value
n 9 10
Pretreatment 1.00 ) 0.44 0.94 ) 0.36
At the first day 1.51 ) 0.86 1.03 ) 0.44
At the third day 2.41 ) 1.45 1.42 ) 0.61
At the sixth day 3.84 ) 2.28 1.98 ) 0.92 <0.05
Senior patients (53-73 years old) were treated with amikacin (0.4 g/day for 6 days), with either placebo or natural Cordyceps (6 g/day) for 7 days.
Data are adapted from Bao et al. (1991) and are expressed as fractions of mean pretreatment values for the placebo group
Table 9. Clinical Improvement in Patients with Gentamicin Nephrotoxicity After Cs-4 Treatment
Control Cs-4 p value
n 28 29
Precovery rate at 45% 89% <0.01
the sixth day
Urine test recovery 6.9 ) 2.1 3.8 ) 1.1 <0.01
(days)
Patients with gentamicin nephrotoxic damage were treated with either conventional therapy (adenosine triphosphate [ATP], co-enzyme A, and cytochrome-C), or Cs-4 (4.5 g/day) for 6 days.
Data are adapted from Bi et al. (1994).
Only cyclosporin A (Xu et al., 1995). Mild increases in Scr, BUN, and NAG were found in those patients receiving the combined treatment, compared to significant increases in a control group that received only cyclosporine A (Table 10).
Therefore, both clinical and animal studies have demonstrated renal-protective effects of Cordyceps against nephrotoxicity of aminoglycosides and cyclosporin A.
EFFECTS ON THE CARDIOVASCULAR SYSTEM
The meanings of some medical terms in TCM are based on their own definition and philosophy, which are sometimes distinct from those in Western medicine. For example, the meaning of “lung” disease in TCM is much broader than that assigned to it in modern medicine; eg, shortness of breath due to limited heart functions may still be under the “lung” disease category. Therefore, although Cordyceps is mainly used to treat respiraory and renal diseases under these TCM categories, it has been used extensively in treating cardiovascular diseases. For instance, the treatment of arrhythmias with Cordyceps and its mycelial fermentation products is reported to have a rate of efficacy ranging from 75% to 88% (Table 11) (Tang and Jiang, 1994; Li et al., 1985; Liu et al., 1990; Xu and Zheng, 1994; Yan et al., 1992a).
In a 3-month, open-label clinical trial, Cs-4 was used to treat 38 elderly patients with varying degrees of intractable arrhythmias caused by varying forms of heart disease (Tang and Jiang, 1994). Among them, the majority diagnosed with superventricular arrhythmia experienced complete or partial recovery of their ECG with clinical improvement (Table 12). Among patients suffering from ventricular arrhythmia or complete blockage of the right branch, the majority gained complete or partial recovery of their ECG. The investigators concluded that Cs-4 appears not only to be effective for tachyarrhythmia, but also for bradyarrhythmia, and that the longer the therapy, the better the clinical improvement.
A randomized, double-blind, placebo-controlled trial (Xu and Zheng, 1994) demonstrated that treatment using another cultured mycelial Cordyceps product, known as Ningxinbao capsule (Cephalosporium sinensis), appeared very effective in completely or partially improving ECG in patients with atrial or ventricular premature beats, as compared to placebo controls. The total effective rate for the treatment group was significantly higher compared to the control group (Table 13).
In an 8-week controlled clinical trial, CS-4 (3 g/day, for 8 weeks) was used to treat 20 patients with ischemic heart disease, as compared to Persantine (dipyridamole, 150 mg/day, Boehringer Ingelheim, Germany) (Che and Lin, 1996). In addition to the significant reduction of total cholesterol, triglycerides, and --lipoprotein as shown in Part I, Table 15 (Zhu et al., 1998), 87%-90% of patients experienced clinical improvement of their chest distress and palpitation. The majority of the patients (65%) had improved ECG after treatment, which was similar (if not better) compared to 55% in the control group. Moreover, blood fibrinogen and viscosity was significantly reduced (Table 14).
The benefits of long-term use of Cs-4 were evaluated in a group of 64 patients with chronic heart failure (Chen, 1995). Patients in one group were treated with Cs-4 in addition to their maintenance therapy for heart failure, and compared to control patients who received only the basic therapy for their heart failure. According to the New York Heart Association (NYHA) functional classification system for cardiac functions, the Cs-4 treatment seemed not to have significantly improved their mortality as compared to controls (p.>0.05). However, echo-
Table 10. Clinical Improvement from Natural Cordyceps in Patients with Cyclosporin A Nephrotoxicity
n ----Urinary NAG--- Pre 15th day ----Serum creatinine--- Pre 15th day ---BUN--- Pre 15th day
Control 39 1.00 ) 0.42 1.42 ) 0.42 1.00 ) 0.13 1.26 ) 0.21 1.00 ) 0.18 1.82 ) 0.18
Cordyceps 30 1.00 ) 0.33 1.17 ) 0.42 1.04 ) 0.08 1.08 ) 0.06 0.91 ) 0.18 1.36 ) 0.27
p value <0.05 <0.05 <0.05
Patients who received kidney transplantation surgery were treated with cyclosporin A (5 mg/kg per day) in combination with either placebo or fermented mycelia of Cordyceps (3 g/day) for 15 days.
Data are adapted from Xu et al. (1995).
Table 11. Summary of Clinical Efficacy of Cordyceps in the Treatment of Arrhythmias
Reference Dose (g/kg) Treatment(g/kg) n Improved---- n %
Tang and Jiang (1994) Cs-4 3 1 38 31 81.6%
Lie et al. (1985) Cephalosporium sinensis 1.5 2 200 149 74.5%
Lie et al. (1990) Cephalosporium sinensis 3 4 37 30 81.1%
Lie et al. (1994) Cephalosporium sinensis 3 2 32 25 78.1%
Yan et al. (1992a) Cephalosporium sinensis 1.5 12 50 44 88.0%
Patients who received kidney transplantation surgery were treated with cyclosporin A (5 mg/kg per day) in combination with either placebo or fermented mycelia of Cordyceps (3 g/day) for 15 days.
Data are adapted from Xu et al. (1995).
Table 12. ECG Improvement of Arrhythmias by Cs-4 Treatment
-- Improved----
n n %
Superventricular arrhythmia 24 20 83%
Ventricular arrhythmia 10 8 80%
Complete blockage of the 4 3 75%
right branch
Total effective rate 38 31 81.6%-----
Patients with arrhythmia of varying types were treated with Cs-4 (3 g/day) for 3 months.
Data are adapted from Tang and Jiang (1994).
Table 13. Clinical Improvement of Premature Beats After 2-Week Ningxinbao (Cephalosporium Sinensis) Treatment
Atrial Ventricular
premature beats-- premature beats--
Improved Improved---
n n % n n %
Placebo 18 4 22.2% 10 1 10.0%
Ningxinbao 17 14 82.4% 13 11 84.6%
p value <0.01 <0.01------
Patients with arrhythmia of varying types were treated with Cs-4 (3 g/day) for 3 months.
Data are adapted from Tang and Jiang (1994).
cardiography demonstrated a significant reduction in the heart rate and a significant increase in the cardiac stroke volume and cardiac index (= cardiac output ' body surface area ) as compared to controls (Table 15). Using the Yale evaluation system to analyze quality of life, the shortness of breathfatigue index was significantly increased in these patients after the Cs-4 adjuvant therapy, in contrast to the control group under the basic maintenance treatment. As analyzed earlier, the Cs-4 adjuvant therapy dramatically improved general physical and emotional conditions of the patients with chronic heart failure (see Part I, Table 5 for details, Zhu et al., 1998). This study suggests that long-term Cs-4 treatment may dramatically improve the quality of life of chronic heart failure patients, together with improvement of their cardiac functions.
Animal studies, in vivo or with isolated organs, have attempted to explore the underlying mechanism of the cardiovascular benefits of Cordyceps. Pharmacological activities of natural Cordyceps and its mycelial fermentation products on the cardiovascular system examined on preclinical animal and isolated tissues are summarized below and in Table 16.
Table 14. Clinical Improvement and Changes of Blood Fibrinogen and Viscosity
in Ischemic Heart Disease Patients in Response to Cs-4 Treatment
Pretreatment Post-treatment p value
Fibrinogen (g/L) 4.10 ) 0.67 3.80 ) 0.56 <0.01
Plasma viscosity (CP) 1.87 ) 0.10 1.76 ) 0.08 <0.01
Whole blood viscosity high shear (CP) 10.3 ) 3.20 6.28 ) 2.40 <0.001
low shear (CP) 9.60 ) 1.80 7.60 ) 2.40 <0.01
Patients (n =40) with ischemic heart disease were treated with Cs-4 (3 g/day, for 8 weeks).
Data are adapted from Che and Lin (1996).
(1) Dilation of arteries and improvement of nutritional blood supply to organs and extremities.
Dilation of arteries in animals or of isolated arteries by natural Cordyceps or its fermentation products has been documented, including dilatio of aorta, coronary arteries, cerebrovasculature, and peripheral arteries.
A) Relaxation of contracted aorta. Artery relaxation was seen in an isolated aorta preparation after water extracts of a mycelial fermentation product (SMIH8819) added to a perfusion solution at a concentration of 50 µg/mL, when aorta was in a persistently contracted condition pre-evoked by addition of 50 mM K+ (Tsunoo et al., 1995).
b) Hypotensive effects in extremities. After intravenous injection of Cs-4 (60 mg/kg), anesthetized dogs displayed a significant decrease in blood pressure (p<0.001 at peak; p<0.02 at 1 to 15 minutes) (Feng et al., 1987). Lower doses of Cs-4 treatment (2.5, 5, or 10 mg/kg, intravenously) did not display such systematic hypotensive effects, but induced a dramatic decrease in femoral arterial resistance (all p<0.02). When the sciatic nerve and the femoral nerve were severed unilaterally, the hypotensive effects of Cs-4 in the femoral artery on the affected side appeared to be moderately muted (from a 45% decrease to a 20% decrease). This indicated that the hypotensive effects were partially mediated by functions of motor nerves. Although there were dramatic changes in resistance and pressure of femoral artery after the Cs-4 treatment, whole body blood pressure of the dogs remained unchanged when Cs-4 was administered through the femoral artery (Feng et al., 1987; Feng, Zhou, Feng, Shuai. Pharmacological studies on fermented mycelia of Cordyceps. Unpublished report, Jianxi Medical College, pp. 45-52.)
The investigators attempted to explore the mechanisms of the arterial dilation produced. Administration of Cs-4 (60 mg/kg) to dogs through the vertebral artery induced a dramatic 48% reduction in blood pressure, while the same dose of Cs-4 could not induce a reduction of blood pressure in the animals (Feng, Zhou, Feng, Shuai. Pharmacological studies on fermented mycelia of Cordyceps. Unpublished report, Jianxi Medical College, 45-52.) The authors believed that such systematic hypotensive effects might be at least partially due to an effect on the central nervous system. Further experiments demonstrated that the effect of Cs-4 on the
Table 15. Improvement of Shortness of Breath/Fatigue Index and Heart Functions of Patients with Chronic Heart Failure in Response to Long-Term Cs-4 Adjuvant Treatment
Control Cs-4 p value
n 30 34
Shortness of breath/fatigue index
Index score after treatment 1.00 ) 0.08 1.27 ) 0.13 <0.01
Increase after treatment 1.00 ) 0.48 2.48 ) 0.61 <0.01
Average percentage increase 25% 66%
Heart rate (beat/min) 1.00 ) 0.06 0.90 ) 0.05 <0.01
Stroke volume (mL) 1.00 ) 0.23 1.21 ) 0.13 <0.01
Cardiac index 1.00 ) 0.22 0.19 ) 0.22 <0.01
(cardiac output ' body surface area)
Patients with chronic heart failure were treated with either Cs-4 or placebo (3-4 g/day, for 26 ) 3 months) in addition to standard treatments for chronic congestive heart failure.
The shortness of breath/fatigue index was assessed according to the Yale grading system. Heart rate and other cardiac function parameters were measured by echocardiography.
Data are adapted from Chen (1995) and are expressed as fractions of mean values of those observed for controls who received only standard treatments.
Table 16. Summary of Preclinical Examinations of Cardiovascular Effects of Cordyceps
Treatment Results Reference
Isolated Aorta SMIH8819 50 µg/mL in medium Relax aorta Tsunoo et al. (1995)
Dogs Cs-4 60 mg/kg, i.v. Lower blood pressure Feng et al. (1987)
Dogs Cs-4 2.5-10 mg/kg, i.v. Lower femoral arterial resistance Feng et al. (1987)
Dogs Cs-4 2.5-10 mg/kg, i.v. Lower cerebro-arterial resistance Feng et al. (1987)
Dogs Cs-4 0.425 g/kg, i.v. Increase coronary blood flow Feng et al. (1987)
Dogs Cs-4 0.425 g/kg, i.v. Lower coronary arterial resistance Feng et al. (1987)
Dogs Cs-4 0.425 g/kg, i.v. Lower heart rate Feng et al. (1987)
Lou et al.
Cardiovascular
pharmacological
studies of Cordyceps
fementation solution.
Unpublished report,
Beijing Medical
University and
Lanzhou National
College, 65-68;
Lou et al. (1986)
Dogs Cs-4 0.25-0.5 g/kg, i.v. Against arrhythmia induced by Lou et al. (1986)
aconitine or barium chloride
Guinea pigs Natural Cordyceps 1.0 g/kg, i.p. Against arrhythmia induced by Quabain Mei et al. (1989)
Rabbits Cs-4 150 mg/kg, i.v. Against myocardial ischemia induced by Pituitrin Lou et al. (1986)
Rats Cs-4 0.9 g/kg, i.g. Against stress-induced myocardial infraction Lou et al. (1986)
Platelets Cs-4 2-4 mg/mL in medium Against platelet aggregation Lou et al. (1986)
Against thrombosis Lou et al. (1986)
Rabbits CsB-851 30 µg/kg/min, i.v. Against thrombosis Zhao et al. (1991)
Animals, isolated organs, and cells were treated with natural Cordyceps or its fermentation products as indicated.
Data are adapted from references: Tsunoo et al. (1995); Feng et al. (1987); Lou, Lu, Liao. Cardiovascular pharmacological studies of Cordyceps fermentation solution. Unpublished report, Beijing Medical University and Lanzhou National College, 65-68; Lou et al. (1986); Mei et a. (1989); Zhao et al. (1991).
.
vasculature was not mediated by stimulation or inhibition of either ,- or -- adrenogenic or histamine receptors, but may be via direct dilatory effects of Cs-4 or partially mediated by M cholinergic receptors (Feng et al., 1987).
C) Dilation of coronary arteries and increased blood supply to the heart. Cs-4 can dilate the coronary arteries, in addition to dilation of the cerebrovasculature and peripheral arteries (Feng et al., 1987). When dogs were administered extracts of Cs-4 (0.425 g/kg, intravenously) under anesthesia, the resistance of coronary arteries was significantly decreased by 49% (p<0.01), with a dramatic reduction of coronary blood pressure (-116.5% on average, p<0.01) and heart rate (-14% on average, p<0.05). Subsequently, the volume of coronary arterial blood flow was dramatically increased (+100% at peak and +35% at 1 minute, both p<0.01). Injection of normal saline in a control group showed no significant change in resistance and blood volume of the coronary system.
d) Dilation of cerebrovascular arteries and increased blood supply to the brain. After anesthetized dogs (n = 7) were treated with Cs-4 (0.6 g/kg, intravenously), vertebral arterial resistance decreased by an average of 75% (p<0.05), (Feng et al., 1987), which indicated that Cs-4 can also dilate the cerebrovasculature. In separate experiments, reductions in vertebral arterial resistance were reported as a function of Cs-4 (5 and 10 mg/kg) when given through the vertebral artery (-25%, p<0.05; and -32%, p<0.01) (Feng et al., 1987). In these experiments, the reductions in arterial resistance following low dosages of Cs-4 were not associated with significant changes in blood pressure of the whole body, indicating reposition of blood circulation. In control groups with injections of equal volumes of normal saline, only a small reduction (1% to 3%) of arterial resistance was seen.
(2) Reducing the heart rate
Natural Cordyceps and its mycelial fermentation products, such as Cs-4 (either an ethanol extract or a concentrate of the fermentation solution), were also effective in reducing the heart rate (Feng et al., 1987; Lou et al., 1986). The negative chronotropic action was also demonstrated in an isolated right cardiac atrium experiment (p<0.05) with no apparent effect on myocardiac contractility (Lou, Lu, Liao. Cardiovascular pharmacological studies of Cordyceps fermentation solution. Unpublished report, Beijing Medical University and Lanzhou National College, pp. 65-68).
(3) Antiarrhythmic effects
Cs-4 ethanol extract was studied for its antiarrhythic effects in animals with experimental arrhythmias (Lou et al., 1986). Cs-4 (0.5 g/kg, i.v.) prolonged the induction period of arrhythmia (n = 10, p<0.01) onset induced by administration of aconitine (0.25-0.33 g/kg, i.v.) and shortened the duration of the arrhythmias (p<0.001) when compared with control rats treated only with placebo (n = 11). The majority of arrhythmias occurring in the Cs-4-treated rats were atrial arrhythmias and bigeminal or trigeminal arrhythmias. These were gnerally much less severe, as a rule, in contrast to those occurring in the control group (ie, ventricular arrhythmias as the majority of arrhythmias, receiving only placebo).
Cs-4 (0.25 g/kg, i.v., n = 7) was also effective in shortening the duration of the arrhythmias induced by barium chloride (1 mg/kg, i.v.) (p<0.02) when compared to the control group (n = 7), although it was not effective in prolonging the induction period of arrhythmia onset (Lou et al., 1986). The authors also observed that during the experimental arrhythmias, intermittent normal sinus rhythm occurred in the Cs-4 treated group.
Similar antiarrhythmic effects were also found after administration of natural Cordyceps (0.5 or 1.0 g/kg, i.p.) when aconitine (1.2 mg/kg, i.p.) was used to induce experimental arrhythmias (Mei et al., 1989). In addition, the
Table 17. Therapeutic Effects of a 3-Month Treatment with a Cultivated Mycelial
Product of Cordyceps in 33 Patients with Chronic Active Hepatittis B
TTT was recovered or improved GPT was recovered or improved Positive-to-negative conversion of HbsAg occurred Albumin was increased ?-Globulin was decreased in 71.9% patients in 78.6% patients in 35.5% patients 10.8 ) 2.54% 10.3 ) 1.79% p<0.001 p<0.001
Thirty-three patients with chronic active hepatitis B were treated with a cultivated mycelial product of Cordyceps (Mortierella hepiali Chen lu Sp. Nov.) (3.75 g/day) for 3 months.
TTT, thymol turbidity test.
Data are adapted from Zhou et al. (1990).
authors demonstrated that natural Cordyceps (1.0 g/kg, i.p.) could significantly enlarge arrhythmia-inducing doses of ouabain (+30% on average, p<0.05 to <0.01). It was found that the antiarrhythmic effects of natural Cordyceps were not due to prolonging functional refractory period, nor altering automatic rhythmicity.
(4) Effects against acute myocardial ischemia and stress-induced myocardial infarction
Natural Cordyceps and its mycelial fermentation products are active in protecting against experimental myocardial ischemia and acute myocardial infarction (Lou, Lu, Liao. Cardiovascular pharmacological studies of Cordyceps fermentation solution. Unpublished report, Beijing Medical University and Lnzhou National College, pp. 65-68), Lou et al., 1986) As described earlier, a fermented mycelial product of Cs-4 could reduce oxygen consumption in animals under experimental conditions and had dramatic anti-anoxic effects in general (Part I, Table 4) (Zhu et al., 1998). In rabbits (Lou, Lu Liao. Cardiovascular pharmacological studies of Cordyceps fermentation solution. Unpublished report, Beijing Medical University and Lanzhou National College, pp. 65-68), a fermented mycelial preparation of Cs-4 (0.15 g/kg, i.v.) was particularly effective (p<0.05) against acute myocardial ischemic ECG changes induced by pituitrin (1.5 U/kg, i.v.). Injection of the Cs-4 preparation (0.9 g/kg, i.g.) from a fermentation solution significantly prevented orthostatic elevation of T wave and elevation of S-T segment (p<0.01) in rats treated with thyroxin (60 mg/rat, i.g.) and noradrenaline (100 mg/rat, i.p.), indicating preventive effects against myocardial ischemia (Lou et al., 1986).
When rats were administrated Cs-4 and thyroxin for 7 consecutive days and noradrenaline on the eights day, changes in Q wave, S-T segment, and T wave during ECG examination were less severe compared to those in the saline control group (Lou et al., 1986). This suggested that Cs-4 might protect rats from severe damage due to stress-induced myocardial infarction. However, on pathological examination without instrumentation, the authors did not find significant differences between the experimental and the control groups.
(5) Effects of thrombosis and anti-aggregation of platelets
In studies with normal platelet-rich plasma, both Cs-4 and Cs-4 fermentation solution preparations (5 or 10 mg/2.5 mL) were effective against platelet aggregation induced by addition of either collagen or adenosisne diphosphate (ADP). When compared with the controls, the aggregation rate of platelets after treatment with Cs-4 appeared to be significantly lower (p<0.005 or <0.001). A lower dose of Cs-4 (1 or 2.5 mg/2.5 mg/2.5 mL) had no significant anti-aggregation activity (Lou et al., 1986).
In studies with rabbits, a preparation of concentrated Cs-4 (CsB-851, 30 or 90 µg/kg per minute, i.v.) significantly inhibited the aggregation of 51Cr-labeled platelets in the de-en-dothelial abdominal aorta: by -51% and -71% (p<0.01), respectively (Zhao et al., 1991).
EFFECTS ON THE HEPATIC SYSTEM
Mycelial fermentation products of Cordyceps (XinGanBao and another cultured mycelial product) have been used clinically for the treatment of chronic hepatitis and related disease conditions.
In an open-label clinical study, 33 patients with chronic active hepatitis B (8 diagnosed with cirrhosis) were treated with a cultivated mycelial product of Cordyceps (Mortierella hepiali Chen lu sp. Nov.) (Zhou et al., 1990). The investigators reported that after the treatment, the thymol turbidity test (TTT) returned to normal in almost a third of the patients who showed an abnormal TTT result prior to the therapy (Table 17). Among the patients with increased serum glutamic-pyruvic transaminase (SGPT), well over half recovered to a normal range. In addition, there was an average 20% increase in serum albumin and an average 29% decrease in ?-globulin after the 3-month treatment.
TO BE CONTINUED- Work in progress
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