ests are underway at hospitals in Japan to determine whether Kampo formulations can increase the resistance of hospitalized patients to pathogenic bacteria and help prevent the spread of contagious diseases such as influenza and MRSA (methicillin-resistant Staphylococcus aureus) within the hospital environment.

Astragalus

This winter, Tsumura is carrying out observational studies on patients at 18 hospitals around Japan in an effort to clarify the basis for using Kampo formulations to prevent hospital-acquired infections.

One Kampo formulation considered especially promising for strengthening the body's immune system is Hochu-ekki-to (*1)

Made up of ten crude herbs, including Astragalus Root, Ginseng Root, Japanese Angelica Root and Bupleurum Root, Hochu-ekki-to is effective in boosting immunity, relieving stress and overcoming fatigue. (Chart 1)

The annual value of Hochu-ekki-to sales in Japan is about $52 million, making it the second-largest selling Kampo formulation, exceeded only by Sho-saiko-to. (Chart 2)

Today, Hochu-ekki-to is used to treat such conditions as general fatigue, poor appetite, low-grade fever and cough, and as an adjunct to treating debilitation resulting from tuberculosis or other chronic diseases. It is also used to help promote overall physical recovery following operations or puerperium, and to supplement or relieve the side effects of cancer chemotherapy or radiation therapy. In addition to relieving stress and fatigue, Hochu-ekki-to improves digestive functions and is used to reinvigorate a patient's disease resistance as well as improve the status of his or her nutrition.

Clinical and basic pharmacological research on Hochu-ekki-to has been extremely active in Japan since the beginning of the 1990's. Below, we introduce some examples of the rich harvest of clinical studies from the last decade.

In October 1991 at the 29th annual meeting of the Japan Society of Clinical Oncology, Dr. Mori et al. of the Respiratory System Department of the Tochigi Prefecture Cancer Center reported on the utility of Hochu-ekki-to for fatigue accompanying chemotherapy for lung cancer.(*2)

For this study, 41 primary lung cancer patients undergoing chemotherapy (principally intravenous Cisplatin administered over a five-day period) were randomly assigned to two groups for comparison. The first group of 21 patients was given granular extract of Hochu-ekki-to (TJ-41; daily dosage: 7.5 grams, divided into three 2.5-gram doses before meals) for a period beginning one week before the administration of Cisplatin chemotherapy and extending until four weeks after its completion. The second group received Cisplatin without the addition of Hochu-ekki-to. (Graph 1)

The effectiveness of the Hochu-ekki-to regimen was evaluated on the basis of weekly health diaries prepared by the patients themselves, as well as from records maintained by their physicians and nurses. Scores from 0 to 4 (with 4 the most severe) were given with regard to each of the following: degree of fatigue and anorexia; extent of nausea and vomiting; and mood.

The results of the study indicated that patients receiving TJ-41 had significantly less fatigue and better appetite as well as significantly improved moods. No significant difference was observed, however, between the two groups in regard to nausea and vomiting. Finally, no side effects were attributed to the TJ-41.

In 1992 - 1993, Dr. Igarashi et al. carried out a study of the effectiveness of Hochu-ekki-to for treating fatigue and poor appetite in patients with gastrointestinal complaints at nine medical treatment institutions in Fukushima Prefecture (*3). The study was conducted on 45 patients (14 males and 31 females) with an average age of 67.6 who had a variety of complaints in conjunction with gastritis, hepatitis and symptoms associated with previous surgery of the digestive tract. Symptoms included exhaustion, both generally and specifically in the arms and the legs, poor appetite and reduced mental faculties. After a daily regimen of 5.0 to 7.5 grams of Hochu-ekki-to over a period of at least four weeks, the patients were asked to evaluate the subjective improvement of their conditions on a scale of 0 to 3. High rates of improvement were reported with regard to overall fatigue (95.5%), poor appetite (92.0%) and feeling of exhaustion in the arms and legs (91.7%). In regard to overall effectiveness, 25 (55.6%) of the 45 patients reported excellent improvement, 15 (33%) reported moderate improvement, 3 (6.7%) reported some improvement, and 2 (4.4%) reported no change.

Believing that immune system disorders, such as a decline in the function of Natural-Killer (NK) cells, play a part in causing chronic fatigue syndrome (CFS), Dr. Uchida et al. of Kyoto University's Radiation Biology Center administered either Hochu-ekki-to or one of two other Kampo formulations to patients as biological response modifiers. He reported in 1993 that, as a result, NK cells were invigorated and that patients experienced a marked reduction in the degree of general fatigue due to CFS (*4).

In addition, throughout 1993 and 1994, Dr. Kuratsune et al. of Osaka University Medical School's Hematology and Tumor (Internal Medicine) Department administered 7.5 grams of Hochu-ekki-to (TJ-41) daily to a group of 29 CFS patients (15 males, 14 females; average age 33.3) whose performance status (PS) was 2 or higher (*5). (The PS scale evaluates patients on ten levels, ranging from 0 to 9. Level 2 patients can manage everyday activities but must rest frequently because of general fatigue; level 9 patients are bedridden and require constant assistance.) After 8 to 12 weeks of this regimen, a high degree of improvement was reported in the incidence of fatigue, feeling of exhaustion, low-grade fever, muscle pain and mental alertness. Specifically, 10 of the 29 patients (34.5%) reported improvement of three levels or more, signifying that their PS fell to below 2 and that comfortable living became possible. This was a double-blind study, and the placebo group's 20% improvement was greatly exceeded by the results for patients receiving Hochu-ekki-to. Further validating the study, strengthened NK activity was evident in nine of the ten CFS patients whose NK activity had declined by less than 20% at the beginning of the study. (Graph 2)

Between July 1994 and August 1995, Dr. Niwa et al. of the External Medicine Department of Yokote National Hospital administered Hochu-ekki-to to 25 post-operative patients (15 males and 10 females, average age 63) who had been operated on for GI cancer (16 with stomach cancer, 6 with colon cancer and 3 with either gall bladder or pancreatic cancer). The patients received a daily dose of 7.5 grams of TJ-41 over a period of 8 weeks (*6). In order to assess the regimen's effectiveness on immune function, blood was assayed at 3 time points to measure both NK and LAK activity: before administering Hochu-ekki-to, at the fourth week and at the eighth week. At the same time, a five-level improvement assessment was carried out for 16 clinical parameters, including: loss of appetite, feeling of general fatigue, heartburn, dizziness, diarrhea and weight loss. The results showed significant improvement with regard to NK activity, which averaged 29.9% prior to administering Hochu-ekki-to but rose to 42.2% at the fourth week, and 43.6% at the eighth week. On the other hand, no significant improvement was found for LAK activity. Overall, particularly good improvement was noted in regard to appetite, fatigue and diarrhea.

As indicated at the outset, Hochu-ekki-to's apparent biological protective mechanism has received particular attention in protecting hospitalized patients against infection by MRSA. For example, Dr. Kitahara et al. of Isinomaki Red Cross Hospital's Neurological Surgery Department reported in 1993 about his hospital's experience in administering Hochu-ekki-to to two patients infected with MRSA for whom various types of antibiotics had proved ineffective. The MRSA, as assessed from five consecutive cultures taken at 3 day intervals, became negative for one patient 12 weeks after he began receiving Hochu-ekki-to. For a second patient the bacterial count in the sputum and in a decubitus was decreased (*7). (If no MRSA was detected over the course of at least five consecutive MRSA bacillus culture examinations at three-day intervals, a negative reading was determined.)

Dr. Karibe et al. of the Brain and Neurological Surgery Department of Tohoku University Hospital administered Hochu-ekki-to to 18 patients and other Kampo formulations to 26 hospitalized MRSA carriers (28 patients with damage to cerebral blood vessels; 10 with external injuries; and 6 with other conditions). As a control, their progress was compared to that of 52 other patients who did not receive any Kampo (*8). None of the 44 patients who received Hochu-ekki-to received vancomycin or other antibiotic used for treating MRSA, nor did the 52 patients in the control group. MRSA readings were negative for 29 of the 44 patients receiving Kampo medicines (65.9%), including 11 of the 18 patients receiving Hochu-ekki-to (61.6%). Control of MRSA was achieved, however, in only 15 of the 52 control patients (28.8%). In addition, administration of Hochu-ekki-to significantly shortened the time necessary for achieving a negative MRSA reading. Recovery was also more rapid in the Kampo-treated groups, averaging 47.0 +/- 5.5 days for the Hochu-ekki-to group, 44.7 +/- 7.3 days for the other Kampo treatments and 88.4 +/- 12.8 days for the control group. (Graph 3)

Greater stress makes NK activity decline, and CFS patients typically complain of an extreme degree of fatigue and general feeling of exhaustion, along with depression and a decline in mental faculties and memory. Patients receiving cancer medication exhibit similar complaints. Administering Hochu-ekki-to to such patients increases NK activity, and, as indicated by the aforementioned studies, either reduces or eliminates these vexing clinical symptoms.

In addition, it is recognized that a decline in nutritional status and immune function are among the factors that give rise to MRSA infections. Thus, we believe that Hochu-ekki-to and other Kampo medicines are effective against MRSA infections because they improve nutritional status and activate immune function.

Various basic research studies are helping to clarify the mechanism of Hochu-ekki-to's biological protective mechanism, which appears to work through the nervous and endocrine systems as well as on the immune system. In the next issue of Kampo Today, we will summarize research on the effects of Hochu-ekki-to on a number of animal models of disease.