By Shi Yushan et al.

Abstract: The therapeutic effects of the “Tong Luo Kai Bi Tablets (Tablet for Dredging Meridians and Easing Bi-syndrome) in 120 patients with rheumatoid arthritis were observed in this clinical trial by means of the randomized double blind method. Both the observed group and the control group each had 60 patients. In the observed group treated with the “Tong Luo Kai Bi Table" 1 case (1.7%) was cured clinically, 27 cases (45.0%) improved markedly, 26 cases (43.3%) improved, with a total effective rate of 90.0%. In the control group treated with “Rheumatic Semen Strychni Tablet" no case was cured, 16 cases (26.7%) improved markedly, 33 cases (55.0%) improved, with a total effective rate of 81.7%. Statistical data showed the “Tong Luo Kai Bi Tablet"had much better therapeutic effectiveness clinically than the “Rheumatic Semen Strychni Tablet"(P<0.05 in all).

The “Tong Luo Kai Bi Tablets" a new traditional Chinese drug developed by China Academy of Traditional Chinese Medicine, has the actions of relaxing muscles and tendons, removing obstruction in meridians, subduing swelling and relieving pain. Its therapeutic effectiveness in 120 cases of rheumatoid arthritis was observed in a clinical trial by the randomized double blind method from May of 1995 to June of l996.The result is reported below.

General Data
120 patients observed in this clinical trial were divided into the observed group (60 cases) and the control group (60 cases). There were l7 males and 43 females in the observed group, and l5 males and 45 females in the control group. The age of the patients varied from l9 to 65 years, with an average of 44.65 years. The duration of illness was from 1 month to 27 years, averaging 5.23 years. The functional grade of rheumatoid arthritis: in the observed group 6 cases were grade I, 34 grade II, and 20 grade III; in the control group, 9 cases were grade I, 34 grade II, and 12 grade III. The sex, age, illness duration and other clinical data between the two groups had no significant difference (P>0.05 in all).

Methods of Treatment and Observation
l). Selection of patients:
Diagnostic criteria of modern medicine: The criteria for diagnosis of rheumatoid arthritis set by American Association of Rheumatology in l987 were used: morning stiffness of joints (lasting more than 1 hour); symmetrical joint swelling (lasting more than 6 weeks); over 3 swelling joints (lasting 6 weeks); proximal-finger swelling joints of hands (lasting more than 6 weeks); rheumatoid factor (+); rheumatoid nodu1es found; and pathogenic change of fingers found by x-ray examination. Patients who met 4 items of the above criteria were diagnosed as having rheumatoid arthritis.
Diagnostic criteria of traditional Chinese medicine: Wandering and tendering pains in muscles and joints; a chilly or hot feeling mixed in the pain locality with normal temperature locally and no obvious systemic heat symptoms; 1ocal swelling and scleroma, or joint stiffness or deformity; a dark or ecchymosed tongue with white, yellow, or white-yellowish coating; wiry-rapid or deep-thready pulse. Differentiation of syndromes: interlocking of cold and heat; obstruction of collaterals by blood stasis.
Criteria for selection of patients: Patients who were diagnosed as having rheumatoid arthritis, with simultaneous occurrence of cold and heat symptoms, and obstruction of collaterals by blood stasis.
Criteria for elimination of patients: Patients who have used various other drugs for the disease even though these drugs have been used for a long time (but a maintenance dose or reduced dose of non-steroid antiinflammatory drugs is allowed), patients who have deformity, maimed, or disability at the advanced stage of the disease; patients whose age is under l8 years or over 65 years; pregnant or lactating patients, allergic patients or patients who have strychnine reactions to the powder of Maqianzi (Semen Strychni) or to drugs that contain Maqianzi (Semen Strychni); patients who accompanied with serious primary diseases of the cardiovascular liver kidney and hemopoietic system, and mental disease; other patients failing to meet the criteria for selection of patients, to follow doctor's instruction, and to supply complete data for the case.
2). Therapeutic method:
The “Tong Luo Kai Bi Tablet"consist of 8 traditional Chinese drugs, such as Maqianzi (Semen Strychni), (Chuan) Niuxi (Radix Cyathulae), Danggui (Radix Angelicae Sinensis), Honghua (Flos Carthami), Mugua (Fructus Chaenomelis), Jingjie (Herba Schizonepetae), Fangfeng (Radix Saposhnikoviae) and Quanxie (Scorpio), 0.3g/tablet. The subjects in the observed group take the tablets after supper, 3 tablets a day, 2months constituting one treatment course. The subjects in the control group take the “Rheumatic Semen Strychni Tablets"(produced by Mianyang Pharmaceutical Factory, Sichuan Province), administered in the same way as “Tong Luo Kai Bi Tablets.
3). Observation indicators:
Indicators for safety: General physical examination, routine blood examination, routine urine examination, electrocardiography, liver function, kidney function (creatinine assay) and neurotoxic reaction of strychnine.
Indicator for therapeutic effectiveness: Morning stiffness, pain levels of joint number of pain joints, swelling levels of joints, number of swelling joints, local tenderness, temperature of joints, gripping power of both hands, time for a l5-meter walk, joint function, general symptoms, changes of the tongue and pulse, erythrocytic sedimentation rate, rheumatoid factor (RF), serum C-reactive protein (CRP), IgG, IgA, IgM, prostaglandin Ez (PGEz), and roentgenography of the involved joints. Assessment of main symptoms and signs: Levels of joint pain (at rest), swelling and tenderness were scored as 1, 2, 3 and 4 from mild to severe. In addition, morning stiffness, time for a l5-meter walk (second), and gripping power (mmHg) were recorded before and after treatment. Symptoms including pain, induration, ecchymosis, local cold or heat feeling with normal temperature were recorded, using as positive or negative to indicate the symptoms before treatment, and eliminated, improved, or ineffective for the situation after treatment. Symptoms of secondary importance were scored from mild to severe to be 1, 2, 3,by interrogation.

Analyses of Results
1). Criteria for therapeutic effect:
Cured clinically: All symptoms disappear, normal functions of the joints recover, and main results of experimental examination change into normal.
Improved markedly: All or main symptoms disappear, most functions of the joints recover, the patient can be competent at general jobs, and main results of experimental examination change into normal.
Improved: Main symptoms disappear general1y, main functions of the joints recover generally or are obviously improved, the patient can take care by himself or herself, labor ability can be improved to some extent, main resu1ts of experimental examination change into normal generally.
Ineffective: various symptoms, signs and results of experimental examination do not improve.
Therapeutic effectiveness by traditional Chinese medicine may be divided into 3 levels.
Disappearance: the symptoms and signs disappear.
Improved: total marks of symptoms and signs are decreased by l/3 or more as compared with that before treatment.
Ineffective: the marks are decreased by less than l/3.
2. Therapeutic results:
In the observed group, l case (l.7%) was cured clinically, 27 (45.0%) improved markedly, 26 (43.3%) improved, 6 (10.0%) ineffective, with a total effective rate of 90.0%. In the control group, no case was cured clinically, l6 (26.7%) improved markedly, 33 (55.0%) improved, l1 (l8.3%) ineffective, with a total effective rate of 8l.7%. The “Tong Luo Kai Bi Tablets"had a much better therapeutic effectiveness than the “Rheumatic Semen Strychni Tablets"statistically (P<0.05).

3. Change of the marks of main symptoms and signs between the observed and control groups:

Table l shows that in the observed and control groups, the mark differences in pain, swelling and tenderness of joints before and after treatment have markedly statistical significance (P<0.05 in all). The mark differences in the three symptoms and signs after treatment between the observed and control groups also show markedly statistical significance (P<0.05 in all).

Table 1. Comparison of Mark Change of Main Symptoms 
and Signs between the Observed and Control Groups

4. Changes in clinical indexes before and after treatment between the two groups:

It can be seen in Table 2 that 6 clinical indexes, including the number of pain joints, the number of swelling joints, the number of tender joints, the time for a l5-m walk, gripping power (mmHg) and time for morning stiffness (min.), all changed obviously before and after treatment. The differences before and after treatment and between the two groups show markedly statistical significance. In the observed group, the start  time for analgesic action and detumescence was 8.62±2.4l days and 9.58±2.l9 days, respectively. In the control group, it was 8.95±2.02 days and 10.34±3.52 days, respectively. The differences between the two groups showed no statistical significance (P>0.05).

Table 2. Changes of clinical Indexes before and After 
Treatment between the Observed and Control Group

*Note: In every item of the Table, the data in the upper lines are "mean before treatment, ~ mean after treatment, the data in the lower lines are "mean deviation ± SE". * differences before and after treatment have very markedly statistical significance ( P<0.01). △difference between the two groups have markedly statistical significance  (P<0.01).

Table 3. Comparison of Symptoms of Traditional 
Chinese Medicine between the Two Groups
　　

RF and CRP: The negative transformation rate of RF in the observed group was 30.0%, while that in the control group 25.7%. The negative transformation rate of CRP in the observed group was 55.3%,while that in the control group 48.7%. The difference between the two groups showed no statistical significance (both P>0.05).
Immunoglobulin: The difference of IgG before and after treatment in the observed and control groups was 0.86l±0.52 g/L and 0.35 ±0.48 g/L respectively; the differences of IgA before and after treatment in the observed and control groups --0.07 ± 0.l7 g/L and -0.47 ±0.32 g/L respectively; the difference of IgM before and after treatment in the observed and control groups 0.0l ±0'08 g/L and 0.09±0.09 g/L respectively The three immunoglobulin differences between the two groups had no statistical significance (P>0.05).
PGEz: In 30 cases of the observed group, PGE2 before and after treatment was 566 pg/ml and 246 pg/ml, a decrease of 320±23.6 pg/ml (P<0.0l). In 30 cases of the control group, PGEz before and after treatment was 523 pg/ml and 240 pg/ml respectively a decrease of 284 ± 23.7 pg/ml (P<0.01).
Adverse reactions: The results of blood routine, urine routine and tests of liver function, kidney function and electrocardiography after treatment were similar to those before treatment in both groups. In the observed group , 2 cases felt dizzy in 2~3 days after starting administration, l case had abdominal discomfort and 1 case dry mouth. In the control group, 4 cases had dizziness, 2 cases abdominal discomfort , and l case dry mouth. No toxic symptoms resulting from Maqianzi (Semen Strychni) were found in both two groups .

Discussion
There is no specific treatment for rheumatoid arthritis today. Van de Putt thinks that T cells play an important action in the disease according to the study on the
pathogenesis of the rheumatoid arthritis, but removal of T cells as a treatment is not
successful. So D-penicillamine, hydroxychloroquine, salicylazosulfapyridine and
amethopterin are sti1l used to treat the disease at present . According to the theory of
traditional Chinese medicine, this disease is caused by deficiency of vital-Qi and obstruction of Qi and blood resulting from pathogenic factors such as wind, cold, dampness and heat invading the meridians and collaterals of the body. The main symptoms of this disease are simultaneous occurrence of cold and heat syndromes, and obstruction of collaterals by blood stasis. Maqianzi (Semen Strychni) has the action of dispelling heat in blood, promoting subsidence of swelling and induration, and removing obstruction in collaterals to relieve pain, but the dose of Maqianzi (Semen Strychni) is kept within the limit set by Chinese Pharmacopoeia. It can be seen from the double blind clinical trial that the “Tong Luo Kai Bi Tablets"have better therapeutic effects and few adverse reactions with a total effective rate of 90.0%. Its therapeutic effectiveness is better than that in the control group. UP to now no report has been seen in double blind trial with preparations of pure traditional Chinese drugs (including Semen Strychni) for the rheumatoid arthritis.
Some experimental studies also have showed that “Tong Luo Kai Bi Tablets"can
inhibit adjuvant arthritis, foot swelling caused by carrageenin, egg white, or formaldehyde, and delayed hypersensitivity caused by PC. Its analgesic action in mice, resistance to increase of capillary permeability in the abdominal cavity of mice caused by stimulation of acetic acid, inhibition of inflammatory effect in rats induced by carboxymethyl cellulose, and inhibition of granulomatous formation by cotton ball have been observed in experimental studies.
The mechanism of the therapeutic effects of the “Tong Luo Kai Bi Tablets"needs to be further studied.