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formulas, this one contained no Ma-Huang, a source of ephedrine that has been reported to cause central nervous system stimulatory activity, increased blood pressure, and heart palpitations.
The researchers first tested this blend of herbs in a mouse model of allergic asthma. Mice were sensitized to an egg-white protein and then challenged with it. The mice reacted with allergic asthma including pulmonary eosinophilia, airway hyperreactivity (AHR), and increased antigen-specific IgE associated with inflammatory cytokines, including IL-4 and IL-5 in bronchial lavage fluids.
In the Journal of Allergy and Clinical Immunology, they report that treating mice with this formula “virtually eliminated airway hyperreactivity and markedly reduced the total number of cells and the percent eosinophils in bronchoalveolar fluid compared with the sham-treated group.” Inflammation and mucus were reduced in the lungs as well. Treatment with MSSM-002 twenty-four hours after intratracheal antigen challenge of sensitized mice virtually eliminated airway hyperreactivity and this effect was equivalent to dexamethasone. MSSM-002 down-regulated inflammatory cytokines including IL-4, IL-5 and IL-13, all involved in chronic asthma.
In comparison, “one of the most potent corticosteroids, dexamethasone, also suppressed antigen-induced airway hyperreactivity and eosinophilic inflammation in this model. However, unlike MSSM-002, dexamethasone suppressed Th1 responses.” The researchers concluded that the herbal formula was as effective as the potent corticosteroid, dexamethasone—without the harmful side effects.
The researchers then “used the concept of traditional Chinese medicine to reformulate several herbal blends into simplified formulas, and tested these new formulas,” says senior study researcher Xiu-Min Li, M.D., Associate Professor, Pediatrics and Assistant Professor, Center For Immunobiology, at the Mt. Sinai School of Medicine. The formula the researchers found most effective in mice contained three Chinese herbal extracts—Ling-Zhi (Ganoderma lucidum), Ku-Shen (Sophora flavescens) and Gan-Cao (Glycyrrhiza uralensis), also known as Reishi, Shrubby Sophora and Chinese Licorice—and was dubbed ASHMI (anti-asthma herbal medicine intervention). The ASHMI formula demonstrated the same broad spectrum of therapeutic effects on the major pathogenic mechanisms of asthma. “This formula was almost as effective as the original fourteen herbs, and was the simplest,” Li explains. All three herbs have a long history of human use in China and are considered to be safe when used according to TCM practice either alone or in formulas.
The next Mt. Sinai, NIH-sponsored study was on ASHMI in humans, and was published in the Journal of Allergy and Clinical Immunology in September of 2005. It reported the remarkable finding that ASHMI was as effective as steroids, without suppressing cortisol or immune function. This study included thirteen researchers—eleven of them physicians—from the Weifang Asthma Hospital, the Weifang School of Medicine, and the Mt. Sinai School of Medicine, and was remarkable for its methodical, careful design. Forty-five non-steroid dependent individuals received oral ASHMI capsules and prednisone placebo tablets, and forty-six non-steroid dependent individuals received oral prednisone tablets (20 milligrams) and ASHMI placebo capsules for four weeks. Serum cortisol, cytokine and IgE levels were evaluated before and after treatment, as well as symptom scores, side effects and spirometry measurements. Spirometry literally means “the measuring of breath” and is the most common pulmonary function test.
The study began with a week-long “run-in period” before initiating treatment. Average daily symptom scores were evaluated during this period to establish a baseline. Beta-agonist inhalation was allowed as needed during the study, but all other medications, such as leukotriene modifiers, antihistamines, and either inhaled or intravenous steroids, were prohibited.
Symptom scores rated cough, chest tightness, wheezing, dyspnea, night awakening or early morning awakening caused by dyspnea, allergic rhinitis, and beta-agonist use. Lung function was evaluated with a spirometer, and serum levels of IgE, eosinophils, cortisol and cytokines including IL-5, IL-13 and IFN-gamma were measured. After four weeks both groups showed an equal, significant improvement in symptom scores, pulmonary function and eosinophil levels.
In both groups, pre-treatment cortisol levels were slightly below normal, as is common in asthma. However, after treatment, the corticosteroid group showed suppression of the hypothalamic-pituitary-adrenal axis, marked by even more depressed cortisol levels. In contrast, patients in the ASHMI formula group showed increased levels of serum cortisol into the normal range. After four weeks, the prednisone group had significant weight gain, while the ASHMI group did not. The difference between the two groups was statistically significant.
“The relationship between cytokine imbalance and the expression of both atopy and asthma is of considerable interest and importance,” the researchers note. “A Th1-Th2 imbalance has been hypothesized in asthma, with a shift in immune responses away from Th1 (IFN-gamma) toward Th2 (IL-4, IL-5 and IL-13). In a cohort study, patients with severe asthma exhibited significantly reduced IFN-gamma production in response to allergen compared with control subjects and subjects with resolved asthma. In addition, all patients with asthma…showed increased generation of IL-5." Numerous studies confirm that IL-4, IL-5 and IL-13 secretion is the major driving force behind persistent asthma.
ASHMI significantly reduced IL-3 and IL-5 levels. It also increased human interferon-gamma (IFN-gamma), a potent antiviral and immunomodulator, while cortisone suppressed IFN-gamma. These findings suggest strong immunotherapeutic effects of the Chinese herbal. Now, says Li, “we have an ongoing FDA-approved clinical trial using ASHMI as an investigational new drug. In the last study our patients were not steroid dependent. In this study our patients are steroid dependent, and we are trying to wean them off their steroids. They really don’t want to be on steroids anymore, and our results will be more significant if, with the use of ASHMI, we can reduce or replace steroids. We are almost finished with our Phase I trial, which included 18 patients, and we will begin our Phase II trial with 60 patients.”
How Do These Herbs Work?
Individually, these herbs all have a long history of use in asthma and other allergic, autoimmune and immune disorders, allergic rhinitis, hepatitis B, jaundice, adrenal insufficiency, peptic ulcers, and many other conditions. The researchers speculate that these herbs work both individually and synergistically. For instance, the increase in serum cortisol into the normal range could be in part due to the glycyrrhizin in Chinese licorice, “which affects the conversion of cortisol to cortisone by inhibition of 11-beta-hydroxysteroid dehydrogenase enzyme activity.” In addition, previous research has shown that Chinese licorice decreases IgE levels. Chinese licorice is a staple botanical in TCM for asthma and allergic rhinitis.
Ku-Shen, in turn, has been widely used for eczema, pruritus and asthma. Ku-Shen is particularly interesting. It is proving to have therapeutic value for a surprisingly wide range of conditions. The impact of Ku-Shen, which has excitatory modulator activity, was studied by Ba Hoang and colleagues. An open and selective 3-year follow-up of 14 chronic refractory asthmatics aged between 22 and 70 was used.
Participants received an extract of Sophora flavescens. Medication use, a diary card of symptoms, and respiratory function were recorded. The study was retrospective and all patients gave written informed consent. The quality of life, clinical symptoms and respiratory function improved during all periods of measurement. The use of inhaled corticosteroid and beta-agonists were reduced or eliminated. There were no significant adverse reactions reported. It appears that the extract of S. flavescens as an excitatory modulator may be safe and effective for chronic refractory asthma.
Within two weeks of starting therapy with Ku-Shen, the patients had reduced daytime and nighttime symptoms of asthma, and had begun to reduce their beta-agonist doses. By three years, all patients were off their corticosteroid medication, had almost entirely eliminated beta-agonist medications, and their symptoms of asthma were significantly reduced.
How does Ku-Shen work? Though the plant contains a rich cornucopia of chemicals, the focus has been on two principle alkaloids, matrine and oxymatrine, which have been the subject of research for years. The toxicity of both alkaloids is very low, and Ku-Shen may contain about 2% of these two alkaloids. According to Dr. Ba Hoang’s theory, these alkaloids “act as modulators of membrane excitability…they can decrease body temperature, have a significant analgesic effect, have a tranquilizing effect, and an inhibitory action on glutamate-induced excitatory nerve impulses. They can also have an antiarrhythmic effect.” Glutamate receptors have been found in the lungs and airways, and the activation of glutamate receptors has led to increased airway submucosal glandular secretion. Activation of the glutamate receptor might be an important, unrecognized mechanism of airway inflammation and hyper-reactivity, and might explain one of the ways that Ku-Shen helps in asthma.
In fact, Dr. Ba and Dr. Levine propose a novel mechanism for asthma in a 2006 article in Medical Hypotheses entitled, “Bronchial epilepsy or broncho-pulmonary hyperexcitability as a model of asthma pathogenesis.” In this separate paper, Ba and Levine have hypothesized that membrane hyperexcitability may reflect a more generalized disease mechanism.
In sum, not only are the herbs in ASHMI remarkably effective in asthma, but the increase in cortisol levels and the shift away from inflammatory cytokines toward a balanced immune response, suggests that adrenal and immune function are being restored. This would argue for a far wider use of herbal formulas like ASHMI, in conditions associated with low cortisol, chronic inflammation and adrenal fatigue. Illnesses treated with corticosteroids would theoretically benefit from herbal formulas like that of ASHMI.
References:
1) Guo R, Pittler MH, Ernst E. Herbal medicines for the treatment of allergic rhinitis: a systematic review. Ann Allergy Asthma Immunol. 2007 Dec;99(6):483-95.
2) Wen MC, Wei CH, Hu ZQ, Srivastava K, Ko J, Xi ST, Mu DZ, Du JB, Li GH, Wallenstein S, Sampson H, Kattan M, Li XM. Efficacy and tolerability of anti-asthma herbal medicine intervention in adult patients with moderate-severe allergic asthma. J Allergy Clin Immunol. 2005 Sep;116(3):517-24
3) Li XM, Huang CK, Zhang TF, Teper AA, Srivastava, K, Schofield BH, Sampson HA. The Chinese herbal medicine formula MSSM-002 suppresses allergic airway hyperreactivity and modulates Th1/Th2 responses in a murine model of allergic asthma. J Allergy Clin Imunol. 2000 Oct; 106(4):660-8.
4) Hoang BX, Shaw DG, Levine S, Hoang C, Pham P. New approach in asthma treatment using excitatory modulator. Phytotherapy Research 2007 Jun:21(6): 554-7
5) Hoang BX, Levine SA, Shaw DG, Pham P, Hoang C. Bronchial epilepsy or broncho-pulmonary hyper-excitability as a model of asthma pathogenesis. Med Hypotheses. 2006 Jun;67(5):1042-51
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